Epicardial placement of human placental membrane allografts in coronary artery bypass graft surgery is associated with reduced postoperative atrial fibrillation: a pilot study for a future multi-center randomized controlled trial.

BACKGROUND: Post-operative atrial fibrillation (POAF) occurs in up to 40% of patients following coronary artery bypass grafting (CABG) and is associated with a higher risk of stroke and mortality. This study investigates how POAF may be mitigated by epicardial placement of aseptically processed human placental membrane allografts (HPMAs) before pericardial closure in CABG surgery. This study was conducted as a pilot feasibility study to collect preliminary for a forthcoming multi-center randomized controlled trial. METHODS: This retrospective observational study of patients undergoing CABG surgery excluded patients with pre-operative heart failure, chronic kidney disease, or a history of atrial fibrillation. The "treatment" group (n = 24) had three HPMAs placed epicardially following cardiopulmonary bypass decannulation but before partial pericardial approximation and chest closure. The only difference in clinical protocol for the control group (n = 54) was that they did not receive HPMA. RESULTS: HPMA-treated patients saw a significant, greater than four-fold reduction in POAF incidence compared to controls (35.2-8.3%, p = 0.0136). Univariate analysis demonstrated that HPMA treatment was associated with an 83% reduction in POAF (OR = 0.17, p = 0.0248). Multivariable analysis yielded similar results (OR = 0.07, p = 0.0156) after controlling for other covariates. Overall length of stay (LOS) between groups was similar, but ICU LOS trended lower with HPMA treatment (p = 0.0677). Post-operative inotrope and vasopressor requirements were similar among groups. There was no new-onset post-operative heart failure, stroke, or death reported up to thirty days in either group. CONCLUSIONS: Epicardial HPMA placement can be a simple intervention at the end of CABG surgery that may provide a new approach to reduce post-operative atrial fibrillation by modulating local inflammation, possibly reducing ICU and hospital stay, and ultimately improving patient outcomes.

Posterior pericardiotomy and the prevention of post-operative atrial fibrillation and cardiac tamponade in isolated coronary artery bypass grafting - A retrospective analysis.

BACKGROUND: Post-Operative Atrial Fibrillation (POAF) is the most frequent complication of cardiac surgery and is associated with reduced survival, increased rates of cognitive changes and cerebrovascular accidents, heart failure, renal dysfunction, infection, length of stay and hospital costs. Cardiac tamponade although less common, carries high morbidity and mortality. Shed mediastinal blood in the pericardial space is a major source of intrapericardial oxidative stress and inflammation that triggers POAF. The utilisation of a posterior pericardiotomy (PP) aims to shunt blood from pericardium into the pleural space and have a role in the prevention of POAF as well as cardiac tamponade. METHODS: 2168 patients had undergone isolated Coronary Artery Bypass Grafting at Royal Hobart Hospital from 2008 to 2022. They were divided into PP group vs. control group. Patient baseline demographics, intraoperative data and post-operative outcomes were reviewed retrospectively. RESULTS: Total incidence of new POAF and cardiac tamponade was 24% and 0.74% respectively. Primary outcome of both the incidence of POAF (20.2% vs. 26.3%, p < 0.05) and Cardiac Tamponade (0% vs. 1.1%, p < 0.05) were less in the pericardiotomy group. A subgroup analysis of patients with recent myocardial infarction showed reduced incidence of POAF in the PP group (p < 0.05). Increasing age, Body Mass Index, poor left ventricular ejection fraction (EF < 30%) and return to theatre were independent predictors of developing POAF. There were similar rates of return to theatre for bleeding however, no cases of tamponade in the pericardiotomy group. There were no complications attributable to left posterior pericardiotomy and the time added to the duration of surgery was minimal. CONCLUSION: Posterior pericardiotomy is associated with a significant reduction in the incidence of POAF and cardiac tamponade which is safe and efficient.

Exenatide reduces atrial fibrillation susceptibility by inhibiting hKv1.5 and hNav1.5 channels.

Exenatide, a promising cardioprotective agent, protects against cardiac structural remodeling and diastolic dysfunction. Combined blockade of sodium and potassium channels is valuable for managing atrial fibrillation (AF). Here, we explored whether exenatide displayed anti-AF effects by inhibiting human Kv1.5 and Nav1.5 channels. We used the whole-cell patch-clamp technique to investigate the effects of exenatide on hKv1.5 and hNav1.5 channels expressed in human embryonic kidney 293 cells and studied the effects of exenatide on action potential (AP) and other cardiac ionic currents in rat atrial myocytes. Additionally, an electrical mapping system was used to explore the effects of exenatide on electrical properties and AF activity in isolated rat hearts. Finally, a rat AF model, established using acetylcholine and calcium chloride, was employed to evaluate the anti-AF potential of exenatide in rats. Exenatide reversibly suppressed IKv1.5 with IC50 of 3.08 µM, preferentially blocked the hKv1.5 channel in its closed state, and positively shifted the voltage-dependent activation curve. Exenatide also reversibly inhibited INav1.5 with IC50 of 3.30 µM, negatively shifted the voltage-dependent inactivation curve, and slowed its recovery from inactivation with significant use-dependency at 5 and 10 Hz. Furthermore, exenatide prolonged AP duration and suppressed the sustained K+ current (Iss) and transient outward K+ current (Ito), but without inhibition of L-type Ca2+ current (ICa,L) in rat atrial myocytes. Exenatide prevented AF incidence and duration in rat hearts and rats. These findings demonstrate that exenatide inhibits IKv1.5 and INav1.5in vitro and reduces AF susceptibility in isolated rat hearts and rats.

Efficacy and Safety of Botulinum Toxin Type A for the Prevention of Postoperative Atrial Fibrillation.

BACKGROUND: Postoperative atrial fibrillation (POAF) is associated with increased morbidity and mortality. Epicardial injection of botulinum toxin may suppress POAF. OBJECTIVES: This study sought to assess the safety and efficacy of AGN-151607 for the prevention of POAF after cardiac surgery. METHODS: This phase 2, randomized, placebo-controlled trial assessed the safety and efficacy of AGN-151607, 125 U and 250 U vs placebo (1:1:1), for the prevention of POAF after cardiac surgery. Randomization was stratified by age (<65, ≥65 years) and type of surgery (nonvalvular/valve surgery). The primary endpoint was the occurrence of continuous AF ≥30 seconds. RESULTS: Among 312 modified intention-to-treat participants (placebo, n = 102; 125 U, n = 104; and 250 U, n = 106), the mean age was 66.9 ± 6.8 years; 17% were female; and 64% had coronary artery bypass graft (CABG) only, 12% had CABG + valve, and 24% had valve surgery. The primary endpoint occurred in 46.1% of the placebo group, 36.5% of the 125-U group (relative risk [RR] vs placebo: 0.80; 95% CI: 0.58-1.10; P = 0.16), and 47.2% of the 250-U group (RR vs placebo: 1.04; 95% CI: 0.79-1.37; P = 0.78). The primary endpoint was reduced in the 125-U group in those ≥65 years of age (RR: 0.64; 95% CI: 0.43-0.94; P = 0.02) with a greater reduction in CABG-only participants ≥65 years of age (RR: 0.49; 95% CI: 0.27-0.87; P = 0.01). Rehospitalization and rates of adverse events were similar across the 3 groups. CONCLUSIONS: There were no significant differences in the rate of POAF with either dose compared with placebo; however, there was a lower rate of POAF in participants ≥65 years undergoing CABG only and receiving 125 U of AGN-151607. These hypothesis-generating findings require investigation in a larger, adequately powered randomized clinical trial. (Botulinum Toxin Type A [AGN-151607] for the Prevention of Post-operative Atrial Fibrillation in Adult Participants Undergoing Open-chest Cardiac Surgery [NOVA]; NCT03779841); A Phase 2, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Dose Ranging Study to Evaluate the Efficacy and Safety of Botulinum Toxin Type A [AGN 151607] Injections into the Epicardial Fat Pads to Prevent Post-Operative Atrial Fibrillation in Patients Undergoing Open-Chest Cardiac Surgery; 2017-004399-68).

Efficacy and safety of colchicine for atrial fibrillation prevention: An updated meta-analysis of randomized controlled trials.

BACKGROUND: Atrial fibrillation (AF), the most common arrhythmia, is closely related to inflammation. Colchicine has the potent anti-inflammatory effects. Several randomized clinical trials (RCTs) have evaluated the efficacy and safety of colchicine in the prevention of AF but the results are inconsistent. OBJECTIVE: The purpose of our study was to evaluate the impact of colchicine on AF. METHOD AND RESULTS: PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov were searched for related studies until Jan 8, 2024. A total of 17 studies including 16,238 participants were included. Compared to the placebo group, there were fewer incidences of AF in the colchicine group (RR: 0.75, 95%CI: 0.68-0.83, P < 0.001). The incidence of overall adverse events and overall gastrointestinal intolerance did not differ significantly between the two groups. However, diarrhea, nausea, and discontinuation occurred more frequently in patients treated with colchicine. CONCLUSION: Colchicine can prevent patients from the incidence of AF, regardless of the mean age of patients, type of atrial fibrillation, maintenance dose, duration of colchicine use, cumulative daily dose, and follow-up time with more diarrhea, nausea and discontinuation. These adverse events can be avoided by low doses (0.5 mg once daily) and long period time of colchicine use.

Prevention of esophageal lesions during atrial fibrillation catheter ablation using esophageal temperature monitoring: A systematic review and meta-analysis.

INTRODUCTION: The use of esophageal temperature monitoring (ETM) for the prevention of esophageal injury during atrial fibrillation (AF) ablation is often advocated. However, evidence supporting its use is scarce and controversial. We therefore aimed to review the evidence assessing the efficacy of ETM for the prevention of esophageal injury. METHODS: We performed a meta-analysis and systematic review of the available literature from inception to December 31, 2022. All studies comparing the use of ETM, versus no ETM, during radiofrequency (RF) AF ablation and which reported the incidence of endoscopically detected esophageal lesions (EDELs) were included. RESULTS: Eleven studies with a total of 1112 patients undergoing RF AF ablation were identified. Of those patients, 627 were assigned to ETM (56%). The overall incidence of EDELs was 9.8%. The use of ETM during AF ablation was associated with a non significant increase in the incidence of EDELs (12.3% with ETM, vs. 6.6 % without ETM, odds ratio, 1.44, 95%CI, 0.49, 4.22, p = .51, I2 = 72%). The use of ETM was associated with a significant increase in the energy delivered specifically on the posterior wall compared to patients without ETM (mean power difference: 5.13 Watts, 95% CI, 1.52, 8.74, p = .005). CONCLUSIONS: The use of ETM does not reduce the incidence of EDELs during RF AF ablation. The higher energy delivered on the posterior wall is likely attributable to a false sense of safety that may explain the lack of benefit of ETM. Further randomized controlled trials are needed to provide conclusive results.

Partial CArdiac Denervation to Prevent Postoperative Atrial Fibrillation After Coronary Artery Bypass Grafting (pCAD-POAF): Study Protocol for a Randomized Controlled Trial.

Postoperative atrial fibrillation (POAF) is commonly seen in patients who underwent coronary artery bypass grafting (CABG), increasing the risk of morbidity, mortality, and hospital expenses. This study aimed to evaluate the effect of partial cardiac denervation, which is achieved by cutting off the ligament of Marshall and resecting the fat pad along the Waterston groove, on the prevention of POAF after CABG. Patients planned for CABG at our center were screened for eligibility in this study. A total of 430 patients were randomized into the intervention (partial cardiac denervation) group and control group. Intraoperative high-frequency electrical stimulation and further histologic analysis were performed in a certain number of patients to confirm the existence of ganglia. All patients were continuously monitored for the incidence of POAF through an electrophysiologic device until the sixth day postoperatively, and required to complete a 30-day follow-up (12-lead electrocardiogram and echocardiogram assessment) after discharge. The primary end point is the incidence of POAF, whereas the secondary end points are the cost-effectiveness and safety outcomes. In conclusion, this trial will evaluate whether partial cardiac denervation through cutting off the ligament of Marshall and resecting the fat pad along the Waterston groove can reduce the incidence of POAF after CABG. If this procedure is revealed to be effective and safe, it may provide a potential therapeutic approach to prevent POAF in this group of patients.

Effect of physical activity on incident atrial fibrillation in individuals with varying duration of diabetes: a nationwide population study.

BACKGROUND: Diabetes mellitus (DM) duration affects incident atrial fibrillation (AF) risk; the effect of physical activity on mitigating AF risk related to varying DM duration remains unknown. We assessed the effect of physical activity on incident AF in patients with DM with respect to known DM duration. METHODS: Patients with type 2 DM who underwent the Korean National Health Insurance Service health examination in 2015-2016 were grouped by DM duration: new onset and < 5, 5-9, and ≥ 10 years. Physical activity was classified into four levels: 0, < 500, 500-999, 1,000-1,499, and ≥ 1,500 metabolic equivalent task (MET)-min/week, with the primary outcome being new-onset AF. RESULTS: The study enrolled 2,392,486 patients (aged 59.3 ± 12.0 years, 39.8% female) with an average follow-up of 3.9 ± 0.8 years and mean DM duration of 5.3 ± 5.1 years. Greater physical activity was associated with a lower AF risk. Lowering of incident AF risk varied with different amounts of physical activity in relation to known DM duration. Among patients with new-onset DM, DM duration < 5 years and 5-9 years and 1,000-1,499 MET-min/week exhibited the lowest AF risk. Physical activity ≥ 1,500 MET-min/week was associated with the lowest incident AF risk in patients with DM duration ≥ 10 years (by 15%), followed DM duration of 5-9 years (12%) and < 5 years (9%) (p-for-interaction = 0.002). CONCLUSIONS: Longer DM duration was associated with a high risk of incident AF, while increased physical activity generally reduced AF risk. Engaging in > 1,500 MET-min/week was associated with the greatest AF risk reduction in patients with longer DM duration, highlighting the potential benefits of higher activity levels for AF prevention.

Stroke prevention strategies for cardiac surgery: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Stroke is a much-feared complication of cardiac surgery, but existing literature on preventive strategies is fragmented. Hence, a systematic review and meta-analysis of stroke prevention strategies for cardiac surgery was conducted. METHODS: An electronic literature search was conducted to retrieve randomized controlled trials (RCTs) investigating perioperative interventions for cardiac surgery, with stroke as an outcome. Random-effects meta-analyses were conducted to generate risk ratios (RRs), 95% confidence intervals (95% CI), and forest plots. Descriptive analysis and synthesis of literature was conducted for interventions not amenable to meta-analysis, focusing on risks of stroke, myocardial infarction and study-defined major adverse cardiovascular events (MACE). RESULTS: Fifty-six RCTs (61 894 patients) were retrieved. Many included trials were underpowered to detect differences in stroke risk. Among pharmacological therapies, only preoperative amiodarone was shown to reduce stroke risk in one trial. Concomitant left atrial appendage closure (LAAC) significantly reduced stroke risk (RR = 0.55, 95% CI = 0.36-0.84, P = 0.006) in patients with preoperative atrial fibrillation, and there was no difference in on-pump versus off-pump coronary artery bypass grafting (CABG) (RR = 0.94, 95% CI = 0.64-1.37, P = 0.735). Much controversy exists in literature on the timing of carotid endarterectomy relative to CABG in patients with severe carotid stenosis. The use of preoperative remote ischemic preconditioning was not found to reduce rates of stroke or MACE. CONCLUSION: This review presents a comprehensive synthesis of existing interventions for stroke prevention in cardiac surgery, and identifies gaps in research which may benefit from future, large-scale RCTs. LAAC should be considered to reduce stroke incidence in patients with preoperative atrial fibrillation.

Impact of maintaining serum potassium concentration ≥ 3.6mEq/L versus ≥ 4.5mEq/L for 120 hours after isolated coronary artery bypass graft surgery on incidence of new onset atrial fibrillation: Protocol for a randomized non-inferiority trial.

BACKGROUND: Atrial Fibrillation After Cardiac Surgery (AFACS) occurs in about one in three patients following Coronary Artery Bypass Grafting (CABG). It is associated with increased short- and long-term morbidity, mortality and costs. To reduce AFACS incidence, efforts are often made to maintain serum potassium in the high-normal range (≥ 4.5mEq/L). However, there is no evidence that this strategy is efficacious. Furthermore, the approach is costly, often unpleasant for patients, and risks causing harm. We describe the protocol of a planned randomized non-inferiority trial to investigate the impact of intervening to maintain serum potassium ≥ 3.6 mEq/L vs ≥ 4.5 mEq/L on incidence of new-onset AFACS after isolated elective CABG. METHODS: Patients undergoing isolated CABG at sites in the UK and Germany will be recruited, randomized 1:1 and stratified by site to protocols maintaining serum potassium at either ≥ 3.6 mEq/L or ≥ 4.5 mEq/L. Participants will not be blind to treatment allocation. The primary endpoint is AFACS, defined as an episode of atrial fibrillation, flutter or tachycardia lasting ≥ 30 seconds until hour 120 after surgery, which is both clinically detected and electrocardiographically confirmed. Assuming a 35% incidence of AFACS in the 'tight control group', and allowing for a 10% loss to follow-up, 1684 participants are required to provide 90% certainty that the upper limit of a one-sided 97.5% confidence interval (CI) will exclude a > 10% difference in favour of tight potassium control. Secondary endpoints include mortality, use of hospital resources and incidence of dysrhythmias not meeting the primary endpoint (detected using continuous heart rhythm monitoring). DISCUSSION: The Tight K Trial will assess whether a protocol to maintain serum potassium ≥ 3.6 mEq/L is non inferior to maintaining serum potassium ≥ 4.5 mEq/L in preventing new-onset AFACS after isolated CABG. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04053816. Registered on 13 August 2019. Last update 7 January 2021.

Administration of USP7 inhibitor p22077 alleviates Angiotensin II (Ang II)-induced atrial fibrillation in Mice.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is an important contributor to mortality and morbidity. Ubquitin-specific protease 7 (USP7), one of the most abundant ubiquitin-specific proteases (USP), participated in many cellular events, such as cell proliferation, apoptosis, and tumourigenesis. However, its role in AF remains unknown. Here, the mice were treated with Ang II infusion to induce the AF model. Echocardiography was used to measure the atrial diameter. Electrical stimulation was programmed to measure the induction and duration of AF. The changes in atrial remodeling were measured using routine histologic analysis. Here, a significant increase in USP7 expression was observed in Ang II-stimulated atrial cardiomyocytes and atrial tissues, as well as in atrial tissues from patients with AF. The administration of p22077, the inhibitor of USP7, attenuated Ang II-induced inducibility and duration of AF, atrial dilatation, connexin dysfunction, atrial fibrosis, atrial inflammation, and atrial oxidase stress, and then inhibited the progression of AF. Mechanistically, the administration of p22077 alleviated Ang II-induced activation of TGF-ß/Smad2, NF-κB/NLRP3, NADPH oxidases (NOX2 and NOX4) signals, the up-regulation of CX43, ox-CaMKII, CaMKII, Kir2.1, and down-regulation of SERCA2a. Together, this study, for the first time, suggests that USP7 is a critical driver of AF and revealing USP7 may present a new target for atrial fibrillation therapeutic strategies.

Inhibition of the P2X7 receptor prevents atrial proarrhythmic remodeling in experimental post-operative atrial fibrillation.

BACKGROUND: Post-operative atrial fibrillation (POAF) is a common complication in patients undergoing cardiac surgery. The purinergic receptor P2X7 (P2X7R) is involved in some cardiovascular diseases, whereas its effects on atrial fibrillation (AF) are unclear. OBJECTIVE: This study was to assess the effect of P2X7R on atrial arrhythmogenic remodeling in the rat model of sterile pericarditis (SP). METHODS: Male Sprague-Dawley (SD) rats were used to induce the SP model. Electrocardiogram, atrial electrophysiological protocol, histology, mRNA sequencing, real-time quantitative PCR, western blot, and Elisa assay were performed. RESULTS: SP significantly up-regulated P2X7R expression; increased AF susceptibility; reduced the protein expression of ion channels including Nav1.5, Cav1.2, Kv4.2, Kv4.3, and Kv1.5; caused atrial fibrosis; increased norepinephrine (NE) level in plasma; promoted the production of inflammatory cytokines such as TNF-α, IL-1ß, and IL-6; increased the accumulation of immune cells (CD68- and MPO- positive cells); and activated NLRP3 inflammasome signaling pathway. P2X7R antagonist Brilliant Blue G (BBG) mitigated SP-induced alterations. The mRNA sequencing demonstrated that BBG prevented POAF mainly by regulating the immune system. In addition, another selective P2X7R antagonist A740003, and IL-1R antagonist anakinra also reduced AF inducibility in the SP model. CONCLUSIONS: P2X7R inhibition prevents SP-induced atrial proarrhythmic remodeling, which is closely associated with the improvement of inflammatory changes, ion channel expression, atrial fibrosis, and sympathetic activation. The findings point to P2X7R inhibition as a promising target for AF (particularly POAF) and perhaps other conditions.

Flecainide to prevent atrial arrhythmia after patent foramen ovale closure, Rationale and design of the randomized AFLOAT study.

INTRODUCTION: Atrial arrhythmia is the most common complication of patent foramen ovale (PFO) closure. The real incidence of post-PFO closure atrial arrhytmia and whether this complication can be prevented is unknown. METHODS/DESIGN: The Assessment of Flecainide to Lower the PFO closure risk of Atrial fibrillation or Tachycardia (AFLOAT) trial is a prospective, national, multicentre, randomized, open-label, superiority trial with a blind evaluation of all the endpoints (PROBE design). A total of 186 patients are randomized in a 1:1:1 ratio immediately after PFO closure to receive Flecainide (150 mg per day in a single sustained-release (SR) dose) for 6 months (Group 1), Flecainide (150 mg per day in a single SR dose) for 3 months (Group 2), or no additional treatment (standard of care) for 6 months (Group 3). The primary endpoint is the percentage of patients with at least one episode of symptomatic or asymptomatic atrial arrhythmia episode (≥30 s) recorded within 3 months after PFO closure on long-term monitoring with an insertable cardiac monitor. Whether 3 months of treatment is sufficient compared to 6 months will be analysed as a secondary objective of the study. CONCLUSION: AFLOAT is the first trial to test the hypothesis that a short treatment with oral Flecainide can prevent the new-onset of atrial arrhythmia after PFO closure. CLINICAL TRIAL REGISTRATION: NCT05213104 (clinicaltrials.gov).

Inhibition of the acetylcholine-regulated potassium current prevents transient apnea-related atrial arrhythmogenic changes in a porcine model.

BACKGROUND: More than 50% of patients with atrial fibrillation (AF) suffer from sleep disordered breathing (SDB). Obstructive respiratory events contribute to a transient, vagally mediated atrial arrhythmogenic substrate, which is resistant to most available antiarrhythmic drugs. OBJECTIVE: The purpose of this study was to investigate the effect of pharmacologic inhibition of the G-protein-gated acetylcholine-regulated potassium current (IK,ACh) with and without acute autonomic nervous system activation by nicotine in a pig model for obstructive respiratory events. METHODS: In 21 pigs, SDB was simulated by applying an intermittent negative upper airway pressure (INAP). AF inducibility and atrial effective refractory periods (aERPs) were determined before and during INAP by an S1S2 atrial pacing-protocol. Pigs were randomized into 3 groups-group 1: vehicle (n = 4); group 2: XAF-1407 (IK,ACh inhibitor) (n = 7); and group 3: nicotine followed by XAF-1407 (n = 10). RESULTS: In group 1, INAP shortened aERP (ΔaERP -42.6 ms; P = .004) and transiently increased AF inducibility from 0% to 31%. In group 2, XAF-1407 prolonged aERP by 25.2 ms (P = .005) during normal breathing and prevented INAP-induced aERP shortening (ΔaERP -3.6 ms; P = .3) and AF inducibility. In group 3, INAP transiently shortened aERP during nicotine perfusion (ΔaERP -33.6 ms; P = .004) and increased AF inducibility up to 61%, which both were prevented by XAF-1407. CONCLUSION: Simulated obstructive respiratory events transiently shorten aERP and increase AF inducibility, which can be prevented by the IK,ACh-inhibitor XAF-1407. XAF-1407 also prevents these arrhythmogenic changes induced by obstructive respiratory events during nicotine perfusion. Whether IK,ACh channels represent a target for SDB-related AF in humans warrants further study.

Inactivation of the NLRP3 inflammasome mediates exosome-based prevention of atrial fibrillation.

Rationale: Extracellular vesicles (EVs) from human explant-derived cells injected directly into the atria wall muscle at the time of open chest surgery reduce atrial fibrosis, atrial inflammation, and atrial fibrillation (AF) in a rat model of sterile pericarditis. Albeit a promising solution to prevent postoperative AF, the mechanism(s) underlying this effect are unknown and it is not clear if this benefit is dependent on EV dose. Methods: To determine the dose-efficacy relationship of EVs from human explant-derived cells in a rat model of sterile pericarditis. Increasing doses of EVs (106, 107, 108 or 109) or vehicle control were injected into the atria of middle-age male Sprague-Dawley rats at the time of talc application. A sham control group was included to demonstrate background inducibility. Three days after surgery, all rats underwent invasive electrophysiological testing prior to sacrifice. Results: Pericarditis increased the likelihood of inducing AF (p<0.05 vs. sham). All doses decreased the probability of inducing AF with maximal effects seen after treatment with the highest dose (109, p<0.05 vs. vehicle). Pericarditis increased atrial fibrosis while EV treatment limited the effect of pericarditis on atrial fibrosis with maximal effects seen after treatment with 108 or 109 EVs. Increasing EV dose was associated with progressive decreases in pro-inflammatory cytokine content, inflammatory cell infiltration, and oxidative stress. EVs decreased NLRP3 (NACHT, LRR, and PYD domains-containing protein-3) inflammasome activation though a direct effect on resident atrial fibroblasts and macrophages. This suppressive effect was exclusive to EVs produced by heart-derived cells as application of EVs from bone marrow or umbilical cords did not alter NLRP3 activity. Conclusions: Intramyocardial injection of incremental doses of EVs at the time of open chest surgery led to progressive reductions in atrial fibrosis and inflammatory markers. These effects combined to render atria resistant to the pro-arrhythmic effects of pericarditis which is mechanistically related to suppression of the NLRP3 inflammasome.

In noncardiac thoracic surgery, low-dose colchicine did not reduce AF or myocardial injury after noncardiac surgery at 14 d.

SOURCE CITATION: Conen D, Ke Wang M, Popova E, et al; COP-AF Investigators. Effect of colchicine on perioperative atrial fibrillation and myocardial injury after non-cardiac surgery in patients undergoing major thoracic surgery (COP-AF): an international randomised trial. Lancet. 2023;402:1627-1635. 37640035.