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Blocking Intermediate-Conductance Calcium-Activated Potassium Channels in the Macrophages Around Ganglionated Plexi Suppresses Atrial Fibrillation Vulnerability in Canines With Rapid Atrial Pacing.

ABSTRACT: Previous studies have indicated that ganglionated plexi (GP) function influences atrial fibrillation (AF) vulnerability, and intermediate-conductance calcium-activated potassium channels (SK4) have a close relationship with cardiomyocyte automaticity and the induction of AF. However, the effects of the SK4 inhibitor on GP function and AF vulnerability are unknown. Eighteen beagles were randomly divided into a control group (n = 6), rapid atrial pacing (RAP) group (n = 6), and triarylmethane-34 (TRAM-34, an SK4 inhibitor) group (n = 6). TRAM-34 (0.3 ml, 15 mmol/L) and saline were locally injected into GPs in the TRAM-34 group dogs and dogs from the other groups, respectively. After that, dogs in the RAP and TRAM-34 groups were subjected to RAP, and the neural activity of anterior right GP (ARGP) and atrial electrophysiology were measured. The levels of inflammatory cytokines and function of macrophages in the ARGP were measured in the three groups. At 10 min after TRAM-34 injection, ARGP activity and atrial electrophysiology did not significantly change. The atrial pacing shortened effective refractory period (ERP) values at all sites and increased the AF vulnerability and ARGP neural activity, while TRAM-34 reversed these changes. The levels of CD68 ⁺ cells, induced nitric oxide synthase (iNOS), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in the ARGP tissues were higher in the RAP group and TRAM-34 group than they were in the control group. Furthermore, the levels of the CD68 ⁺ cells, iNOS, and inflammatory cytokines in the ARGP tissues were higher in the pacing group than those in the TRAM-34 group. Based on these results, administration of TRAM-34 into the atrial GP can suppress GP activity and AF vulnerability during atrial pacing. The effects of TRAM-34 might be related to macrophage polarization and the inflammatory response of GP.

SUBMITTER: Ma Y

PROVIDER: S-EPMC9010666 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

Project description:The aim of our study was to investigate, whether enhancement of left atrial cryoablation by ablation of the autonomic nervous system of left atrium leads to influencing the outcomes of surgical treatment of atrial fibrillation in patients with structural heart disease undergoing open-heart surgery.The observed patient file consisted of 100 patients, who have undergone a combined open-heart surgery at our department between July 2012 and December 2014. The patients were indicated for the surgical procedure due to structural heart disease, and suffered from paroxysmal, persistent, or long-standing persistent atrial fibrillation. In all cases, left atrial cryoablation was performed in the extent of isolation of pulmonary veins, box lesion, connecting lesion with mitral annulus, amputation of the left atrial appendage and connecting lesion of the appendage base with left pulmonary veins. Furthermore, 35 of the patients underwent mapping and radiofrequency ablation of ganglionated plexi, together with discision and ablation of the ligament of Marshall (Group GP). A control group was consisted of 65 patients without ganglionated plexi intervention (Group LA). The main primary outcome was establishment and duration of sinus rhythm in the course of one-year follow-up.Evaluation of the number of patients with a normal sinus rhythm in per cent has shown comparable values in both groups (Group GP - 93.75%, Group LA - 86.67%, p = 0.485); comparable results were also observed in patients with normal sinus rhythm without anti-arrhythmic treatment in the 12th month (Group GP - 50%, Group LA - 47%, p = 0.306). We have not observed any relation between the recurrence of atrial fibrillation and the presence of a mitral valve surgery, or between the presence of a mitral and tricuspid valves surgery and between the left atrial diameter > 50 mm.Enhancement of left atrial cryoablation by gangionated plexi ablation did not influence the outcomes of surgical ablation due to atrial fibrillation in our population in the course of 12-month follow-up.The study was approved retrospectively by the Ethics Committee of the University Hospital Ostrava ( reference number 867/2016).

Project description:Sustained atrial tachycardia leads to multiple molecular and cellular effects collectively defined as atrial tachycardia remodeling (ATR). ATR is thought to play a major role in the self-perpetuating nature of atrial fibrillation (AF) and has been a subject of intense research in large mammalian models of AF. Recently, rodents are increasingly used to gain insight on the pathophysiology AF. However, little is known regarding the effects of rapid pacing on the atria of rats and mice mainly due to technical challenges in electrophysiological studies of unanesthetized rodents. Using an implantable device for electrophysiological studies in unanesthetized rodents we examine, on a daily basis, the effects of continuous rapid atrial pacing (RAP) for at least 4 consecutive days on the developed AF substrate of Sprague-Dawley rats and C57BL6 mice. AF induction protocol consisted 10 aggressive bursts (20 seconds, double diastolic threshold, 10 ms cycle length [CL]). This protocol failed to induce AF at baseline in both species, but repeatedly induced AF episodes in rats following 2 days of sustained RAP. Microarray study of left atrial tissue from rats exposed for 2 days to RAP (70 ms CL) vs control pacing (140 ms CL) identified 304 differentially expressed genes (155 upregulated and 149 downregulated). Real-time qt-PCR confirmed the validity of the microarray. Enrichment analysis and comparison with a dataset of atrial tissue from AF patients revealed indications of increased carbohydrate metabolism, and changes in pathways that are thought to have critical role in human AF including TGF-beta and IL-6 signaling. Among 19 commonly affected genes in comparison with human AF, downregulation of FOXP1 and upregulation of the KCNK2 gene encoding the Kir2.1 potassium channel were conspicuous finding suggesting NFAT activation. Further results in line with NFAT activation included reduced expression of MIR-26, MIR-101, which were linked to upregulation of the KCNK2 in human AF. Our results demonstrate electrophysiological evidence for AF promoting effects of RAP in rats and some important molecular similarities between the effects of RAP in large and small mammalian models. The effects of atrial tachypacing are well documented in large mammals but very little is know regarding the effects of tacypacing on the rodent atria.

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Blocking Intermediate-Conductance Calcium-Activated Potassium Channels in the Macrophages Around Ganglionated Plexi Suppresses Atrial Fibrillation Vulnerability in Canines With Rapid Atrial Pacing.

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