Duration Of Refractory Period Research Articles

HE EFFECT OF PROBENECID ON α-1-ADRENOCEPTOR STIMULATION INDUCED PROARRHYTHMIC CONDUCTION IN THE ATRIOVENTRICULAR NODE OF RAT HEART

Cardiac tissue contains adrenergic receptors (AR) not only of the beta type, but also of the alpha type (α-AR). Both types of ARs play signifi cant role in regulation of cardiomyocytes electrophysiology in diff erent parts of the heart, including the atrioventricular node (AVN). An augmentation of α1-AR mediated component of adrenergic signaling results in impaired conduction of excitation in the heart and onset of various rhythm disturbances including AVNassociated arrhythmias. The activation of α1-AR facilitates anionic transmembrane transport causing electrophysiological changes in myocytes. Current study is aimed to the investigation of the eff ects of anion/chloride blockade on α1-AR-mediated proarrhythmic alteration of AVN functioning. Functional characteristics of AVN including AVN conduction time, AVN refractoriness and the AVN conduction alterations were examined via recording of surface electrograms in Langendorff -perfused isolated rat heart (Wistar, 250 ± 30 g). Phenylephrine was used as α1-AR agonist. Probenecid demonstrating anion/chloride transmembrane conductance blocking activity was used to modify Phe-induced α1-AR-mediated eff ects in AVN. The activation of α1-AR by Phe results in a signifi cant increase in the duration of AV intervals (N = 10, p < 0.001) and eff ective refractory period (ERP) in the AVN (by 9.8% ± 1.2%, n = 10, p < 0.001). Also, Phe induces AV-blocks of conduction and oscillations in atrioventricular delay (N = 10) at the stimulation rates close to ERP. Probenecid signifi cantly reduces the magnitude of AVD oscillations during non-stationary conduction in the AV node. In addition, probenecid attenuates ERP prolongation caused by Phe (107 ± 4 ms, N = 6) and 114.2 ± 5.35 ms (N = 10) in presence of only Phe and Phe with probenecid, respectively, returning its values toward typical for normal conditions. In conclusion, probenecid maintains physiological mode of AVN conduction when α1-AR are stimulated. This also suggests that chloride ion channels and anion carriers may contribute to the α1-AR-mediated AVN arrhythmias.

The Influence of Hibernation on Electrical Activity and Potassium Currents in Myocardium of Long-Tailed Ground Squirrel

Hibernating mammals are capable of reducing the temperature of their bodies down to 0°C. During this process, their heart is highly resistant to the occurrence of arrhythmias caused by temperature fall. In this research we have for the first-time studied potassium currents in the myocardium of a hibernating mammal on the example of long-tailed ground squirrel (Citellus undulatus) and its change upon hibernation. Using patch clamp method, we studied transient outward current Ito and background inward rectifier current IK1 in isolated ventricular and atrial myocytes from summer (active) and winter (hibernating) ground squirrels. The study revealed, that at room temperature and at positive holding potentials peak amplitude of Ito in cardiomyocytes from hibernating group of animals is lower than that of the summer group. The downregulation of Ito upon hibernation was more pronounced in ventricular myocardium in comparison to that in atrial. Background inward rectifier current IK1 was enhanced in ventricular myocardium of winter group of animals, upon the adaptation to hibernation. In atrial myocardium there were no statistically significant differences of IK1 between the two groups. We also recorded action potentials in isolated ventricular cardiomyocytes. The duration of action potentials at the levels of 50 and 90% repolarization did not differ between the groups, we also did not find significant differences in maximum upstroke velocity and in the level of resting membrane potential. Taken together, the revealed differences in the amplitude of Ito and IK1 between active and hibernating ground squirrels can serve as mechanisms increasing the duration of refractory period and to maintaining the level of resting membrane potential at low temperatures.

Duration of skin prick test refractory period following food-induced allergic reactions.

Duration of skin prick test refractory period following food-induced allergic reactions.

(200) Anatomic Maps of Erogenous Sensation & Pleasure in the Penis: Do Circumcised Men Report These Differently Than Uncircumcised Men?

Abstract Introduction For thousands of years male circumcision (MC) has been performed for cultural, religious, aesthetic, and public health reasons, and it continues to be among the most common surgical procedure performed worldwide. The effects of MC on sexual function remains controversial, despite recent systematic reviews demonstrating no adverse effects. A key area of debate regarding MC has been the impact of MC on penile sensation. Existing literature evaluating changes in penile sensitivity and pleasure following MC have primarily focused on the penis glans and the frenulum-area of the shaft. Additionally, studies describing the effects of MC on orgasm have focused on the changes in ease of reaching orgasm/ejaculatory latency. In truth, although patients rely on providers to counsel them about what results they might expect to occur with MC, the effects of MC on erogenous sensation and other orgasm-related domains of sexual function are still not well understood. Objective We sought to expand on the existing literature by assessing erogenous sensation throughout the entire penis surface area, and to evaluate differences in reported orgasm function among circumcised and uncircumcised men. Methods Adult male subjects recruited from a paid anonymous online survey platform (QualtricsTM, USA) were shown anatomic illustrations of a penis whose entire surface area was divided into 12 different regions. Subjects were instructed to identify regions they found pleasurable when touched during sex, and to rate each on a 1-10 scale. Subjects were also asked to characterize their typical orgasm across the following six domains: 1. Lead-time, 2. Orgasm duration, 3. Perceived body-location(s) of orgasm-sensation, 4. Classification of orgasm experience as a single or multiple-peak event, 5. Refractory period duration, and 6. Overall satisfaction. Comparisons between circumcised and uncircumcised men were performed with a 2-tailed T-test. The Benjamini-Hochberg Procedure with FDR=0.05 was applied to control for multiple comparisons. Results The survey was completed by 227 circumcised (mean age ± SD, 46.6 ± 17.7y) and 175 uncircumcised men (47.8 ± 18.1y). There were no significant differences in ratings across all twelve regions among circumcised and uncircumcised cohorts. However, when subjects were asked to identify which regions gave pleasure when touched during sex, significantly more circumcised (vs. uncircumcised) men reported a preference for the penis-tip (38% vs 17%, p=0.024) and the middle third of their ventral shaft (63% vs 48%, p=0.036). There were no significant differences in reported experience with orgasm quality and function across all six queried domains among circumcised and uncircumcised cohorts. Conclusions Our findings suggest that both circumcised and uncircumcised men experience pleasure in their penis and experiences with orgasm function similarly. Although we often think of the tip of the penis as being the “most erogenous” location for men, we found that scored erogeneity was generally similar across the entire length of the penis. Although overall erogeneity ratings did not differ, we found that circumcised men reported more areas of their penis as “pleasurable when touched during sex”, as compared to their uncircumcised counterparts. These findings will be important to share with patients and their families considering MC. Disclosure No

Effects of Gender-affirming Hormone Therapy on Orgasm Function of Transgender Men and Women: A Long Term Follow Up

To assess the reported changes in orgasm quality and function of transgender men (TM) and transgender women (TW) after commencing gender-affirming hormone therapy (GAHT). We queried potential changes in orgasm function before and after commencing GAHT (minimum 1 year) among 130 consecutive TW and 33 TM. We queried the following domains under a uniform condition (masturbation): (1) Lead-time to reach orgasm, (2) Duration of orgasm, (3) Body location of orgasm sensation, (4) Description of orgasm as either a single or multiple-peak event, (5) Duration of post-orgasm refractory period, and (6) Overall satisfaction with orgasm quality. Within groups by gender, TW and TM reported similar responses to our inventory before starting GAHT. After commencing GAHT, TW reported notable changes in orgasm function: increase in lead-time necessary to reach orgasm, orgasm duration, and overall orgasm satisfaction. Similarly, TM reported an increase in duration of orgasm and increased overall satisfaction with orgasm quality. Over half of the TW reported experiencing orgasms in new/additional body locations. Additionally, prior to commencing GAHT, the majority of TM and TW patients reported their orgasms as a short, single-peak event but following GAHT these same patients reported longer and protracted multiple-peak orgasms. GAHT has the potential to positively improve orgasm quality for transgender patients undergoing gender transition. It is important to share such data with patients prospectively before treatments.

Increased vulnerability to atrial and ventricular arrhythmias caused by different types of inhaled tobacco or marijuana products

The emergence of a plethora of new tobacco products marketed as being less harmful than smoking, such as electronic cigarettes and heated tobacco products, and the increased popularity of recreational marijuana have raised concerns about the potential cardiovascular risk associated with their use. The purpose of this study was to investigate whether the use of novel tobacco products or marijuana can cause the development of proarrhythmic substrate and eventually lead to arrhythmias. Rats were exposed to smoke from tobacco, marijuana, or cannabinoid-depleted marijuana, to aerosol from electronic cigarettes or heated tobacco products, or to clean air once per day for 8 weeks, following by assays for blood pressure, cardiac function, ex vivo electrophysiology, and histochemistry. The rats exposed to tobacco or marijuana products exhibited progressively increased systolic blood pressure, decreased cardiac systolic function with chamber dilation, and reduced overall heart rate variability, relative to the clean air negative control group. Atrial fibrillation and ventricular tachycardia testing by ex vivo optical mapping revealed a significantly higher susceptibility to each, with a shortened effective refractory period and prolonged calcium transient duration. Histological analysis indicated that in all exposure conditions except for air, exposure to smoke or aerosol from tobacco or marijuana products caused severe fibrosis with decreased microvessel density and higher level of sympathetic nerve innervation. These pathophysiological results indicate that tobacco and marijuana products can induce arrhythmogenic substrates involved in cardiac electrical, structural, and neural remodeling, facilitating the development of arrhythmias.

Pinocembrin alleviates the susceptibility to atrial fibrillation in isoproterenol-induced rats

BackgroundInflammation can contribute to the initiation and progression of atrial fibrillation (AF), and pinocembrin can suppress downstream inflammatory cytokine production by inhibiting the inflammation pathway. In our previous studies, pinocembrin was also beneficial in ameliorating cardiac arrhythmia in different models of rats, such as depression, myocardial infarction, and heart failure. This study aims to investigate the effect of pinocembrin on the susceptibility to AF in isoproterenol-induced rats. MethodsRats were randomly divided into four groups. Pinocembrin was injected through the tail vein. Isoproterenol was treated by intraperitoneal injection for one week (5 mg/kg/day). We evaluated the susceptibility to AF by atrial electrophysiological experiments. Masson staining was used to evaluate the fibrosis area. The protein levels of connexin (Cx) 40, Cav1.2, Kv4.2, collagen I, collagen III, α-SMA, transforming growth factor (TGF)-β, NLRP3, caspase 1, and interleukin (IL)-1β were detected by western blot. ResultsOur data demonstrated that pinocembrin could prolong the atrial effective refractory period (ERP) and action potential duration (APD), and decrease AF inducibility. Isoproterenol increased the expression of Cav1.2 and Kv4.2 ion channels whereas pinocembrin could alleviate this change. Pinocembrin could reduce the fibrosis area, fibrosis-related protein collagen I, collagen III, α-SMA, and TGF-β and upregulate gap junction protein Cx40. In addition, pinocembrin reduced the expression of NLRP3, caspase 1, and IL-1β. ConclusionsOur study indicated that pinocembrin was beneficial to alleviate atrial electrical remodeling and fibrosis. Accompanied the downregulation of ion channels and upregulation of gap junction protein Cx40. Pinocembrin may produce these effects by inhibiting the NLRP3 pathway.

The female Euscepes postfasciatus refractory period is induced by the male but length is determined by the female

Females of many animals mate multiple times during their lives (i.e., polyandry). The period between matings (mating interval) is called the refractory period (RP). In the West Indian sweet potato weevil (Euscepes postfasciatus), males use the ejaculate to induce the RP in females to prevent re-mating. By measuring the RP, a large variation of 1–49 days was observed. This variation may be due to the males (ejaculate quantity and quality) and females (ejaculate sensitivity/degradation ability and body size) and their interactions, but the exact mechanisms are currently unclear. Here, we investigated a tendency towards a particular female RP duration and the associated traits of males and females to test the following three factors responsible for variation in the length of the RP: male manipulation of ejaculate volume, individual differences in male ejaculation substances, and ejaculate sensitivity/degradation ability in females. We prepared virgin males and females to create mating pairs. The following day, another mate was introduced to the females, and the first RP was measured. The same procedure was used for measuring the second RP. The males were also provided with another female (second female), mated, and then the RP of the second female was measured. In addition, the relationship between the length of the RP and female fitness was investigated. The results showed that there was a significant positive correlation between the first and second RP in the focal females, while no significant correlation was observed between the RP of the first and second females induced by the same male. It was also found that the length of the RP did not affect female fitness. This indicated that the males did not adaptively manipulate ejaculation volume depending on the quality of the females, and variance in the length of the RP may be explained by variation in the female physiological ability against ejaculate.

Metabolism regulator adiponectin prevents cardiac remodeling and ventricular arrhythmias via sympathetic modulation in a myocardial infarction model.

The stellate ganglia play an important role in cardiac remodeling after myocardial infarction (MI). This study aimed to investigate whether adiponectin (APN), an adipokine mainly secreted by adipose tissue, could modulate the left stellate ganglion (LSG) and exert cardioprotective effects through the sympathetic nervous system (SNS) in a canine model of MI. APN microinjection and APN overexpression with recombinant adeno-associated virus vector in the LSG were performed in acute and chronic MI models, respectively. The results showed that acute APN microinjection decreased LSG function and neural activity, and suppressed ischemia-induced ventricular arrhythmia. Chronic MI led to a decrease in the effective refractory period and action potential duration at 90% and deterioration in echocardiography performance, all of which was blunted by APN overexpression. Moreover, APN gene transfer resulted in favorable heart rate variability alteration, and decreased cardiac SNS activity, serum noradrenaline and neuropeptide Y, which were augmented after MI. APN overexpression also decreased the expression of nerve growth factor and growth associated protein 43 in the LSG and peri-infarct myocardium, respectively. Furthermore, RNA sequencing of LSG indicated that 4-week MI up-regulated the mRNA levels of macrophage/microglia activation marker Iba1, chemokine ligands (CXCL10, CCL20), chemokine receptor CCR5andpro-inflammatory cytokine IL6, and downregulated IL1RN and IL10 mRNA, which were reversed by APN overexpression. Our results reveal that APN inhibits cardiac sympathetic remodeling and mitigates cardiac remodeling after MI. APN-mediated gene therapy may provide a potential therapeutic strategy for the treatment of MI.

PO-690-05 NOVEL LAPAROSCOPY-BASED RENAL DENERVATION FOR MODULATING AF INDUCIBILITY USING A SWINE MODEL

Renal denervation (RDN) may control atrial fibrillation (AF) by modulating autonomic tone. The study aimed to validate the acute effects of a novel laparoscopy-based RDN for modulating AF inducibility using a swine model. Each 4 swine were assigned for the sham operation and laparoscopy-based RDN. Vagal nerve stimulation (VNS; 10 Hz, 50 ms, 5-20 V, 30 sec) was performed at the right vagal nerve to enhance AF inducibility. Burst atrial pacing (100 ms, 1-5 V, 90 sec) at the right atrium was used to induce AF. Atrial effective refractory period (AERP) and AF duration were compared before and after the sham operation or RDN. Laparoscopy-based RDN was done using an instrument with linear bipolar electrodes that wraps around the renal artery (Figure 1A). It delivers the radiofrequency energy to the adventitia to ablate renal sympathetic nerves. Both proximal and distal parts of renal artery were ablated (Figure 2A). Renal arterial biopsy was done and stained with tyrosine hydroxylase to identify sympathetic nerves and compared between both groups. For the sham group, VNS significantly reduced AERP from median 180 to 150 ms and 170 to 150 ms before and after the sham operation, respectively (both p =0.009) (Figure 2A). VNS numerically increased AF duration from median 4.5 to 10.5 sec and 6.0 to 9.5 sec before and after the sham operation (p =0.06 and 0.11, respectively) (Figure 2B). The effect of VNS on AF duration was significant (p =0.005), while the sham operation did not (p =0.79). For the RDN group, VNS numerically reduced AERP from 160 to 130 ms and 180 to 160 ms before and after RDN (p =0.24 and 0.54, respectively) (Figure 2A). VNS did not induce significant difference in AF duration regardless of RDN. However, RDN significantly reduced AF duration regardless of VNS (from mean 23.0 to 4.8 sec; difference between means 18.3 sec (95% CI 6.4-30.1 sec); p =0.03) (Figure 2B). The effect of RDN on AF duration was significant (p =0.003). In histology analysis, renal sympathetic nerve tissue was degenerated after laparoscopic RDN, whereas normal renal sympathetic nerves were intact in the sham group (Figure 2B). A novel laparoscopy-based RDN significantly reduced AF inducibility in swine models. The long-term effect of this novel laparoscopy-based RDN would be investigated.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

ATRIAL STRETCH-DEPENDENT TUMOR NECROSIS FACTOR-MEDIATED ADVERSE ATRIAL REMODELING AND ATRIAL ARRHYTHMIA INDUCIBILITY IN A MOUSE MODEL OF AORTIC REGURGITATION

<h3>BACKGROUND</h3> Atrial fibrillation (AF) is the most common sustained supraventricular arrhythmia worldwide, with its incidence linked to cardiovascular (CV) disease and, paradoxically, endurance exercise. Most conditions linked to AF are associated with elevated atrial pressures and stretch, which are powerful stimuli for atrial hypertrophy, fibrosis, and inflammation. We previously established adverse atrial changes and arrhythmogenesis required the pro-inflammatory and mechanosensitive cytokine tumor necrosis factor (TNF) in intense swim exercised mice. Thus, we hypothesize that stretch-mediated TNF-dependent signaling may provide a unifying mechanism linking AF in exercise and disease. <h3>METHODS AND RESULTS</h3> We developed a clinically-relevant mouse model of aortic regurgitation (AR), which is characterized by diastolic volume overload and elevated left ventricular end-diastolic (LVEDPs) and atrial pressures, to study atrial stretch-dependent TNF-mediated AF pathogenesis. AR was induced by retrograde puncture of the aortic valve in 8-week-old CD1 wild-type and whole-body TNF knockout (TNF-/-) mice. Four weeks after regurgitation, AR resulted in volume overload-mediated progressive LV dilatation, functional impairment, hypertrophy, and elevated LVEDPs in the absence of ventricular arrhythmia inducibility in both groups. In wild-type mice, AR resulted in adverse atrial remodeling, characterized by atrial hypertrophy and fibrosis, decreased conduction velocity, reduced atrial effective refractory period and action potential duration, and increased in vivo and ex vivo AF susceptibility. By contrast, TNF-/- prevented AR-induced adverse atrial remodeling and arrhythmia inducibility, independent of ventricular changes. <h3>CONCLUSION</h3> Our results establish that adverse atrial remodeling and AF vulnerability with AR requires TNF, providing a mechanistic link between elevated atrial pressures, adverse remodeling, and AF susceptibility with CV disease and exercise.

MP36-06 EFFECTS OF GENDER-AFFIRMING HORMONE THERAPY ON SEXUAL FUNCTION OF TRANSGENDER MEN AND WOMEN

You have accessJournal of UrologySexual Function/Dysfunction: Medical, Hormonal & Non-surgical Therapy II (MP36)1 Sep 2021MP36-06 EFFECTS OF GENDER-AFFIRMING HORMONE THERAPY ON SEXUAL FUNCTION OF TRANSGENDER MEN AND WOMEN Michael Zaliznyak, Marie Lauzon, Jenna Stelmar, Nance Yuan, and Maurice Garcia Michael ZaliznyakMichael Zaliznyak More articles by this author , Marie LauzonMarie Lauzon More articles by this author , Jenna StelmarJenna Stelmar More articles by this author , Nance YuanNance Yuan More articles by this author , and Maurice GarciaMaurice Garcia More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002045.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Transgender patients who present for medical and surgical care are treated with hormone medications and genital surgeries that affect, and often significantly change, sexual function. Although patients rely on providers to counsel them about what effects they might expect, the effects of such treatments on sexual function are not well described or understood. We sought to assess the impact of gender affirming hormone therapy (GAHT) on patients’ sexual function. METHODS: We queried potential changes in orgasm function before and after commencing GAHT (minimum 1 year) among 130 consecutive transgender women (TW) and 33 transgender men (TM). TW presented to either undergo initial vaginoplasty surgery (N=96), or who had previously had vaginoplasty (N=34), and all TM had no prior history of gender affirming genital surgery (n=33). We queried the following specific domains under a uniform condition (masturbation): 1. Lead-time to achieve orgasm, 2. Duration of orgasm, 3. Body location of orgasm sensation; 4. Description of orgasm as either a single or multiple-peak event, 5. Duration of post-orgasm refractory period, and 6. Overall satisfaction with orgasm quality. RESULTS: Within groups by gender, TW and TM cohorts reported similar responses to our inventory before starting GAHT. After GAHT, TW in both pre- and post-vaginoplasty surgery groups reported similar changes in orgasm function: increase in lead-time necessary to achieve orgasm, orgasm duration, and overall orgasm satisfaction; and decrease in post-orgasm refractory period. Similarly, TM reported an increase in duration of orgasm and overall satisfaction with orgasm quality; and a decrease in post-orgasm refractory period. Over half of the TW and TM patients reported experiencing orgasms in additional body locations. Additionally, prior to commencing GAHT, the majority of TM and TW patients reported their orgasms as a short, single-peak event but following GAHT these same patients reported longer and multiple-peak orgasms. Reported dissatisfaction was driven by longer time to orgasm. CONCLUSIONS: Our findings suggest that, with GAHT, TW and TM experience considerable change in several sexual function domains- but also improved overall orgasm quality and satisfaction. Interestingly, among TW, GAHT results in orgasm function and quality that more closely resembles what cis-women describe- something that has not been reported to date. It is important to share such data with patients prospectively before treatments. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e637-e638 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michael Zaliznyak More articles by this author Marie Lauzon More articles by this author Jenna Stelmar More articles by this author Nance Yuan More articles by this author Maurice Garcia More articles by this author Expand All Advertisement Loading ...

Inhibition of KCa3.1 Channels Suppresses Atrial Fibrillation via the Attenuation of Macrophage Pro-inflammatory Polarization in a Canine Model With Prolonged Rapid Atrial Pacing.

Aims: To investigate the role of KCa3. 1 inhibition in macrophage pro-inflammatory polarization and vulnerability to atrial fibrillation (AF) in a canine model with prolonged rapid atrial pacing.Materials and Methods: Twenty beagle dogs (weighing 8–10 kg) were randomly assigned to a sham group (n = 6), pacing group (n = 7) and pacing+TRAM-34 group (n = 7). An experimental model of AF was established by rapid pacing. TRAM-34 was administered to the Pacing+TRAM-34 group by slow intravenous injection (10 mg/kg), 3 times each day. After 7 days of pacing, the electrophysiology was measured in vivo. The levels of interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), CD68, c-Fos, p38, and NF-κB p65 in both atriums were measured by Western blotting, and the levels of inducible nitric oxide synthase (iNOS) and arginase1 (Arg-1) were measured by real-time PCR. Macrophage and KCa3.1 in macrophage in the atrium were quantized following double labeled immunofluorescent.Results: Greater inducibility of AF, an extended duration of AF and lower atrial effective refractory period (AERP) were observed in the pacing group compared with those in the sham group. Both CD68-labeled macrophage and the expression of KCa3.1 in macrophage were elevated in the pacing group and inhibited by TRAM-34, led to higher iNOS expression, lower Arg-1 expression, elevated levels of IL-1β, MCP-1, and TNF-α in the atria, which could be reversed by TRAM-34 treatment (all P < 0.01). KCa3.1 channels were possibly activated via the p38/AP-1/NF-κB signaling pathway.Conclusions: Inhibition of KCa3.1 suppresses vulnerability to AF by attenuating macrophage pro-inflammatory polarization and inflammatory cytokine secretion in a canine model with prolonged rapid atrial pacing.

Atrial Stretch‐Dependent Tumor Necrosis Factor (TNF)‐Mediated Adverse Atrial Remodeling and Atrial Arrhythmia Inducibility in a Mouse Model of Aortic Regurgitation

Atrial fibrillation (AF) is the most common sustained supraventricular arrhythmia worldwide, with its incidence linked to cardiovascular (CV) disease and, paradoxically, endurance exercise. Most conditions linked to AF are associated with elevated atrial pressures and stretch, which are powerful stimuli for atrial hypertrophy, fibrosis, and inflammation. We previously established adverse atrial changes and arrhythmogenesis required the pro-inflammatory and mechanosensitive cytokine tumor necrosis factor (TNF) in intense swim exercised mice. Thus, we hypothesize that stretch-mediated TNF-dependent signaling may provide a unifying mechanism linking AF in exercise and disease. We developed a clinically-relevant mouse model of aortic regurgitation (AR), which is characterized by chronic diastolic volume overload and elevated left ventricular end-diastolic (LVEDPs) and atrial pressures, to study atrial stretch-dependent TNF-mediated AF pathogenesis. AR was induced by retrograde puncture of the aortic valve in 8-week-old CD1 wild-type and whole-body TNF knockout (TNF-/-) mice and cardiac and electrophysiological changes were assessed using echocardiography, invasive hemodynamics, histology, in vivo intracardiacs, and ex vivo optical mapping in isolated atria. Four weeks after regurgitation, AR resulted in volume overload-mediated progressive LV dilatation, functional impairment, hypertrophy, and elevated LVEDPs in the absence of ventricular arrhythmia inducibility in both groups. In wild-type mice, AR resulted in adverse atrial remodeling, characterized by atrial hypertrophy and fibrosis, decreased conduction velocity, reduced atrial effective refractory period and action potential duration, and increased in vivo and ex vivo AF susceptibility. By contrast, TNF-/- prevented AR-induced adverse atrial remodeling and arrhythmia inducibility, independent of ventricular changes. Our results establish that adverse atrial remodeling and AF vulnerability with AR requires TNF, providing a mechanistic link between elevated atrial pressures, adverse atrial remodeling, and AF susceptibility with CV disease and exercise.

An Asymmetrical Hypothesis for the NREM-REM Sleep Alternation-What Is the NREM-REM Cycle?

Since the discovery of rapid eye movement (REM) sleep (Aserinsky and Kleitman, 1953), sleep has been described as a succession of cycles of non-REM (NREM) and REM sleep episodes. The hypothesis of short-term REM sleep homeostasis, which is currently the basis of most credible theories on sleep regulation, is built upon a positive correlation between the duration of a REM sleep episode and the duration of the interval until the next REM sleep episode (inter-REM interval): the duration of REM sleep would therefore predict the duration of this interval. However, the high variability of inter-REM intervals, especially in polyphasic sleep, argues against a simple oscillator model. A new “asymmetrical” hypothesis is presented here, where REM sleep episodes only determine the duration of a proportional post-REM refractory period (PRRP), during which REM sleep is forbidden and the only remaining options are isolated NREM episodes or waking. After the PRRP, all three options are available again (NREM, REM, and Wake). I will explain why I think this hypothesis also calls into question the notion of NREM-REM sleep cycles.

EPIGENOMIC EFFECTS OF EXPOSURE OF PREGNANT RATS TO LOW DOSE OF BISPHENOL A REGARDING THE NEUROENDOCRINE SYSTEM OF THE MALE F1 GENERATION (short communication)

Aim: To study the long-term effects of exposure of pregnant Wistar rats to low dose of bisphenol A (BPA) by measuring to the level of steroid hormones and sexual behavior of adult male offspring of the first generation. Material and research methods: BPA as part of the Dorfman gel was gavaged during the last week of pregnancy, when androgen-dependent sexual brain differentiation occurs, in a daily dose of 25 mcg/kg b.w. (threshold teratogenic dose). Male sexual behavior was evaluated by proceptive reactions, the duration of latent and refractory periods, the number of mounts, intromissions and ejaculations in the presence of a receptive female. Female sexual behavior was assessed by lordosis reactions of orchidectomized and activated by the introduction of estradiol and progesterone males in the presence of a normal male. A neuromorphological analysis of the sex-dimorphic area of the brain, the medial preoptic nucleus of the hypothalamus, was performed by histological examination and karyometry of neurons. Results: Prenatally administered BPA caused a very slight increase in the anogenital distance in newborn animals and did not affect the terms of puberty. The levels of testosterone and corticosterone in the blood plasma of males of 6 months of age did not differ from the control indices. At 10 months of age, all experimental males showed sharply weakened sexual motivation for mating with females, and in 4 from 5 animals, copulative components of sexual behavior were absent. There was no ejaculations in the 5th male as well, while numbers of the mounts without intromissions and ones with intromissions significantly reduced. In the BPA group, all descendants showed active female behavior in the presence of a normal male, which manifested in lordosis reactions and a high lordosis index. According to the histological study of medial preoptic nucleus, the activity of neurocytes in the male offspring of BPA-exposed females was significantly reduced, and their nuclei volume distribution was some different from the control. Conclusions: The data obtained indicate epigenetic disorders of the sexual brain differentiation program due to the prenatal exposure to BPA in dose that does not cause significant teratogenic effects. This should be taken into account when evaluating the potential hazard of BPA for reproductive health. Key words: bisphenol A, prenatal effect, male rats, sexual behavior, corticosterone, testosterone.

Pinocembrin attenuates autonomic dysfunction and atrial fibrillation susceptibility via inhibition of the NF-κB/TNF-α pathway in a rat model of myocardial infarction

Previous studies indicate that myocardial infarction (MI) may contribute to atrial fibrillation (AF). Emerging evidence has shown that pinocembrin protects myocardial ischemic injury (I/R)-induced cardiac fibrosis and arrhythmias in animals via its anti-inflammatory or antioxidant activities. However, the effects of pinocembrin on MI-induced atrial arrhythmias remain unknown. Thus, this study aimed to investigate the effects of pinocembrin on autonomic dysfunction and AF susceptibility in MI rats and the possible mechanism. In a standard experimental MI model, Sprague-Dawley rats received permanent ligation of the left anterior descending (LAD) coronary artery and were treated with pinocembrin or saline for 6 days. Our results demonstrated that pinocembrin treatment significantly decreased sympathetic activity, augmented parasympathetic activity, improved heart rate variability (HRV), prolonged the atrial effective refractory period (ERP) and action potential duration (APD), shortened activation latency (AL), lowered the indicibility rate of AF, attenuated atrial fibrosis, and decreased concentrations of norepinephrine (NE), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in the serum and the left atrial (LA). Furthermore, pinocembrin treatment significantly increased the expression levels of Cx43 and Cav1.2 and suppressed the phosphorylation of inhibitor-κBα (IκBα) and the activation of nuclear factor-kappa B (NF-κB)subunit p65. In conclusion, the findings indicate that pinocembrin treatment decreases autonomic remodeling, lowers atrial fibrosis, ameliorates atrial electrical remodeling, and suppresses MI-induced inflammatory responses, which suggests a potential novel strategy for atrial arrhythmias.

P1888Autoantiboides to Muscarinic M2 cholinoceptors in patients with paroxysmal atrial fibrillation

Abstract Introduction Atrial fibrillation (AFib) is the most frequenly encountered arrhythmia. In the majority of cases AFib occurs in patients with cardiovascular diseases such as arterial hypertension (AH). In 10–15% of cases AFib occurs in the absense of comorbidities in structurally normal heart. It is reffered to as “lone AFib” and the cause of this arrhythmia remains unknown. Activation of cardiac M2-actylcholinoreceptors (M2-CR) leads to decrease in duration of atrial refractory periods that may contribute to development of AFib. Autoantibodies against M2-CR has cholinomimetic properties, but role of these autoantibodies in development and maintenance of AFib has not been studied. Purpose To assess autoantibodies against M2-CR in patients with paroxysmal lone AFib, in patients with AFib and AH and healthy people. Methods 100 patints with lone Afib, 100 patients with Afib and AH and 25 healthy people were included. Patients underwent clinical blood and urinlysis, assessment of biochemistry blood panel, 12-lead ECG, 24-hour Holter monitoring, echocardiography and stress-testing (treadmill or stress-echocardiography). Assesment of IgM and IgG autoantibodies to M2-CR was performed by indirect immunoenzyme assay. The following peptide molecules were used as epitopes for detection of autoantibodies: M1-amino acid sequence YTVIGYWPLGVVCDL (83–98) of the first extracellular loop of M2-CR; M2-sequence VRTVEDGECYIQFFSNAAVTFGTAI (168–192) of the second extracellular loop of M2-CR; M3-sequence NTFCAPCIPNTV (410–421) of the third extracellular loop of M2-CR, M4-short sequence VEDGECYIQFFS (171–182) of the second extracellular loop of M2-CR; M1+M4-chimeric molecule formed by sequences of the first and the second extacellular loops of M2-CR connected by disulfide bound YTVIGYWPLGVVCDL+VEDGECTIQFFS (83–98+171–182). Results IgG to M2-CR were found in 32% of patients with AFib and in 12% of healthy subjects (p&lt;0,05). IgM to M2-CR were found in 25% of patients with AFib and in 32% of healthy subjects (p&lt;0,05). In patients with lone AFib prevalence of IgG to M2-CR were greater than in patients with AFib and AH (39% vs 25%; p&lt;0,05). Patients with lone AFib and AFib and AH had higher prevalence of IgG to all amino-acid sequences and difference was statistically significant for M2, M4, M1+M4 epitopes (see fig.). Prevalence of IgG to M2-CR epitopes Conclusion Higher prevalence of IgG to M2-CR in patients with AFib than in healthy subjects may suppose an active role of autoimmune processes in arrhythmogenesis.

Chronic inhibition of the sigma-1 receptor exacerbates atrial fibrillation susceptibility in rats by promoting atrial remodeling

AimsThis study aimed to evaluate the effects of the sigma-1 receptor (S1R) on atrial fibrillation (AF) susceptibility in rats. Main methodsRats were randomly assigned into three groups for intraperitoneal treatment with saline (CTL group), BD1047 (an antagonist of the S1R, BD group) or BD1047 plus fluvoxamine (an agonist of the S1R, BD + F group) for 4 weeks. The heart rate variability (HRV) and atrial electrophysiological parameters were measured via the PowerLab system and analyzed by LabChart 8.0 software. Atrial histology was determined with Masson staining. The protein levels of connexin (Cx) 40, Cav1.2, S1R, eNOS, p-eNOS, and p-AKT were detected by western blot assays. Key findingsOur results showed that BD1047 significantly shortened the atrial effective refractory period (ERP) and action potential duration (APD), increased AF inducibility and duration, augmented sympathetic activity, depressed parasympathetic activity, and reduced heart rate variability (HRV) compared with the CTL group. Masson staining also showed a significant increase in atrial fibrosis in the BD group. Furthermore, the expressions of S1R, Cx40, Cav1.2, p-eNOS, and p-AKT were dramatically reduced in the BD group compared with the CTL group (all P < 0.01). However, fluvoxamine administration mitigated most of the abovementioned alterations. SignificanceOur findings indicated that S1R inhibition contributed to atrial electrical remodeling, cardiac autonomic remodeling and atrial fibrosis, which could be attenuated by fluvoxamine, thus providing new insights into the relationship between the S1R and AF.

The effects of interleukin 17A on left stellate ganglion remodeling are mediated by neuroimmune communication in normal structural hearts

BackgroundIt is reported interleukin (IL)-17A, a classical proinflammatory cytokine, is implicated in neuroimmune-associated remodeling in neural plasticity and pathological conditions. However, the effect of IL-17A on left stellate ganglion (LSG) remodeling remains unclear. ObjectiveThis study was performed to determine whether exogenous IL-17A promotes LSG remodeling and destabilize ventricular electrophysiological properties (EPs) in normal canines. Methods24 beagles were randomly allocated into three groups. In the first group, animals were subjected to 0.1 ml phosphate buffer saline (PBS) microinjection of into LSG (n = 8), an equivalent IL-17A was administrated in the second group (n = 8), and an equivalent anti-IL-17A mAb plus IL-17A was administrated in the third group (n = 8). The ventricular EPs, neural function and activity of the LSG were determined at baseline and 30 min after administration. In the end, LSG tissues were collected. ResultsCompared with the control group, the experimental group had a significantly shorter effective refractory period (ERP) and action potential duration (APD)90, an increased ERP, APD90, Smax dispersion, and APD alternans cycle length; and steepened APD restitution curves. In addition, IL-17A enhanced the neural function and activity of the LSG, upregulated the expressions of neuropeptides and proinflammatory cytokines and cells. And all these effects were attenuated by anti-IL-17A mAb. Importantly, IL-17 receptor A (IL-17R-A) was detected in sympathetic neurons in the LSG. ConclusionIL-17A promoted LSG remodeling by regulating the neural inflammation response. It did so by binding to IL-17R-A, resulting in unstable ventricular electrophysiology in normal structural hearts.