Shortening Of Refractory Period Research Articles

Mechanisms of ischaemia-induced arrhythmias in hypertrophic cardiomyopathy: a large-scale computational study.

Lethal arrhythmias in hypertrophic cardiomyopathy (HCM) are widely attributed to myocardial ischaemia and fibrosis. How these factors modulate arrhythmic risk remains largely unknown, especially as invasive mapping protocols are not routinely used in these patients. By leveraging multiscale digital-twin technologies, we aim to investigate ischaemic mechanisms of increased arrhythmic risk in HCM. Computational models of human HCM cardiomyocytes, tissue and ventricles were used to simulate outcomes of phase 1A acute myocardial ischaemia. Cellular response predictions were validated with patch-clamp studies of human HCM cardiomyocytes (n=12 cells, N=5 patients). Ventricular simulations were informed by typical distributions of subendocardial/transmural ischaemia as analysed in perfusion scans (N=28 patients). S1-S2 pacing protocols were used to quantify arrhythmic risk for scenarios in which regions of septal obstructive hypertrophy were affected by (i) ischaemia, (ii) ischaemia and impaired repolarisation, and (iii) ischaemia, impaired repolarisation, and diffuse fibrosis.HCM cardiomyocytes exhibited enhanced action potential and abnormal effective refractory period shortening to ischaemic insults. Analysis of c.a. 75,000 re-entry induction cases revealed that the abnormal HCM cellular response enabled establishment of arrhythmia at milder ischaemia than otherwise possible in healthy myocardium, due to larger refractoriness gradients that promoted conduction block. Arrhythmias were more easily sustained in transmural than subendocardial ischaemia. Mechanisms of ischaemia-fibrosis interaction were strongly electrophysiology dependent. Fibrosis enabled asymmetric re-entry patterns and break-up into sustained ventricular tachycardia. HCM ventricles exhibited an increased risk to non-sustained and sustained re-entry, largely dominated by an impaired cellular response and deleterious interactions with the diffuse fibrotic substrate.

Relationship between electrical activity and left atrial volume during atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Pulmonary veins (PV) ostia were previously identified as the left atrium (LA) areas with the shortest refractory period during sinus rhythm. Pulmonary veins isolation (PVI) became standard of care, but clinical results are still suboptimal. Currently, atrial fibrillation (AF) cycle length mapping (CLM) is possible due to a special tool of the Carto® electroanatomical mapping, which identifies areas in the left atria with shortest refractory period, during AF. Purpose Using this new EAM feature, our study aimed to assess the relationship between short refractory period LA areas and left atrial volume and AF type, known predictors of AF relapse. Methods Retrospective analysis of an unicentric registry of individuals with symptomatic drug-refractory AF who underwent PVI AF ablation with Carto® EAM. CLM was performed. CL maps were created with a high-density mapping Pentaray® catheter before and after PVI. We assessed areas of short cycle length (SCL) (defined as 120 to 250ms), and their relationships with complex fractionated atrial electrograms (CFAE), and low-voltage zones (from 0.1 to 0.3mV). Results A total of 35 patients (21 men, median age 62 IQR 53-71 years) were included. Most patients presented with persistent AF (n=23, 66%), and 8 patients (23%) had a previous PVI. The mean shortest measured cycle length in AF was 134ms (SD ± 23ms). There was a negative correlation between LA volume and SCL areas after PVI (Spearman Correlation coefficient [ρ] = - 0.47, P = 0.037). There was no correlation between LA volume and SCL areas before the PVI procedure (ρ = -0.06, P = 0.776), nor between AF type and SCL (ρ = -0.118, P = 0.620). All patients presented areas of SCL located in the PVs or their insertion, 76% in the posterior/roof region adjacent to the left superior pulmonary vein (LSPV) and 76% in the anterior region of the wall adjacent to the right superior pulmonary vein (RSPV). These two areas remained the fastest even after PVI. The anterior mitral region rarely presented SCL (16%). SCL were related to low-voltage areas in 93% and were adjacent to CFAE in 84% of the cases. Low-voltage areas and CFAE were more frequent and had a larger LA dispersion than SCL. Conclusion Our study shows that LA volume, not AF type, is correlated with remaining SCL areas after a pulmonary vein isolation procedure. This finding suggests a possible causal link between increased LA volume and AF relapse post-PVI. More studies are needed to assess the role of the SCL areas as a potential ablation target and their impact on AF ablation outcomes.

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

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

Electrophysiological and therapeutic effects of amiodarone in patients with preexcited atrial fibrillation.

Atrial fibrillation (AF) with fast ventricular response over an overt accessory pathway (AP) (preexcited AF) with a short anterograde refractory period is a potentially malignant arrhythmia. This study aimed to evaluate the safety and efficacy of amiodarone for preexcited AF management. This study enrolled 103 patients with evidence of AP in electrocardiography. Patients with preexcited AF were included in the study. Intravenous amiodarone (300 mg) was infused for 30 min for all patients in the AF rhythm. Electrophysiological parameters were evaluated before amiodarone injection and 2 h after pharmacological or electrical cardioversion. Antegrade and retrograde refractory periods of the atrioventricular node (AVN) and AP, as well as antegrade and retrograde Wenckebach points of AVN, were increased significantly after amiodarone infusion. Furthermore, the mean of the shortest preexcited RR interval was increased during the monitoring period. Comparing the preexcited index at the beginning of the study and before cardioversion (2 h later) revealed that the QRS complexes changed to a wider pattern as the preexcitation index changed from 80.61 to 92.26 (P < 0.001). Nineteen (18.4%) patients converted to the sinus rhythm with amiodarone infusion. No ventricular arrhythmia was detected during monitoring. Amiodarone could be considered a safe drug in patients with preexcited AF for rate control despite its relatively low efficacy in conversion to the sinus rhythm.

Arrhythmias in adults with congenital heart disease and heart failure.

Arrhythmias and heart failure are among the most common complications encountered by adults with congenital heart disease (CHD). In this contemporary review, we explore the interactions between arrhythmias and heart failure and discuss management strategies. Major knowledge gaps are highlighted throughout. Interactions between arrhythmias and heart failure are complex and bidirectional, with one begetting the other. Arrhythmias can provoke heart failure through various mechanisms: conduction disturbances may contribute to inefficient ventricular filling and contraction patterns; bradyarrhythmias and tachyarrhythmias can result in a reduction in cardiac output; hypoxemia may be exacerbated by right-to-left shunting; and tachycardia-induced cardiomyopathy has potentially devastating consequences if the diagnosis is delayed. In turn, heart failure promotes arrhythmogenesis through various structural (eg, fibrosis, chamber dilation, hypertrophy) and electrical remodeling effects that include changes to ion currents and channels and connexin expression, along with shortening of atrial and ventricular refractory periods with increased heterogeneity. Several shared comorbidities can contribute to, and modulate the impact of, arrhythmias and heart failure. Preemptive arrhythmia management can potentially mitigate effects on heart failure exacerbations. Similarly, optimal heart failure control could curtail its impact on arrhythmogenesis. Treatment strategies to prevent or treat heart failure in adults with CHD encompass pharmacological agents, catheter ablation, and device therapies including defibrillators, cardiac resynchronization therapy, and His bundle pacing. High-priority research avenues with major knowledge gaps include tachycardia-induced cardiomyopathy, catheter ablation of atrial fibrillation, defibrillator indications in high-risk subsets, and the role of cardiac resynchronization therapy and His bundle pacing in diverse forms of CHD.

Electrical anatomy of the left atrium during atrial fibrillation

Abstract Introduction Twenty years ago, pulmonary veins (PV) ostia were identified as the left atrium (LA) areas with the shortest refractory period during sinus rhythm. Pulmonary veins isolation (PVI) became standard of care, but clinical results are still suboptimal. Today, a special tool using the Carto® electroanatomical mapping (EAM) allows for AF cycle length mapping (CLM), to identify the areas in the left atria with shortest refractory period, during atrial fibrillation. Using this EAM tool, our study aimed to find the LA areas with the shortest refractory period to better recognize electrical targets for catheter ablation. Methods Retrospective analysis of an unicentric registry of individuals with symptomatic drug-refractory AF who underwent PVI with Carto® EAM. CLM was performed with a high-density mapping Pentaray® catheter before and after PVI and in 4 redo procedures. We assessed areas of short cycle length (SCL) (defined as 120 to 250ms), and their relationships with complex fractionated atrial electrograms (CFAE), and low-voltage zones (from 0.1 to 0.3mV). Results A total of 18 patients (8 men, median age 63 IQR 58–71 years) were included. Most patients presented with persistent AF (n=12, 67%), and 4 patients (22%) had a previous PVI. The mean shortest measured cycle length in AF was 140ms (SD ±27ms). All patients presented areas of SCL located in the PVs or their insertion, 70% in the posterior/roof region adjacent to the left superior pulmonary vein (LSPV) (figure 1) and 60% in the anterior region of the right superior pulmonary vein (RSPV). These two areas remained the fastest even after PVI. The anterior mitral region rarely presented SCL (17%). SCL were related to low-voltage areas in 94% and were adjacent to CFAE. Low-voltage areas and CFAE were more frequent and had a larger LA dispersion than SCL. Conclusion We confirmed in 3D mapping that PVs are the LA zones with shortest refractory period, not only in sinus rhythm but also during AF. The persistence of SCL areas in the border zones of the PVI lines suggest the benefit of a more extensive CLM guided ablation. Larger studies are needed. Funding Acknowledgement Type of funding sources: None. Short cycle length mapping

Antidromic atrioventricular reentrant tachycardia in a patient with Wolff‐Parkinson‐White syndrome and unapparent preexcitation: A case report

This is a case of antidromic AVRT in a patient with unapparent preexcitation, and we could successfully diagnose and treat with the careful interpretation of wide QRS tachycardia. We should keep in mind that differentiation between intermittent and unapparent preexcitation is difficult, and some patients with unapparent preexcitation have short refractory periods of those accessory pathways, leading to sudden death.

Significant anisotropic neuronal refractory period plasticity

Refractory periods are an unavoidable feature of excitable elements, resulting in necessary time-lags for re-excitation. Herein, we measure neuronal absolute refractory periods (ARPs) in synaptic blocked neuronal cultures. In so doing, we show that their duration can be significantly extended by dozens of milliseconds using preceding evoked spikes generated by extracellular stimulations. The ARP increases with the frequency of preceding stimulations, and saturates at the intermittent phase of the neuronal response latency, where a short relative refractory period might appear. Nevertheless, preceding stimulations via a different extracellular route does not affect the ARP. It is also found to be independent of preceding intracellular stimulations. All these features strongly suggest that the anisotropic ARPs originate in neuronal dendrites. The results demonstrate the fast and significant plasticity of the neuronal ARP, depending on the firing activity of its connecting neurons, which is expected to affect network dynamics.

Electrical anatomy of the left atrium during atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Twenty years ago, pulmonary veins (PV) ostia were identified as the left atrium (LA) areas with the shortest refractory period during sinus rhythm. Pulmonary veins isolation (PVI) became standard of care, but clinical results are still suboptimal. Today, a special tool using the Carto® electroanatomical mapping (EAM) allows for AF cycle length mapping (CLM), to identify the areas in the left atria with shortest refractory period, during atrial fibrillation. Using this EAM tool, our study aimed to find the LA areas with the shortest refractory period to better recognize electrical targets for catheter ablation. Methods Retrospective analysis of an unicentric registry of individuals with symptomatic drug-refractory AF who underwent PVI with Carto® EAM. CLM was performed with a high-density mapping Pentaray® catheter before and after PVI and in 4 redo procedures. We assessed areas of short cycle length (SCL) (defined as 120 to 250ms), and their relationships with complex fractionated atrial electrograms (CFAE), and low-voltage zones (from 0.1 to 0.3mV). Results A total of 18 patients (8 men, median age 63 IQR 58-71 years) were included. Most patients presented with persistent AF (n = 12, 67%), and 4 patients (22%) had a previous PVI. The mean shortest measured cycle length in AF was 140ms (SD ±27ms). All patients presented areas of SCL located in the PVs or their insertion, 70% in the posterior/roof region adjacent to the left superior pulmonary vein (LSPV) (figure 1) and 60% in the anterior region of the right superior pulmonary vein (RSPV). These two areas remained the fastest even after PVI. The anterior mitral region rarely presented SCL (17%). SCL were related to low-voltage areas in 94% and were adjacent to CFAE. Low-voltage areas and CFAE were more frequent and had a larger LA dispersion than SCL. Conclusion We confirmed in 3D mapping that PVs are the LA zones with shortest refractory period, not only in sinus rhythm but also during AF. The persistence of SCL areas in the border zones of the PVI lines suggest the benefit of a more extensive CLM guided ablation. Larger studies are needed. Abstract Figure 1

Thymic Engraftment by in vitro-Derived Progenitor T Cells in Young and Aged Mice.

T cells play a critical role in mediating antigen-specific and long-term immunity against viral and bacterial pathogens, and their development relies on the highly specialized thymic microenvironment. T cell immunodeficiency can be acquired in the form of inborn errors, or can result from perturbations to the thymus due to aging or irradiation/chemotherapy required for cancer treatment. Hematopoietic stem cell transplant (HSCT) from compatible donors is a cornerstone for the treatment of hematological malignancies and immunodeficiency. Although it can restore a functional immune system, profound impairments exist in recovery of the T cell compartment. T cells remain absent or low in number for many months after HSCT, depending on a variety of factors including the age of the recipient. While younger patients have a shorter refractory period, the prolonged T cell recovery observed in older patients can lead to a higher risk of opportunistic infections and increased predisposition to relapse. Thus, strategies for enhancing T cell recovery in aged individuals are needed to counter thymic damage induced by radiation and chemotherapy toxicities, in addition to naturally occurring age-related thymic involution. Preclinical results have shown that robust and rapid long-term thymic reconstitution can be achieved when progenitor T cells, generated in vitro from HSCs, are co-administered during HSCT. Progenitor T cells appear to rely on lymphostromal crosstalk via receptor activator of NF-κB (RANK) and RANK-ligand (RANKL) interactions, creating chemokine-rich niches within the cortex and medulla that likely favor the recruitment of bone marrow-derived thymus seeding progenitors. Here, we employed preclinical mouse models to demonstrate that in vitro-generated progenitor T cells can effectively engraft involuted aged thymuses, which could potentially improve T cell recovery. The utility of progenitor T cells for aged recipients positions them as a promising cellular therapy for immune recovery and intrathymic repair following irradiation and chemotherapy, even in a post-involution thymus.

Unmasking latent preexcitation of a right-sided accessory pathway with intravenous adenosine after unexplained sudden cardiac arrest.

Intravenous adenosine is a simple test that can uncover latent preexcitation via an accessory pathway and is useful in the diagnostic workup of sudden cardiac arrest survivors without an identifiable cause. Latent preexcitation is usually associated with left free wall pathways but may also occur in right-sided accessory pathways with slow antegrade conduction. Although intermittent ECG evidence of preexcitation is generally considered a marker of low risk for sudden death, if this is due to an accessory pathway with long atrioventricular conduction time and short effective refractory period (rather than true intermittent conduction via the pathway), the risk for sudden death may be equal to those accessory pathways with manifest preexcitation.

Proarrhythmic effects from competitive atrial pacing and potential programming solutions

Programmed long AV delays and intrinsic long first degree AV block may increase risk for competitive atrial pacing (CAP) in devices without CAP avoidance algorithms. Patients identified with CAP-induced mode switch episodes were followed clinically from September 2013 to August 2019. Attempts to avoid CAP included shortening of postventricular atrial refractory period (PVARP) or postventricular atrial blanking period (PVAB), or change to AAI or DDI modes. After observing associations with sensor-driven pacing, rate response was inactivated in a subset. Among 23 patients identified with CAP (22 St Jude Medical [Abbott]; one Boston Scientific Corporation devices), atrial fibrillation (AF) was induced in 12 (52%), lasting 10seconds to 28hours and 32minutes. In one patient with an ICD CAP-induced AF with rapid ventricular rates that triggered a shock, inducing ventricular fibrillation, syncope, and another shock. Changing AV delays and shortening of PVARP failed to resolve CAP. After noting that all had CAP during sensor-driven pacing, rate response was inactivated in seven, resolving further device-induced AF in the three of seven that had prior CAP-induced AF. In two patients with intact AV conduction, AAI(R) pacing resolved further documentation of CAP. CAP predominantly occurs during sensor-driven atrial pacing that competes with intrinsic atrial events falling in PVARP. Inactivation of the activity sensor or change to atrial-based pacing modes (AAI/R) appears to effectively prevent induction of device-induced atrial proarrhythmia. Ultimately, a corrective algorithm is needed to avoid CAP-induced proarrhythmia.

Peripherally Restricted Dual Cannabinoid Receptor Agonist Modifies Mitochondrial Signaling and Inhibits Atrial Electrical Remodeling in a Tachypaced Ex Vivo Rat Model

Atrial fibrillation (AF) leads to rate‐dependent changes, which progressively increase the risk for recurrence and persistence of the arrhythmia (collectively defined as atrial remodelling). Atrial effective refractory period (AERP) shortening and conduction velocity prolongation are hallmarks of atrial remodelling markedly promoting AF substrate. The molecular mechanisms underlying atrial remodelling are not fully elucidated and therapeutic strategies to reduce AF burden by preventing atrial remodelling are not yet available. Cannabinoid (CB) receptor ligands exert cardioprotective effects. We hypothesized that CB13, a peripherally restricted dual CB receptor agonist with limited brain penetration, would reduce atrial remodelling.Sprague Dawley (SD) rat hearts were excised and hung on a Langendorff set‐up, and supplemented with CB13 (1μM) or without (control) (paced and non‐paced). Coronary pressure of 60–80 mmHg was maintained. Electrophysiological (EP) parameters were measured by placing a mini‐hook platinum‐iridium quadrupole electrode on the right atrium (RA) for pacing and atrial recording (CB13 n=8; control n=8). RA were tachypaced for 90 min at double diastolic threshold and a cycle length of 5 ms higher than failed 1:1 atrial capture. S1S2 stimulation protocol was used to measure AERP, defined as the longest interval with failed 1:1 capture. The effects of CB13 on atrial refractoriness and AF substrate were assessed by analysis of high resolution electrogram recordings and protein expression via western blot.Post‐tachypacing EP recordings showed reduced AERP in control compared to pre‐tachypacing (54.38±3.05 vs. 44.75±3.67 ms; p&lt;0.01). AERP post‐tachypacing in CB13‐treated hearts remained unchanged compared to pre‐tachypacing (55.25±3.46 vs. 55.50±2.67 ms; ns). Thus, CB13‐treatment resulted in preservation of AERP compared to control (103.6±9.2 vs. 82.3±4.4 % of baseline; p&lt;0.05). Protein expression of PGC1α was significantly increased by CB13 compared to controls (paced and non‐paced). Upregulation of mitochondrial biogenesis may be related to increased phosphorylation of AMPKα at residue threonine 172 (compared to total AMPKα, p=0.12, CB13 vs. control paced). Furthermore, gap junction connexin 43 was significantly downregulated in paced controls vs. non‐paced controls, while CB13 remained upregulated (no significance vs. controls).CB13 exposure during tachypacing prevents AERP reduction and gap junction downregulation probably through mechanisms involving mitochondrial biogenesis. Thus, by inhibiting atrial remodeling CB13 and the subsequent activation of CB receptors may be a viable treatment strategy for AF.Support or Funding InformationThis work was supported by studentships from the Canadian Institutes of Health Research and Mitacs (D.L.)

P6591Arrhythmogenic effects of non-steroidal anti-inflammatory drugs (NSAID)

Abstract Background Clinical and experimental data suggest potential deleterious effects of non-steroidal anti-inflammatory drugs (NSAID) in cardiac disease. The aim of the present study was to characterize potential direct arrhythmogenic effects of ibuprofen or indometacin on cardiac electrophysiology. Methods and results In 13 isolated rabbit hearts, indometacin was administered in increasing concentrations (10, 30 and 50μM) after obtaining baseline data. In further 13 hearts, ibuprofen was infused (10, 30 and 50μM). Eight endo- and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant decrease of QT-interval in indometacin- (50μM: −60ms, p&lt;0.05) and ibuprofen-treated hearts (50μM: −81ms, p&lt;0.01). This was accompanied by a similar decrease of action potential duration (APD). Effective refractory period (ERP) was also reduced by indometacin (−24ms, p&lt;0.05) and ibuprofen (−22ms, p&lt;0.05) while spatial dispersion of repolarisation remained stable with both drugs. Programmed ventricular stimulation and burst stimulation were employed for provocation of ventricular arrhythmias. In the indomethacin group 7 episodes of ventricular arrhythmias were inducible at baseline. The incidence was increased to 22 (10μM), 37 (30μM) and 51 (50μM) with higher concentrations of indometacin. In the ibuprofen group 15 episodes were inducible at baseline. After infusion of 10μM ibuprofen, also 15 episodes of ventricular arrhythmias occurred while 34 episodes were inducible with 30μM ibuprofen. Conclusion Infusion of the NSAID ibuprofen and indometacin resulted in a significant abbreviation of myocardial repolarization and a shortening of ventricular refractory periods. This resulted in an enhanced inducibility of ventricular arrhythmias and may contribute to the proposed deleterious effects of NSAID in the presence of cardiac disease.

Cardiac Afferent Denervation Abolishes Ganglionated Plexi and Sympathetic Responses to Apnea: Implications for Atrial Fibrillation.

Background The autonomic nervous system response to apnea and its mechanistic connection to atrial fibrillation (AF) are unclear. We hypothesize that sensory neurons within the ganglionated plexi (GP) play a role. We aimed to delineate the autonomic response to apnea and to test the effects of ablation of cardiac sensory neurons with resiniferatoxin (RTX), a neurotoxic TRPV1 (transient receptor potential vanilloid 1) agonist. Methods Sixteen dogs were anesthetized and ventilated. Apnea was induced by stopping ventilation until oxygen saturations decreased to 80%. Nerve recordings from bilateral vagal nerves, left stellate ganglion, and anterior right GP were obtained before and during apnea, before and after RTX injection in the anterior right GP (protocol 1, n=7). Atrial effective refractory period and AF inducibility on single extrastimulation were assessed before and during apnea, and before and after intrapericardial RTX administration (protocol 2, n=9). GPs underwent immunohistochemical staining for TRPV1. Results Apnea increased anterior right GP activity, followed by clustered crescendo vagal bursts synchronized with heart rate and blood pressure oscillations. On further oxygen desaturation, a tonic increase in stellate ganglion activity and blood pressure ensued. Apnea-induced effective refractory period shortening from 110.20±31.3 ms to 90.6±29.1 ms ( P<0.001), and AF induction in 9/9 dogs versus 0/9 at baseline. After RTX administration, increases in GP and stellate ganglion activity and blood pressure during apnea were abolished, effective refractory period increased to 126.7±26.9 ms ( P=0.0001), and AF was not induced. Vagal bursts remained unchanged. GP cells showed cytoplasmic microvacuolization and apoptosis. Conclusions Apnea increases GP activity, followed by vagal bursts and tonic stellate ganglion firing. RTX decreases sympathetic and GP nerve activity, abolishes apnea's electrophysiological response, and AF inducibility. Sensory neurons play a role in apnea-induced AF.

Information Theoretic Based Comparative Analysis of Different Communication Signals in Plants

This paper compares the information-theoretic aspects of different communication signals in plants. To be specific, we consider two signals responsible for the inter-cellular communication in plants: electro-chemical and mechanosensitive signals. There is a need for a comprehensive comparison of the communication properties of these different signals in plants for different configurations of receiver cells. In this work we address this research problem using molecular communication theory. We compare the mutual information and the information propagation speed for these communication signals. In addition we compare the impact of refractory period on the mutual information and information propagation speed for these signals in plants. The key result of this paper is that, based on the propagation mechanism, better communication performance can be achieved by electro-chemical signals as compared to mechanosensitive signals. We further find that a short refractory period leads to higher mutual information and propagation speeds.

Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation.

Atrial fibrillation (AF) is frequently associated with enhanced inflammatory response. The NLRP3 (NACHT, LRR, and PYD domain containing protein 3) inflammasome mediates caspase-1 activation and interleukin-1β release in immune cells but is not known to play a role in cardiomyocytes (CMs). Here, we assessed the role of CM NLRP3 inflammasome in AF. NLRP3 inflammasome activation was assessed by immunoblot in atrial whole-tissue lysates and CMs from patients with paroxysmal AF or long-standing persistent (chronic) AF. To determine whether CM-specific activation of NLPR3 is sufficient to promote AF, a CM-specific knockin mouse model expressing constitutively active NLRP3 (CM-KI) was established. In vivo electrophysiology was used to assess atrial arrhythmia vulnerability. To evaluate the mechanism of AF, electric activation pattern, Ca2+ spark frequency, atrial effective refractory period, and morphology of atria were evaluated in CM-KI mice and wild-type littermates. NLRP3 inflammasome activity was increased in the atrial CMs of patients with paroxysmal AF and chronic AF. CM-KI mice developed spontaneous premature atrial contractions and inducible AF, which was attenuated by a specific NLRP3 inflammasome inhibitor, MCC950. CM-KI mice exhibited ectopic activity, abnormal sarcoplasmic reticulum Ca2+ release, atrial effective refractory period shortening, and atrial hypertrophy. Adeno-associated virus subtype-9-mediated CM-specific knockdown of Nlrp3 suppressed AF development in CM-KI mice. Finally, genetic inhibition of Nlrp3 prevented AF development in CREM transgenic mice, a well-characterized mouse model of spontaneous AF. Our study establishes a novel pathophysiological role for CM NLRP3 inflammasome signaling, with a mechanistic link to the pathogenesis of AF, and establishes the inhibition of NLRP3 as a potential novel AF therapy approach.

Renal Denervation Reduced Ventricular Arrhythmia After Myocardial Infarction by Inhibiting Sympathetic Activity and Remodeling.

BackgroundVentricular arrhythmia after myocardial infarction is the most important risk factor for sudden cardiac death, which poses a serious threat to human health. As the correlation between autonomic nervous systemic dysfunction and heart rhythm abnormality has been gradually revealed, remedies targeting autonomic nervous system dysfunction, especially the sympathetic nerve, have emerged. Among them, renal denervation is noted for its powerful effect on the inhibition of sympathetic nerve activity. We aim to investigate whether renal denervation can reduce ventricular arrhythmia after myocardial infarction and thus decrease the risk of sudden cardiac death. In addition, we explore the potential mechanism with respect to nerve activity and remodeling.Methods and ResultsTwenty‐four beagles were randomized into the control (n=4), renal denervation (n=10), and sham (n=10) groups. Permanent left anterior descending artery ligation was performed to establish myocardial infarction in the latter 2 groups. Animals in the renal denervation group underwent both surgical and chemical renal denervation. Compared with dogs in the sham group, dogs in the renal denervation group demonstrated attenuated effective refractory period shortening and inhomogeneity, flattened restitution curve, increased ventricular threshold, and decreased ventricular arrhythmia. Heart rate variability assessment, catecholamine measurement, and nerve discharge recordings all indicated that renal denervation could reduce whole‐body and local tissue sympathetic tone. Tissue analysis revealed a significant decrease in neural remodeling in both the heart and stellate ganglion.ConclusionsSurgical and chemical renal denervation decreased whole‐body and local tissue sympathetic activity and reversed neural remodeling in the heart and stellate ganglion. Consequently, renal denervation led to beneficial remodeling of the electrophysiological characteristics in the infarction border zone, translating to a decrease in ventricular arrhythmia after myocardial infarction.

Effects of refractory gradients and ablation on fibrillatory activity

BackgroundThe mechanisms involved in onset, maintenance, and termination of atrial fibrillation are not well understood. A biophysical model could be useful to determine how the events unfold. MethodA two-dimensional cellular automaton consisting of 576 × 576 grid nodes was implemented to demonstrate the types of electrical activity that may occur in compromised atrial substrate. Electrical activation between nodes was made anisotropic (2:1), and the refractory period (RP) was adjusted from 74 to 192 ms in the spatial domain. Presence of collagen fibers were simulated as short lines of conduction block at many random grid sites, while ablation lesions were delineated as longer lines of block. An S1-S2 pulse from one grid corner was utilized to initiate simulated electrical activity. Simulations were done in which 1. no ablation lines, 2. random ablation lines, and 3. parallel ablation lines were added to the grid to determine how this affected the formation and annihilation of rotational activity after S1-S2 stimulation. ResultsAs the premature (S2) wavefront traversed the grid, rotational activity formed near boundaries where wavefronts propagated from shorter to longer refractory regions, causing unidirectional block, and were anchored by fiber clusters. Multiple wavelets appeared when wavefronts originating from different driving rotational features collided, and/or by their encounter with RP discontinuities. With the addition of randomly orientated simulated ablation lesions, followed by reinduction of fibrillatory activity, mean activation interval (AI) prolonged from a baseline level of 144.2 ms–160.3 ms (p < 0.001 in most comparisons). During fibrillatory activity, when parallel ablation lines were added to short RP regions, AI prolonged to 150.4 ms (p < 0.001), and when added to long RP regions, AI prolonged to 185.3 ms (p < 0.001). In all cases, AI prolongation after simulated ablation resulted from reduced number and/or from the isolation of local drivers, so that distant drivers in short RP regions activated long RP regions N:1, while distant drivers in long RP regions activated short RP regions at a relatively slow rate. ConclusionsAn automaton model was found useful to generate and test hypotheses concerning fibrillatory activity, which can then be validated in the clinical electrophysiology laboratory.

Comparison of Electrical and Ultrasound Neurostimulation in Rat Motor Cortex

Ultrasound (US) is known to non-invasively stimulate and modulate brain function; however, the mechanism of action is poorly understood. This study tested US stimulation of rat motor cortex (100 W/cm2, 200 kHz) in combination with epidural cortical stimulation. US directly evoked hindlimb movement. This response occurred even with short US bursts (3 ms) and had short latency (10 ms) and long refractory (3 s) periods. Unexpectedly, the epidural cortical stimulation hindlimb response was not altered during the 3-s refractory period of the US hindlimb response. This finding suggests that the US refractory period is not a general suppression of motor cortex, but rather the recovery time of a US-specific mechanism.