Atrial Effective Refractory Period Research Articles

The influence of subclavian ansae stimulation on cardiac hemodynamics and electrophysiology in atrial fibrillation- exploring a novel target for neuromodulation in atrial fibrillation (SAS-AF study)

Abstract Background Sympathetic nervous system activation plays a significant role in arrhythmia development and maintenance.Neuromodulation techniques such as stellate ganglion block and sympathectomy, are limited by off-target side effects and complex targeting.The Subclavian Ansae (SA,a nerve cord encircling the subclavian artery) may be an intravascular site allowing specific targeting of the cardiac afferent sympathetic system.Preclinical studies have revealed increased sympathetic tone upon selective SA stimulation. Objective We sought to define for the first time in Humans the functional anatomy and physiology of Subclavian Ansae via a percutaneous approach. Methods A prior cadaveric study defined the anatomical course of the subclavian ansae, encircling the subclavian arteries and connecting the middle cervical ganglia to inferior cervical ganglia/stellate.Patients undergoing catheter ablation for paroxysmal atrial fibrillation(pAF) under general anesthesia were prospectively recruited for the study. Subclavian Ansae stimulation (SAS) was performed on the left and/or the right (L/SAS ± R/SAS) within the subclavian artery using the TactiCath Ablation Catheter introduced via a femoral arterial sheath. Stimulation parameters included up to 70 V output, 10 Hz frequency, and pulse width of 2-4ms for 20-30s. Test pulses ensured no cardiac capture during stimulation. Participants discontinued antiarrhythmic agents at least 4-5 half-lives prior to the procedure. Invasive arterial blood pressure(BP), heart rate (HR), and electrophysiological parameters were recorded in response to selective stimulation. An increase of ten percent or more in either arterial blood pressure(BP) or heart rate(HR) from the initial baseline measurements was deemed a positive response. Results 15 patients (62±11 years, 9 males, pAF duration 51±24 months) underwent the simulation protocol prior to their clinical AF ablation procedure. A positive hemodynamic response was observed in nine patients, and among them, arrhythmia was inducible in 3 patients (atrial fibrillation in 2 patients and repeated runs of atrial ectopy in 1 patient) in response to SAS. Mean sinus cycle length(CL) decreased(chronotropic) after stimulation,particularly with a significant change observed in response to R/SAS. Additionally,L/SAS led to a notable increase in mean systolic (SBP) and diastolic(DBP) blood pressure (inotropic). While the mean right atrial effective refractory period (ERP) did not significantly decrease after stimulation, there was a demonstrable difference in interatrial conduction time(dromotropy). Six patients, including the initial 3 subjected to low-energy stimulation (up to 12V), did not exhibit an adrenergic response. Conclusion This study represents the first successful application of selective SAS in humans. A heterogeneity in electrophysiological modulation by SAS exists, including laterality.The SA is a potential important target for targeted autonomic neuromodulation therapy

Catheter-based pulmonary vein isolation fails to prevent transient atrial arrhythmogenic changes related to acute obstructive respiratory events in a porcine model.

Pulmonary vein isolation (PVI) is the corner stone of modern rhythm control strategies in patients with atrial fibrillation (AF). Sleep-disordered breathing (SDB) is prevalent in more than 50% of patients undergoing AF ablation, and studies have indicated a greater recurrence rate after PVI in patients with SDB. Herein, we study the effect of catheter-based PVI on AF in a pig model for SDB. In 11 sedated spontaneously breathing pigs, obstructive apnoeas were simulated by 75 s of intermittent negative upper airway pressure (INAP) applied by a negative pressure device connected to the endotracheal tube. Intermittent negative upper airway pressures were performed before and after PVI. AF-inducibility and atrial effective refractory periods (aERPs) were determined before and during INAP by programmed atrial stimulation. Pulmonary vein isolation prolonged the aERP by 48 ± 27 ms in the right atrium (RA) (P < 0.0001) and by 40 ± 34 ms in the left atrium (LA) (P = 0.0004). Following PVI, AF-inducibility dropped from 28 ± 26% to 0% (P = 0.0009). Intermittent negative upper airway pressure was associated with a transient aERP-shortening (ΔaERP) in both atria, which was not prevented by PVI (INAP indued ΔaERP after PVI in the RA: -57 ± 34 ms, P = 0.0002; in the LA: -42 ± 24 ms, P < 0.0001). Intermittent negative upper airway pressure was associated with a transient increase in AF-inducibility (from 28 ± 26% to 69 ± 21%; P = 0.0008), which was not attenuated by PVI [INAP-associated AF-inducibility after PVI: 58 ± 33% (P = 0.5)]. Transient atrial arrhythmogenic changes related to acute obstructive respiratory events are not prevented by electrical isolation of the pulmonary veins, which partially explains the increased AF recurrence in patients with SDB after PVI procedures.

The SK4 channel allosteric blocker, BA6b9, reduces atrial fibrillation substrate in rats with reduced ejection fraction.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is strongly associated with several comorbidities including heart failure (HF). AF in general, and specifically in the context of HF, is progressive in nature and associated with poor clinical outcomes. Current therapies for AF are limited in number and efficacy and do not target the underlying causes of atrial remodeling such as inflammation or fibrosis. We previously identified the calcium-activated SK4 K+ channels, which are preferentially expressed in the atria relative to the ventricles in both rat and human hearts, as attractive druggable target for AF treatment. Here, we examined the ability of BA6b9, a novel allosteric inhibitor of SK4 channels that targets the specific calmodulin-PIP2 binding domain, to alter AF susceptibility and atrial remodeling in a systolic HF rat postmyocardial infarction (post-MI) model. Daily BA6b9 injection (20 mg/kg/day) for 3 weeks starting 1-week post-MI prolonged the atrial effective refractory period, reduced AF induction and duration, and dramatically prevented atrial structural remodeling. In the post-MI left atrium (LA), pronounced upregulation of the SK4 K+ channel was observed, with corresponding increases in collagen deposition, α-SMA levels, and NLRP3 inflammasome expression. Strikingly, BA6b9 treatment reversed these changes while also significantly reducing the lateralization of the atrial connexin Cx43 in the LA of post-MI rats. Our findings indicate that the blockade of SK4 K+ channels using BA6b9 not only favors rhythm control but also remarkably reduces atrial structural remodeling, a property that is highly desirable for novel AF therapies, particularly in patients with comorbid HF.

Preventing Atrial Fibrillation in Hypertrophic Cardiomyopathy using Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin Receptor Blockers (ARBs)

Hypertrophic cardiomyopathy (HCM), a genetic cardiovascular disease, is the leading cause of cardiac death in young people, often due to atrial fibrillation (AF). AF is generally treated using antiarrhythmics and anticoagulants, which have adverse side effects after long-term use, and are therefore unsuitable for young HCM patients. AF is characterized by a rapid and irregular atrial heartbeat, marked by a short action potential duration and atrial effective refractory period in atrial cardiomyocytes. Prior studies have indicated that the renin-angiotensin system is involved in lowering both, so it has been hypothesized that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), which inhibit the renin-angiotensin system, could prevent AF. Therefore, in this study, we propose a research protocol to examine the viability of ACE inhibitors and ARBs as prophylactic measures against the development of AF in HCM patients. To test this, we suggest extracting atrial cardiomyocytes from HCM patients by performing enzyme dissociation on myocardial tissue. The isolated cardiomyocytes will then be treated in vitro with an ACE inhibitor, an ARB, a combination of both, or a control saline solution, and the patch-clamp technique will be used to determine the frequency and duration of their action potentials. We expect action potential duration and atrial effective refractory period to be longer in treated cells, while neither medication will provide a greater advantage, and, as prior research suggests, the combination will not yield significant benefits. The study will continue by testing the effects of ACE inhibitors and ARBs on the function of atrial myocardial organoids created from differentiated stem cells with an HCM mutation. The results of this study could present a new preventative measure against AF for HCM patients which would be safe for long-term use.

LncRNA-056298 Regulates GAP43 and Promotes Cardiac Intrinsic Autonomic Nerve Remodelling in a Canine Model of Atrial Fibrillation Induction after Ganglionated Plexus Ablation.

Cardiac intrinsic autonomic nerve remodelling has been reported to play an important role in the recurrence of atrial fibrillation after radiofrequency ablation, which significantly affects the long-term efficacy of this procedure. lncRNAs have been shown to interact in the pathological processes underlying heart diseases. However, the roles and mechanisms of lncRNAs in cardiac intrinsic autonomic nerve remodelling during atrial fibrillation reduction after ganglionated plexus ablation remain unknown. The aim of this study was to investigate the mechanism by which lncRNA- 056298 modulates GAP43 to affect cardiac intrinsic autonomic nerve remodelling and facilitate the induction of atrial fibrillation after ganglionated plexus ablation. A canine model of right atrial ganglionated plexus ablation was established. The atrial electrophysiological characteristics and neural markers were detected before and after 6 months of ganglionated plexus ablation. High-throughput sequencing was used to screen differentially expressed lncRNAs in target atrial tissues, and lncRNA- 056298 was selected to further explore its effects and mechanisms on cardiac intrinsic autonomic nerve remodelling. The induction rate of atrial fibrillation increased in dogs after ganglionated plexus ablation. Overexpression of lncRNA-056298 by lentivirus can shorten the atrial effective refractory period and increase the induction of atrial fibrillation. lncRNA- 056298 promoted cardiac intrinsic autonomic nerve remodelling via endogenous competition with cfa-miR-185 to induce transcription of its target gene GAP43, thereby affecting the induction of atrial fibrillation. lncRNA-056298 regulates GAP43 by sponging miR-185, which affects cardiac intrinsic autonomic nerve remodelling and mediates atrial fibrillation induction after ganglionated plexus ablation.

Acute alcohol exposure and electrocardiographic changes: Finding from the HOLIDAY trial

BackgroundAlcohol consumption is associated with a higher increased risk of atrial fibrillation (AF), but the acute effects on cardiac electrophysiology in humans remain poorly understood. The HOw ALcohol InDuces Atrial TachYarrhythmias (HOLIDAY) Trial revealed that alcohol shortened pulmonary vein atrial effective refractory periods, but more global electrophysiologic changes gleaned from the surface ECG have not yet been reported. MethodsThis was a secondary analysis of the HOLIDAY Trial. During AF ablation procedures, 100 adults were randomized to intravenous alcohol titrated to 0.08% blood alcohol concentration versus a volume and osmolarity-matched, masked, placebo. Intervals measured from 12‑lead ECGs were compared between pre infusion and at infusion steady state (20 min). ResultsThe average age was 60 years and 11% were female. No significant differences in the P-wave duration, PR, QRS or QT intervals, were present between alcohol and placebo arms. However, infusion of alcohol was associated with a statistically significant relative shortening of the JT interval (r: −14.73, p = 0.048) after multivariable adjustment. ConclusionAcute exposure to alcohol was associated with a relative reduction in the JT interval, reflecting shortening of ventricular repolarization. These acute changes may reflect a more global shortening of refractoriness, suggesting immediate proarrhythmic effects pertinent to the atria and ventricles.

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

BackgroundMore 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. ObjectiveThe 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. MethodsIn 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). ResultsIn 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. ConclusionSimulated 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.

Effect of Flecainide and Ibutilide Alone and in Combination to Terminate and Prevent Recurrence of Atrial Fibrillation.

There is a need for improved approaches to rhythm control therapy of atrial fibrillation (AF). The effectiveness of flecainide (1.5 µmol/L) and ibutilide (20 nmol/L), alone and in combination, to cardiovert and prevent AF recurrence was studied in canine-isolated coronary-perfused right atrioventricular preparations. We also examined the safety of the combination of flecainide (1.5 µmol/L) and ibutilide (50 nmol/L) using canine left ventricular wedge preparations. Sustained AF (>1 hour) was inducible in 100%, 60%, 20%, and 0% of atria in the presence of acetylcholine alone, acetylcholine+ibutilide, acetylcholine+flecainide, and acetylcholine+ibutilide+flecainide, respectively. When used alone, flecainide and ibutilide cardioverted sustained AF in 40% and 20% of atria, respectively, but in 100% of atria when used in combination. Ibutilide prolonged atrial and ventricular effective refractory period by 15% and 8%, respectively, at a cycle length of 500 ms (P<0.05 for both). Flecainide increased the effective refractory period in atria by 27% (P<0.01) but by only 2% in the ventricles. The combination of the 2 drugs lengthened the effective refractory period by 42% in atria (P<0.01) but by only 7% (P<0.05) in the ventricles. In left ventricular wedges, ibutilide prolonged QT and Tpeak-Tend intervals by 25 and 55%, respectively (P<0.05 for both; cycle length, 2000 ms). The addition of flecainide (1.5 µmol/L) partially reversed these effects (P<0.05 for both parameters versus ibutilide alone). Torsades de Pointes score was relatively high with ibutilide alone and low with the drug combination. In our experimental model, a combination of flecainide and ibutilide significantly improves cardioversion and prevents the recurrence of AF compared with monotherapies with little to no risk for the development of long-QT-mediated ventricular proarrhythmia.

Novel laparoscopic renal denervation immediately reduces atrial fibrillation inducibility: a swine model study

Catheter-based approaches may have inherent limitations in achieving effective renal denervation (RDN) and treatment of atrial fibrillation (AF). This study aimed to investigate the acute effects of novel laparoscopic RDN on modulating AF inducibility using a swine model. Four and five swine were randomly allocated to the sham and RDN groups, respectively. Each swine underwent measurement of the atrial effective refractory period (AERP) and AF induction tests using burst atrial pacing before and immediately after sham or RDN procedures with and without vagal nerve stimulation (VNS). A laparoscopic RDN procedure circumferentially ablated the renal nerves round the renal arteries using radiofrequency energy. There was no significant difference in the baseline AERP between the two groups (p > 0.05). Under VNS, AERP was significantly increased by 20 ms after laparoscopic RDN (95% CI = 0–30, p = 0.004). Compared to the sham group, the RDN group showed significantly reduced AF inducibility [OR (95% CI) = 0.32 (0.13–0.76) and 0.24 (0.11–0.57) with and without VNS, respectively]. After laparoscopic RDN, the duration of inducible AF episodes was significantly shortened from 28 (10–77) s to 7 (3–11) s (p < 0.001). The novel laparoscopic RDN can immediately reduce AF inducibility in a swine model.

Impact of isorhamnetin for suppression of action potential aberrations associated with atrial fibrillation

Abstract Background Isorhamnetin, a natural flavonoid, has potent antioxidant, antifibrotic and L-type Cav1.2 channel modulation effects, but its antiarrhythmic effect has not been reported. Purpose The purpose of this study is to investigate the effect of isorhamnetin on angiotensin II (Ang II)-induced atrial fibrillation (AF) in mice. Methods Wild-type male mice (C57BL/6J, 8 weeks old) were randomly divided into the following three groups: 1) control group, 2) Ang II treated group, 3) Ang II+isorhamnetin treated group. Ang II (1000 ng/kg/min) was administered by an implantable osmotic pump for two consecutive weeks, and isorhamnetin (5 mg/kg) was administered intraperitoneally for three weeks, one week before the initiation of Ang II administration. HL-1 cells were also assigned three groups. Ang II (1 μM) was treated for one day, and isorhamnetin (10 μM) was pretreated one hour before the beginning of Ang II treatment. To evaluate the effect of isorhamnetin on AF, electrophysiologic study including AF induction and action potential duration (APD) measurement with atrial tissue and HL-1 cells was performed. The expression of ion channel genes and proteins, including Cav1.2, were also evaluated. Results AF induction rate was markedly increased by Ang II and significantly decreased by isorhamnetin. AF duration was remarkably prolonged by Ang II and significantly shortened by isorhamnetin. Atrial effective refractory period (AERP) shortened by Ang II and reversed by isorhamnetin. Ang II administration significantly prolonged APD; that was alleviated by isorhamnetin. In addition, Ang II increased the frequency of delayed afterdepolarization (DAD), whereas isorhamnetin reduced its frequency. Cav1.2 channel expression was enhanced by Ang II and normalized by isorhamnetin. On the other hand, Ang II and isorhamnetin had no effect on potassium channels. Conclusion The findings in this study suggest that isorhamnetin prevents APD prolongation via the modulation of Cav1.2 channel and reduced the frequency of DAD, which is one of the mechanisms to prevent AF vulnerability.Effect of isorhamnetin on APD

Hypoxia Promotes Atrial Tachyarrhythmias via Opening of ATP-Sensitive Potassium Channels.

Hypoxia-ischemia predisposes to atrial arrhythmia. Atrial ATP-sensitive potassium channel (KATP) modulation during hypoxia has not been explored. We investigated the effects of hypoxia on atrial electrophysiology in mice with global deletion of KATP pore-forming subunits. Whole heart KATP RNA expression was probed. Whole-cell KATP current and action potentials were recorded in isolated wild-type (WT), Kir6.1 global knockout (6.1-gKO), and Kir6.2 global knockout murine atrial myocytes. Langendorff-perfused hearts were assessed for atrial effective refractory period (ERP), conduction velocity, wavefront path length (WFPL), and arrhymogenicity under normoxia/hypoxia using a microelectrode array and programmed electrical stimulation. Heart histology was assessed. Expression patterns were essentially identical for all KATP subunit RNA across human heart, whereas in mouse, Kir6.1 and SUR2 (sulphonylurea receptor) were higher in ventricle than atrium, and Kir6.2 and SUR1 were higher in atrium. Compared with WT, Kir6.2 global knockout atrial myocytes had reduced tolbutamide-sensitive current and action potentials were more depolarized with slower upstroke and reduced peak amplitude. Action potential duration was prolonged in 6.1-gKO atrial myocytes, absent of changes in other ion channel gene expression or atrial myocyte hypertrophy. In Langendorff-perfused hearts, baseline atrial ERP was prolonged and conduction velocity reduced in both KATP knockout mice compared with WT, without histological fibrosis. Compared with baseline, hypoxia led to conduction velocity slowing, stable ERP, and WFPL shortening in WT and 6.1-gKO hearts, whereas WFPL was stable in Kir6.2 global knockout hearts due to ERP prolongation with conduction velocity slowing. Tolbutamide reversed hypoxia-induced WFPL shortening in WT and 6.1-gKO hearts through ERP prolongation. Atrial tachyarrhythmias inducible with programmed electrical stimulation during hypoxia in WT and 6.1-gKO mice correlated with WFPL shortening. Spontaneous arrhythmia was not seen. KATP block/absence leads to cellular and tissue level atrial electrophysiological modification. Kir6.2 global knockout prevents hypoxia-induced atrial WFPL shortening and atrial arrhythmogenicity to programmed electrical stimulation. This mechanism could be explored translationally to treat ischemically driven atrial arrhythmia.

Dual effects of the small-conductance Ca2+-activated K+ current on human atrial electrophysiology and Ca2+-driven arrhythmogenesis: an in silico study.

By sensing changes in intracellular Ca2+, small-conductance Ca2+-activated K+ (SK) channels dynamically regulate the dynamics of the cardiac action potential (AP) on a beat-to-beat basis. Given their predominance in atria versus ventricles, SK channels are considered a promising atrial-selective pharmacological target against atrial fibrillation (AF), the most common cardiac arrhythmia. However, the precise contribution of SK current (ISK) to atrial arrhythmogenesis is poorly understood, and may potentially involve different mechanisms that depend on species, heart rates, and degree of AF-induced atrial remodeling. Both reduced and enhanced ISK have been linked to AF. Similarly, both SK channel up- and downregulation have been reported in chronic AF (cAF) versus normal sinus rhythm (nSR) patient samples. Here, we use our multiscale modeling framework to obtain mechanistic insights into the contribution of ISK in human atrial cardiomyocyte electrophysiology. We simulate several protocols to quantify how ISK modulation affects the regulation of AP duration (APD), Ca2+ transient, refractoriness, and occurrence of alternans and delayed afterdepolarizations (DADs). Our simulations show that ISK activation shortens the APD and atrial effective refractory period, limits Ca2+ cycling, and slightly increases the propensity for alternans in both nSR and cAF conditions. We also show that increasing ISK counteracts DAD development by enhancing the repolarization force that opposes the Ca2+-dependent depolarization. Taken together, our results suggest that increasing ISK in human atrial cardiomyocytes could promote reentry while protecting against triggered activity. Depending on the leading arrhythmogenic mechanism, ISK inhibition may thus be a beneficial or detrimental anti-AF strategy.NEW & NOTEWORTHY Using our established framework for human atrial myocyte simulations, we investigated the role of the small-conductance Ca2+-activated K+ current (ISK) in the regulation of cell function and the development of Ca2+-driven arrhythmias. We found that ISK inhibition, a promising atrial-selective pharmacological strategy against atrial fibrillation, counteracts the reentry-promoting abbreviation of atrial refractoriness, but renders human atrial myocytes more vulnerable to delayed afterdepolarizations, thus potentially increasing the propensity for ectopic (triggered) activity.

Autoimmune Atrial Fibrillation.

Atrial fibrillation (AF) is by far the most common cardiac arrhythmia. In about 3% of individuals, AF develops as a primary disorder without any identifiable trigger (idiopathic or historically termed lone AF). In line with the emerging field of autoantibody-related cardiac arrhythmias, the objective of this study was to explore whether autoantibodies targeting cardiac ion channels can underlie unexplained AF. Peptide microarray was used to screen patient samples for autoantibodies. We compared patients with unexplained AF (n=37 pre-existent AF; n=14 incident AF on follow-up) to age- and sex-matched controls (n=37). Electrophysiological properties of the identified autoantibody were then tested in vitro with the patch clamp technique and in vivo with an experimental mouse model of immunization. A common autoantibody response against Kir3.4 protein was detected in patients with AF and even before the development of clinically apparent AF. Kir3.4 protein forms a heterotetramer that underlies the cardiac acetylcholine-activated inwardly rectifying K+ current, IKACh. Functional studies on human induced pluripotent stem cell-derived atrial cardiomyocytes showed that anti-Kir3.4 IgG purified from patients with AF shortened action potentials and enhanced the constitutive form of IKACh, both key mediators of AF. To establish a causal relationship, we developed a mouse model of Kir3.4 autoimmunity. Electrophysiological study in Kir3.4-immunized mice showed that Kir3.4 autoantibodies significantly reduced atrial effective refractory period and predisposed animals to a 2.8-fold increased susceptibility to AF. To our knowledge, this is the first report of an autoimmune pathogenesis of AF with direct evidence of Kir3.4 autoantibody-mediated AF.

Validation of a new species for studying postoperative atrial fibrillation: Swine sterile pericarditis model.

The canine sterile pericarditis model associated with atrial inflammation is an experimental counterpart of postoperative atrial fibrillation (POAF). However, the use of canines for research is restricted by ethics committees in many countries, and social acceptance is declining. To validate the feasibility of the swine sterile pericarditis model as an experimental counterpart to study POAF. Seven domestic pigs (35-60kg) underwent initial pericarditis surgery. On two or more postoperative days in the closed-chest state, we performed electrophysiological measurements of pacing threshold and atrial effective refractory period (AERP) while pacing from the right atrial appendage (RAA) and the posterior left atrium (PLA). The inducibility of POAF(>5min) by burst pacing was determined in both the conscious and anesthetized closed-chest state. These data were compared to previously published canine sterile pericarditis data for validation. The pacing threshold increased from day 1 to day 3 (2±0.1 to 3.3±0.6mA in the RAA, 2.5±0.1 to 4.8±0.2mA in the PLA). Also, the AERP increased from day 1 to day 3 (118±8 to 157±16ms in the RAA; 98±4 to 124±2ms in the PLA, both p<.05). Induction of sustained POAF occurred in 43% (POAF CL range 74-124ms). All electrophysiologic data from the swine model were consistent with the canine model with respect to (1) the range of both pacing threshold and AERP; (2) the progressive increase in threshold and AERP over time; (3) a 40%-50% incidence of POAF. A newly developed swine sterile pericarditis model demonstrated electrophysiologic properties consistent with the canine model and patients after open heart surgery.

Site-specific effects of dobutamine on cardiac conduction and refractoriness.

Isoproterenol, a non-specific beta agonist, is commonly used during electrophysiology studies (EPS). However, with the significant increase in the price of isoproterenol in 2015 and the increasing number of catheter ablations performed, the cost implications cannot be ignored. Dobutamine is a less expensive synthetic compound developed from isoproterenol with a similar mechanism to enhance cardiac conduction and shorten refractoriness, thus making it a feasible substitute with a lower cost. However, the use of dobutamine for EPS has not been well-reported in the literature. To determine the site-specific effects of various doses of dobutamine on cardiac conduction and refractoriness and assess its safety during EPS. From February 2020 to October 2020, 40 non-consecutive patients scheduled for elective EPS, supraventricular tachycardia, atrial fibrillation, and premature ventricular contraction ablations at a single center were consented and prospectively enrolled to assess the effect of dobutamine on the cardiac conduction system. At the end of each ablation procedure, measures of cardiac conduction and refractoriness were recorded at baseline and with incremental doses of dobutamine at 5, 10, 15, and 20 mcg/kg/min. For the primary analysis, the change per dose of dobutamine from baseline to each dosing level of dobutamine received by the patients, comparing atrioventricular node block cycle length (AVNBCL), ventricular atrial block cycle length (VABCL) and sinus cycle length (SCL), was tested using mixed-effect regression. For the secondary analysis, dobutamine dose level was tested for association with relative changes from baseline of each electrophysiologic parameter (SCL, AVNBCL, VABCL, atrioventricular node effective refractory period (AVNERP), AH, QRS, QT, QTc, atrial effective refractory period (AERP), ventricular effective refractory period (VERP), using mixed-effect regression. Changes in systolic and diastolic blood pressures were also assessed. The Holm-Bonferroni method was used to adjust for multiple testing. For the primary analysis there was no statistically significant change of AVNBCL and VABCL relative to SCL from baseline to each dose level of dobutamine. The SCL, AVNBCL, VABCL, AVNERP, AERP, VERP and the AH, and QT intervals all demonstrated a statistically significant decrease from baseline to at least one dose level with incremental dobutamine dosing. Two patients (5%) developed hypotension during the study and one patient (2.5%) received a vasopressor. Two patients (5%) had induced arrhythmias but otherwise no major adverse events were noted. In this study, there was no statistically significant change of AVNBCL and VABCL relative to SCL from baseline to any dose level of dobutamine. As expected, the AH and QT intervals, and the VABCL, VERP, AERP and AVNERP all significantly decreased from baseline to at least one dose level with an escalation in dobutamine dose. Dobutamine was well-tolerated and safe to use during EPS.

Relationship between the left atrial and pulmonary vein effective refractory period and the development of early atrial fibrillation recurrence after radiofrequency pulmonary vein isolation. First results

Aim. To assess the relationship between the left atrial (LA) and pul­monary vein (PV) effective refractory period and the development of early atrial fibrillation (AF) recurrence after radiofrequency pul­monary vein isolation (PVI).Material and methods. The study included 35 patients with persistent AF refractory to antiarrhythmic therapy (AAT). In all patients, LA and PV effective refractory period (ERP) was assessed, followed by radiofrequency antral PVI. Depending on the ERP values, the patients were divided into 2 groups. Group 1 (n=15) included patients with mean LA and PV ERP values ≥240 ms, while group 2 (n=20) consisted of patients with mean LA and PV ERP values &lt;240 ms. The evaluation of early AF recurrence, depending on the obtained ERP values, was carried out in the first 3 months.Results. We obtained following ERP values: group 1 — LA (LA ap­ pendage) 252±8,9 ms; left superior PV (LSPV) — 252±12,1 ms; left inferior PV (LIPV) — 257,3±8,15 ms; right superior PV (RSPV) — 254,6±11,3 ms; right inferior PV (RIPV) — 260±9,05 ms; group 2 — LA 230±12,1 ms; LSPV — 205±10,5 ms; LIPV — 186,6±22,05 ms; RSPV — 212,2±14 ms; RIPV — 218,8±11,1 ms. During the 3-month follow-up of group 1 patients, there were no recurrences after PVI. Group 2 had 7 early AF recurrences. Correlation analysis revealed a significant inversely proportional relationship (-0,349; p=0,03) between ERP values and the recurrence rate in the groups.Conclusion. The first results demonstrate an inversely proportional relationship between the mean PV and LA ERP and the development of early AF recurrence, which makes it possible to consider the PV and LA ERP &lt;240 ms as a likely predictor of early AF recurrence. However, this fact requires the study continuation with an increase in the sample and an appropriate statistical analysis.

PO-455617-18 SHORT COUPLED PREMATURE ATRIAL COMPLEXES LEAD TO ADVERSE ATRIAL REMODELING AND ATRIAL FIBRILLATION IN A SWINE MODEL

Frequent premature atrial complexes (PACs) are associated with left atrial (LA) myopathy and atrial fibrillation (AF), however, the effect of coupling interval and irregularity on the ensuing atrial myopathy has not been tested. To explore the impact of coupling interval and regularity of atrial ectopics on the development of atrial remodeling and AF in a swine model. Thirty-five swine underwent baseline electrophysiologic study followed by pacemaker implantation and pacing from the lateral LA via the coronary sinus for 16 weeks in 4 groups: 1) controls without PACs (CTRL, n=10); 2) 50% paced PACs at a short coupling interval (CI) of 250ms (Short-PAC, n=10); 3) 50% PACs at a long CI of 400ms (Long-PAC, n=5); and 4) regular pacing at a faster mean atrial rate (130 beats/min) than during PACs (Reg-130, n=10). At the terminal study, a repeat electrophysiologic study was performed followed by sacrifice and histologic analysis. Structural changes: The Short-PAC group had the greater degree of LA dilation (terminal - baseline: Short-PAC 5.9±1.2cm2 vs. Long-PAC 3.9±0.5cm2 vs. Reg-130 3.0±1.0cm2 vs. CTRL 0.9±0.3cm2, p<0.001) and decrease in peak LA strain (terminal - baseline: Short-PAC -17.3±3.2% vs. Long-PAC -12.7±2.9% vs. Reg-130 -8.2±2.9% vs. CTRL -0.7±4.2%, p<0.001). Electrophysiologic changes: The Short-PAC group had slower LA conduction velocity than the Reg-130 and CTRL groups (Short-PAC 1.1±0.2m/s vs. Long-PAC 1.2±0.1m/s vs. Reg-130 1.3±0.1m/s vs. CTRL 1.5±0.2m/s, p<0.001); atrial effective refractory period (ERP) was only decreased in the Reg-130 group (terminal - baseline: Short-PAC -4.0±23.6ms vs. Long-PAC -8.7±17.9ms vs. Reg-130 -23.7±14.3ms vs. CTRL -3.2±23.7ms, p=0.09). Fibrosis: percent LA fibrosis was highest in the Short-PAC group followed by Long-PAC, Reg-130, and then CTRL groups (Figure, Panel A). AF induction: The Short-PAC group had the longest duration of induced AF (Panel B). In a swine model, frequent PACs can cause structural and electrical atrial remodeling with a heightened propensity for AF. PACs led to slow conduction and fibrosis without change in atrial ERP, suggesting a process distinct from tachy-pacing induced atrial remodeling. Moreover, PACs with short CIs resulted in a greater degree of LA remodeling and induced AF duration compared to PACs with long CIs. These findings suggest that frequent, short coupled PACs pose the highest risk for developing atrial remodeling and AF.

PO-01-001 SHORT COUPLED PREMATURE ATRIAL COMPLEXES LEAD TO ADVERSE ATRIAL REMODELING AND ATRIAL FIBRILLATION IN A SWINE MODEL

Frequent premature atrial complexes (PACs) are associated with left atrial (LA) myopathy and atrial fibrillation (AF), however, the effect of coupling interval and irregularity on the ensuing atrial myopathy has not been tested. To explore the impact of coupling interval and regularity of atrial ectopics on the development of atrial remodeling and AF in a swine model. Thirty-five swine underwent baseline electrophysiologic study followed by pacemaker implantation and pacing from the lateral LA via the coronary sinus for 16 weeks in 4 groups: 1) controls without PACs (CTRL, n=10); 2) 50% paced PACs at a short coupling interval (CI) of 250ms (Short-PAC, n=10); 3) 50% PACs at a long CI of 400ms (Long-PAC, n=5); and 4) regular pacing at a faster mean atrial rate (130 beats/min) than during PACs (Reg-130, n=10). At the terminal study, a repeat electrophysiologic study was performed followed by sacrifice and histologic analysis. Structural changes: The Short-PAC group had the greater degree of LA dilation (terminal - baseline: Short-PAC 5.9±1.2cm2 vs. Long-PAC 3.9±0.5cm2 vs. Reg-130 3.0±1.0cm2 vs. CTRL 0.9±0.3cm2, p<0.001) and decrease in peak LA strain (terminal - baseline: Short-PAC -17.3±3.2% vs. Long-PAC -12.7±2.9% vs. Reg-130 -8.2±2.9% vs. CTRL -0.7±4.2%, p<0.001). Electrophysiologic changes: The Short-PAC group had slower LA conduction velocity than the Reg-130 and CTRL groups (Short-PAC 1.1±0.2m/s vs. Long-PAC 1.2±0.1m/s vs. Reg-130 1.3±0.1m/s vs. CTRL 1.5±0.2m/s, p<0.001); atrial effective refractory period (ERP) was only decreased in the Reg-130 group (terminal - baseline: Short-PAC -4.0±23.6ms vs. Long-PAC -8.7±17.9ms vs. Reg-130 -23.7±14.3ms vs. CTRL -3.2±23.7ms, p=0.09). Fibrosis: percent LA fibrosis was highest in the Short-PAC group followed by Long-PAC, Reg-130, and then CTRL groups (Figure, Panel A). AF induction: The Short-PAC group had the longest duration of induced AF (Panel B). In a swine model, frequent PACs can cause structural and electrical atrial remodeling with a heightened propensity for AF. PACs led to slow conduction and fibrosis without change in atrial ERP, suggesting a process distinct from tachy-pacing induced atrial remodeling. Moreover, PACs with short CIs resulted in a greater degree of LA remodeling and induced AF duration compared to PACs with long CIs. These findings suggest that frequent, short coupled PACs pose the highest risk for developing atrial remodeling and AF.

PO-01-148 COMBINATION OF FLECAINIDE AND IBUTILIDE FOR EFFECTIVE AND SAFE MANAGEMENT OF ATRIAL FIBRILLATION

There is a need for improved approaches to rhythm control therapy of atrial fibrillation (AF). To investigate a novel pharmacological approach for rhythm control management of AF. We studied the effectiveness of clinically relevant concentrations of flecainide (1.5 μM) and ibutilide (20 nM), alone and in combination, to prevent the induction of AF and to cardiovert persistent AF, defined here as AF lasting > 1 hr, using canine isolated coronary-perfused right atrial preparations. In addition, we examined the safety of the flecainide and ibutilide (50 nM) combination using canine left ventricular (LV) wedge preparations. Persistent AF could be induced in 100% of preparations following exposure to acetylcholine (0.5 μM; n=5). Persistent AF remained inducible in 60% of atria in the presence of ibutilide alone and in 20% of preparations in the presence of flecainide alone, but in 0% of preparations in the presence of the combination of ibutilide and flecainide (n=5 per group). When used alone, flecainide and ibutilide cardioverted persistent AF in 40% and 20% of atria, respectively, but in 100% of atria when used in combination (n=5 per group). Ibutilide prolonged both atrial and ventricular effective refractory period (ERP; by 15 and 8%, respectively; p<0.05 for both; Cycle length [CL] = 500 ms; n=5 for each). Flecainide significantly prolonged ERP in atria (by 27%; p<0.001) but not in ventricles (2% increase) due to atrial predominant induction of post-repolarization refractoriness. The combination of the two drugs prolonged ERP by 42% in atria (p<0.001 vs. control and 0<0.05 vs. flecainide alone) but by only 7% in ventricles (p<0.05; n=5, CL=500 ms). In separate experiments involving LV wedge preparations, risk factors for Torsade de Pointes were accentuated by ibutilide (50 nM) and slowed pacing (CL= 2000 ms; n=5). Under these conditions, ibutilide induced significant prolongation of QT and Tpeak /Tend intervals (by 25 and 55%, respectively; p<0.01 for both; n=5). Further addition of flecainide (1.5 μM) partially reversed these effects leading to an increase of these parameters by only 15 and 19%, respectively; p<0.05, combination vs. ibutilide; n=5). Torsade de Pointes was never observed with the drug combination. Our experimental data indicate that a combination of flecainide and ibutilide significantly improves pharmacological cardioversion of AF as well as prevention of AF with very little or no risk of long QT-mediated ventricular proarrhythmia.

Mechanism of myocardial fibrosis regulation by IGF-1R in atrial fibrillation through the PI3K/Akt/FoxO3a pathway.

Atrial structural remodeling takes on a critical significance to the occurrence and maintenance of atrial fibrillation (AF). As revealed by recent data, insulin-like growth factor-1 receptor (IGF-1R) plays a certain role in tissue fibrosis. In this study, the mechanism of IGF-1R in atrial structural remodeling was examined based on in vivo and in vitro experiments. First, cluster analysis of AF hub genes was conducted, and then the molecular mechanism was proposed by which IGF-1R regulates myocardial fibrosis via the PI3K/Akt/FoxO3a pathway. Subsequently, the mentioned mechanism was verified in human cardiac fibroblasts (HCFs) and rats transduced with IGF-1 overexpression type 9 adeno-associated viruses. The results indicated that IGF-1R activation up-regulated collagen Ⅰ protein expression and Akt phosphorylation in HCFs and rat atrium. The administration of LY294002 reversed the above phenomenon, improved the shortening of atrial effective refractory period, and reduced the increased incidence of AF and atrial fibrosis in rats. The transfection of FoxO3a siRNA reduced the anti-fibrotic effect of LY294002 in HCFs. The above data revealed that activation of IGF-1R takes on a vital significance to atrial structural remodeling by facilitating myocardial fibrosis and expediting the occurrence and maintenance of AF through the regulation of the PI3K/Akt/FoxO3a signaling pathway.