Atrial ERP Research Articles

Laser catheter ablation of atrial zones with ganglionated plexi: impact on atrial fibrillation inducibility and the risk of esophageal damage in experimental settings

Aim. To study the potential applicability of transcatheter laser ablation for the destruction of atrial ganglionated plexi (GP) zones and the safety of this technique in relation to inadvertent esophageal damage.Methods. This was a two-stage investigation: (1) ex vivo experiments: the risk of esophageal damage during ablation on the dorsal (posterior) left atrial (LA) wall was assessed; three swine organ complexes were used, which included the heart, lungs and esophagus; (2) in vivo experiments assessing the effects of laser catheter ablation of GP zones on the inducibility of atrial fibrillation (AF) and changes in atrial effective refractory period - included 13 landrace pigs (average weight 38.8±1.2 kg).Ex vivo: laser catheter ablations were performed from the endocardial surface of the LA towards the esophagus with a power of 15 watts of varying duration; ablation was performed under thermal scanning of the LA and esophagus; then a macroscopic examination of the myocardial and esophageal walls was performed.In vivo: before and after catheter laser ablation (15 W) of the GP zones in the right atrium and atrial septum, atrial ERP was assessed with programmed stimulation, and AF induction with high-frequency (33 Hz, 2 min) stimulation was evaluated. At the end of the experiment, the animals were euthanized, and the heart and lungs were collected in a single unit.Results. Ex vivo experiments: in two cases, damage to the endocardium of the LA was detected at an exposure time of 30 s. Damage to the esophagus was observed with a longer exposure time (> 30 seconds) with a 11.3-15.4°C increase in temperature. In the in vivo experiments, 78 laser applications (6±1 in one swine) were delivered to the posterior wall of the right atrium and atrial septum. Atrial effective refractory period was not altered after ablation (183±20 ms vs 186±18 ms, P=0.99). At the baseline, AF was induced in 12 out of 13 animals (92%). After ablation, AF was induced in 7 animals (54%) (P=0.03). There was a trend toward a decrease in the duration of AF after laser ablation of GP zones (18 [5; 141] vs. 2 [0; 14] s after ablation, P=0.06). Transmural damage was observed in 46% of the hearts. No damage to extra-cardiac structures was detected.Conclusion. Ex vivo, laser ablation on the dorsal (posterior) wall of the LA with a power of 15 W and duration <30 s does not lead to visible damage to the esophagus. Laser ablation of atrial GP zones is feasible and reduces the inducibility of AF. No change in atrial effective refractory period is detected following GP zones ablation, when performed from the right atrium.

Frequent Premature Atrial Contractions Lead to Adverse Atrial Remodeling and Atrial Fibrillation in a Swine Model.

Frequent premature atrial complexes (PACs) are associated with future incident atrial fibrillation (AF), but whether PACs contribute to development of AF through adverse atrial remodeling has not been studied. This study aimed to explore the effect of frequent PACs from different sites on atrial remodeling in a swine model. Forty swine underwent baseline electrophysiologic studies and echocardiography followed by pacemaker implantations and paced PACs (50% burden) at 250-ms coupling intervals for 16 weeks in 4 groups: (1) lateral left atrium (LA) PACs by the coronary sinus (Lat-PAC; n=10), (2) interatrial septal PACs (Sep-PAC; n=10), (3) regular LA pacing at 130 beats/min (Reg-130; n=10), and (4) controls without PACs (n=10). At the final study, repeat studies were performed, followed by tissue histology and molecular analyses focusing on fibrotic pathways. Lat-PACs were associated with a longer P-wave duration (93.0±9.0 versus 74.2±8.2 and 58.8±7.6 ms; P<0.001) and greater echocardiographic mechanical dyssynchrony (57.5±11.6 versus 35.7±13.0 and 24.4±11.1 ms; P<0.001) compared with Sep-PACs and controls, respectively. After 16 weeks, Lat-PACs led to slower LA conduction velocity (1.1±0.2 versus 1.3±0.2 [Sep-PAC] versus 1.3±0.1 [Reg-130] versus 1.5±0.2 [controls] m/s; P<0.001) without significant change in atrial ERP. The Lat-PAC group had a significantly increased percentage of LA fibrosis and upregulated levels of extracellular matrix proteins (lysyl oxidase and collagen 1 and 8), as well as TGF-β1 (transforming growth factor-β1) signaling proteins (latent and monomer TGF-β1 and phosphorylation/total ratio of SMAD2/3; P<0.05). The Lat-PAC group had the longest inducible AF duration (terminal to baseline: 131 [interquartile range 30, 192] seconds versus 16 [6, 26] seconds [Sep-PAC] versus 22 [11, 64] seconds [Reg-130] versus -1 [-16, 7] seconds [controls]; P<0.001). In this swine model, frequent PACs resulted in adverse atrial structural remodeling with a heightened propensity to AF. PACs originating from the lateral LA produced greater atrial remodeling and longer induced AF duration than the septal-origin PACs. These data provide evidence that frequent PACs can cause adverse atrial remodeling as well as AF, and that the location of ectopic PACs may be clinically meaningful.

VCAM-1 accelerates atrial remodeling in TERT-/- mice

Abstract Background Aging, an independent risk factor for AF, could significantly increase its morbidity and mortality. The mechanism of AF in the elderly population remains to be further elucidated. Atrial remodeling is considered to be an important mechanism of atrial fibrillation. Telomerase dysfunction and telomere shortening are important signs of aging, and the relationship and mechanism between telomerase dysfunction and atrial remodeling is not very clear. Purpose This study aims to explore the mechanism of atrial remodeling caused by telomerase dysfunction. Methods The atrial electrophysiology was used to detect refractory period (ERP) and atrial fibrillation inducibility, and the epicardial electrical mapping technique was used to detect the atrial conduction velocity, direction and conduction heterogeneity to evaluate the atrial electrical remodeling. HE and Masson staining were used to evaluate atrial structural remodeling. RNA-seq analysis screened out the differential genes and corresponding pathways in each model. Results Compared with wild-type (WT) mice, a third-generation of telomerase reverse-transcriptase knockout mice (F3 TERT-/-, hereafter as TERT-/-) showed a shortened atrial ERP, increased atrial fibrillation inducibility, slowed atrial conduction velocity,change in the direction of propagation, and increased atrial fibrosis, suggesting electrical and structural remodeling in TERT-/- mice. RNA-seq revealed significant changes in cell adhesion molecules (CAMs) of TERT-/- mice compared with the WT, among which vascular adhesion molecule (VCAM-1) changed most significantly. Then, TERT-/- mice were treated with anti-VCAM-1 neutralizing antibodies, atrial electrical and structural remodeling was partially relieved compared to untreated TERT-/- mice. RNA-seq and KEGG enrichment analysis were conducted on differential genes, which were mainly concentrated on extracellular matrix (ECM)-receptor interaction. Furthermore, we found that the extracellular matrix LAMC3, Collgen1 and myofibroblast marker α-SMA were reversed in TERT-/- mice treated with anti-VCAM-1 neutralizing antibodies compared with TERT-/- mice. Conclusion VCAM-1 could accelerate the production of extracellular matrix, and ultimately lead to atrial electricity and structural remodeling, and the occurrence of atrial fibrillation in TERT-/- mice.

Pinocembrin attenuates susceptibility to atrial fibrillation in rats with pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) is a disease characterized by pulmonary vascular remodeling that triggers fibrosis and excessive myocardium apoptosis, ultimately facilitating atrial fibrillation (AF). In various rat models, Pinocembrin has anti-fibrotic and anti-apoptotic effects, reducing arrhythmia vulnerability. However, whether pinocembrin alleviates to AF in a PAH model remains unclear. The experiment aims to investigate how pinocembrin affects AF susceptibility in PAH rats and the possible mechanisms involved. MethodsThe PAH model was induced by monocrotaline (MCT; i. p. 60 mg/kg). Concurrently, rats received pinocembrin (i.p.50 mg/kg) or saline. Hemodynamics parameters, electrocardiogram parameters, lung H.E. staining, atrial electrophysiological parameters, histology, Western blot, and TUNEL assay were detected. ResultsCompared to the control rats, MCT-induced PAH rats possessed prominently enhancive mPAP (mean pulmonary artery pressure), pulmonary vascular remodeling, AF inducibility, HRV, right atrial myocardial fibrosis, apoptosis, atrial ERP, APD, and P-wave duration. Additionally, there were lowered protein levels of Cav1.2, Kv4.2, Kv4.3, and connexin 40 (CX40) in the MCT group in right atrial tissue. However, pinocembrin reversed the above pathologies and alleviated the activity of the Rho A/ROCKs signaling pathway, including the expression of Rho A, ROCK1, ROCK2, and its downstream MYPT-1, LIMK2, BCL-2, BAX, cleaved-caspase3 in right atrial and HL-1 cells. ConclusionPresent data exhibited pinocembrin attenuated atrial electrical, ion-channel, and autonomic remodeling, diminished myocardial fibrosis and apoptosis levels, thereby reducing susceptibility to AF in the MCT-induced PAH rats. Furthermore, we found that pinocembrin exerted inhibitory action on the Rho A/ROCK signaling pathway, which may be potentially associated with its anti-AF effects.

Abstract 15072: Targeted Atrial Inhibition of Parasympathetic Signaling With GiGo Inhibitory Peptides Attenuates Electrical Remodeling and Development of Persistent Atrial Fibrillation in a Canine Model

Background: While vagal contribution to paroxysmal atrial fibrillation (AF) is well demonstrated, a role for parasympathetic signaling in persistent AF is less clear. We have shown marked atrial parasympathetic hyperinnervation in a canine rapid atrial pacing (RAP) model of AF. However, the role of these new nerves in AF development is unknown. Hypothesis: RAP-induced parasympathetic hyperinnervation contributes to the onset and maintenance of AF, and a gene therapy approach inhibiting muscarinic M2 signaling (Gα i and Gα o - GiGo) in the atria can prevent persistent AF. Methods: Plasmids expressing GiGo inhibitory peptides (GiGo_ct) were injected in the atria of 7 dogs followed by electroporation to facilitate gene delivery. RAP was performed for up to 12 weeks. At terminal EP study, residual AF was recorded in the posterior left atrium (PLA), left atrial free wall (LAFW) and left atrial appendage (LAA). Regional atrial ERP was measured. Results: Controls developed ≥30 minutes of AF after a median of 4 days, and persistent AF (≥8 hours) after a median of 14 days. GiGo_ct delayed onset of AF of ≥30 minutes, and attenuated development of persistent AF. ERP was markedly shortened in the PLA and LAA of controls, and this was attenuated by GiGo_ct (p&lt;0.001). Residual AF was slower (lower dominant frequency; PLA 9.4±0.6Hz Vs 11.0±0.7Hz; LAFW 7.8±0.3Hz Vs 10.4±0.7Hz; LAA 8.9±0.6Hz Vs 9.9±0.5Hz p&lt;0.01), less fractionated (longer fractionation interval; PLA 70.0.4±5.2ms Vs 68.1±5.2ms; LAFW 98.8±4.1ms Vs 70.9±3.1ms; LAA 88.9±7.8ms Vs 80.3±2.0ms p&lt;0.01) and more organized (lower Shannon's entropy; p&lt;0.05). Conclusion: Newly sprouted atrial parasympathetic nerves play a functional role in development of persistent AF. Gene-based, selective M2 signaling inhibition by GiGo_ct attenuates electrical remodeling and prevents initiation and maintenance AF. Future optimization of gene therapy targeting autonomic remodeling may lead to novel, mechanism-guided treatments for AF.

B-PO02-140 EFFECT OF ATRIAL ECTOPY COUPLING INTERVAL ON ATRIAL STRUCTURAL REMODELLING AND ATRIAL FIBRILLATION IN A SWINE MODEL

Frequent premature atrial complexes (PACs) are associated with incident atrial fibrillation (AF), however, the significance of PAC-coupling interval (CI) on atrial structural remodelling as well as development of AF is unknown. To investigate the impact of PAC-CI on atrial structural remodelling and AF inducibility in a swine model. Fifteen swine underwent pacemaker implantation to create a model of paced PACs (50% burden) from the lateral left atrium (LA) via the coronary sinus and were divided into 3 groups: (1) Short CI of 250ms (Short-CI: n=5), (2) Long CI of 400ms (Long-CI: n=5), and (3) controls without PACs (CTRL, n=5). At baseline and after 4 months of PACs, all swine underwent electrophysiologic (atrial ERP and AF induction with 50ms burst pacing) and echocardiographic studies (LA area and peak atrial longitudinal strain). Short-CI group had more LA enlargement compared with Long-CI and CTRL (terminal - baseline; Short-CI 7.0±0.9 vs. Long-CI 4.0±1.1 vs. CTRL 0.5±0.2 cm2; p<0.001). Both Short-CI and Long-CI group had a significant reduction in peak atrial longitudinal strain compared to CTRL (terminal - baseline; -22.8±9.7 vs. -18.3±3.7 vs. 0.1±4.5 %; p<0.001). No change in atrial ERP was observed (terminal - baseline; 3±20 vs -9 ±18 vs -5 ±34 ms; p=0.76). Short-CI group had the longest duration of burst pacing-induced AF (terminal - baseline; 71.2 [IQR 43.1, 102.9] vs. 34.3 [IQR 17.7, 61.0] vs. 5.3 [IQR 4.8, 9.7] secs; p=0.008). In a swine model, frequent PACs led to an atrial myopathy with heightened propensity to AF. Short-coupled PACs had a greater degree of structural remodelling and may contribute to the future development of AF.

Genetic background, sex, age and pacing cycle length affect left atrial electrophysiology in Langendorff-perfused isolated murine hearts

Abstract Background Studying cardiac electrophysiology in isolated perfused beating murine hearts is a well-established method. The ranges of normal values for left atrial (LA) action potential durations (LA-APD), activation times (LA-AT) and effective refractory periods (atrial ERP) in murine wildtype (WT) are not well known. Purpose This study aimed to establish reference values for LA-APD, LA-AT and atrial ERP and to identify the influence of genetic background, sex and age on these electrophysiological parameters in WT mice. Method We combined results from isolated beating heart Langendorff experiments carried out in WT mice between 2005 and 2019 using an octopolar catheter inserted into the right atrium and a monophasic action potential electrode recording from the LA epicardium. Electrophysiological parameters (LA-APD at 50%, 70%, 90% repolarization (APD50, APD70, APD90), LA-AT and atrial ERP) at different pacing cycle lengths (PCL) were summarized. We analysed effects of PCL, genetic background, age, gender, heart weight to body weight ratio (HW/BW), LA weight to body weight ratio (LAW/BW) as well as coronary flow and temperature as experimental conditions. Results Electrophysiological parameters from 222 isolated hearts (114 female, mean age 6.6±0.25 months, range 2.47–17.7 months) of different backgrounds (77 C57BL/6, 23 FVB/N, 33 MF1, 69 129/Sv and 20 Swiss agouti) were combined. Coronary flow rate, flow temperature and start of isolation to cannulation time were constant experimental conditions over the timespan of experiments. LA-APD was longer while LA-AT decreased with longer PCL throughout all genetic backgrounds (Figure 1A). Genetic background showed strong effects on all electrophysiological parameters. LA-APD70 and atrial ERP were significantly shorter in Swiss agouti background compared to others. LA-APD70 was also significantly prolonged in 129/Sv background compared to MF1 (Figure 1B). LA activation was delayed in 129/Sv compared to other backgrounds (Figure 1C). Atrial ERP was longer in FVB/N compared to other backgrounds. Atrial ERP was also significantly prolonged (+ 3.4 ms, + 13.5%) in female mice compared to males (Figure 1D). Age effects were compared in groups. Atrial ERP was significantly longer in mice younger than 3 months compared to older mice (Figure 1E). Conclusion This dataset summarises left atrial electrophysiological parameters in the beating mouse heart and can serve as a reference for design and interpretation of electrophysiological experiments in murine models of commonly used genetic backgrounds. We demonstrate that PCL, genetic background, age and gender affect atrial electrophysiological parameters. Awareness of these will support successful experimental design. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): This work was partially supported by the European Commission (grant agreements no. 633196 [CATCH ME]) to LF and PK, Deutsche Forschungsgemeinschaft DFG FA413, British Heart Foundation (FS/13/43/30324 to LF and PK; AA/18/2/34218 to LF and PK).The Institute of Cardiovascular Sciences has received the British Heart Foundation (BHF) Accelerator Award (AA/18/2/34218). JO has received financial support for abroad studies within his scholarship of the Studienstiftung des deutschen Volkes (German Academic Scholarship Foundation).

Beneficial electrophysiologic effects of sacubitril in different arrhythmia syndromes

Abstract Background Previous studies report conflicting data regarding anti- or proarrhythmic effects of sacubitril. The aim of the presents study was to assess the impact of sacubitril in different arrhythmia models. Methods and results In 12 isolated rabbit hearts, sacubitril was infused in rising concentrations (3, 5, 10μM) after obtaining baseline data. In 12 further hearts, erythromycin was administered to simulate long QT syndrome-2 (LQT2). Other 12 hearts were perfused with veratridine to mimic long QT syndrome-3 (LQT3). Both LQT groups were treated with sacubitril (5μM). Ventricular vulnerability was assessed by a pacing protocol. AV-blocked bradycardic hearts were perfused with a hypokalemic solution to trigger torsade de pointes (TdP). In further 13 hearts, AF was induced by a combination of acetylcholine and isoproterenol (ACH/ISO) and sacubitril (5μM) was added afterwards. With sacubitril, action potential duration (APD) was abbreviated whereas spatial dispersion of repolarization (SDR) remained stable. In both LQT groups, APD and SDR were increased. Infusion of sacubitril reduced APD and SDR in the LQT2-group (APD: −21 ms, p&amp;lt;0.05; SDR: −8 ms, p=ns) and did not alter APD but reduced SDR in the LQT3-group (APD: +2 ms, p=ns; SDR: −9 ms, p&amp;lt;0.05). Ventricular vulnerability was not altered by sacubitril. No TdP were observed with sacubitril treatment or under baseline conditions in any group. Erythromycin provoked 43 episodes of TdP (p&amp;lt;0.05). Additional treatment with sacubitril significantly suppressed TdP (3 episodes, p&amp;lt;0.05). With veratridine, 16 episodes of TdP (p=0.07) occurred. Further treatment with sacubitril did not reduce TdP (10 episodes, p=ns) significantly. Infusion of ACH/ISO led to an increased inducibility of atrial fibrillation (31 vs. 7 episodes). Additional infusion of sacubitril increased atrial ERP (+21ms, p&amp;lt;0.05) and reduced inducibility of AF (9 episodes). Conclusion Sacubitril abbreviated APD and was not proarrhythmic. SDR is a major pathomechanism of TdP and was reduced by sacubitril in both LQT groups. Thereby, sacubitril exhibits antiarrhythmic effects in LQT2 and may be beneficial in LQT3. Furthermore, sacubitril suppressed AF by prolonging aERP. Our results indicate beneficial effects of sacubitril on cardiac electrophysiology. Funding Acknowledgement Type of funding source: None

1272Effect of age, genetic background and experimental conditions on left atrial monophasic action potential duration, effective refractory period and activation time in Langendorff-perfused murine hearts

Abstract Funding Acknowledgements Supported by EU [CATCH ME] 633196, British Heart Foundation FS/13/43/30324, AA/18/2/34218 LF, PK, DFG FA413 LF, Studienstiftung to JO. Background Studying cardiac electrophysiology in isolated perfused beating murine hearts is a well-established method. The range of normal values for left atrial action potential durations (LA-APD), activation times (LA-AT) and effective refractory periods (atrial ERP) in murine wildtype (WT) is not well known. Purpose This study aimed to establish reference values for LA-APD, LA-AT and atrial ERP and to identify factors that influence these electrophysiological parameters in wildtype (WT) mice. Method We combined results from isolated beating heart Langendorff experiments carried out in WT between 2005 and 2019 using an octopolar catheter inserted into the right atrium and a monophasic action potential electrode recording from the LA epicardium. Electrophysiological parameters (LA-APD at 50%, 70%, 90% repolarization (APD50, APD70, APD90), LA-AT and atrial ERP) at different pacing cycle lengths (PCL) were summarized. We analyzed effects of PCL, genetic background, age, gender, heart weight to body weight ratio (HW/BW), LA weight to body weight ratio (LAW/BW) as well as coronary flow and temperature as experimental conditions. Results Electrophysiological parameters from 222 isolated hearts (114 female, mean age 6.6 ± 0.25 months, range 2.47-17.7 months) of different backgrounds (77 C57BL/6, 23 FVB/N, 33 MF1, 69 129/Sv and 20 Swiss agouti) were combined. Coronary flow rate, flow temperature and start of isolation to cannulation time were constant experimental conditions over the timespan of experiments. LA-APD was longer while LA-AT decreased with longer PCL throughout all genetic backgrounds (Figure 1A). Genetic background showed strong effects on all electrophysiological parameters. LA activation was delayed in 129/Sv compared to other backgrounds (Figure 1D). LA-APD70 and atrial ERP were significantly shorter in Swiss agouti background compared to others. LA-APD70 was also significantly prolonged in 129/Sv background compared to MF1 (Figure 1C). Atrial ERP was longer in FVB/N compared to other backgrounds. Age effects were compared in groups. Atrial ERP was significantly longer in mice ≤ 3 months compared to all older mice. Atrial ERP was also significantly prolonged (+ 3.4ms, + 13.5%) in female mice compared to males (Figure 1B). Conclusion This dataset summarizes left atrial electrophysiological parameters in the beating mouse heart and can serve as a reference for design and interpretation of electrophysiological experiments in murine models of commonly used genetic backgrounds. We confirm that cycle length, genetic background, age and gender affect atrial electrophysiological parameters. Awareness of these will support successful experimental design. Abstract Figure 1

P920Understanding arrhythmia mechanisms in patients with atrial septal defects

Abstract Background Atrial arrhythmias represent a major cause of morbidity and hospitalization in patients with atrial septal defects (ASD). Optimum treatment strategies are unknown since the mechanisms of arrhythmia are undefined in this cohort. Purpose We investigated whether percutaneous ASD closure reduces atrial arrhythmias and subsequently examined the electrical and structural changes underpinning arrhythmogenesis in ASD patients. Methods Meta-analysis was used to study the effect of closure on arrhythmias. Bi-atrial electrical dysfunction was assessed through invasive measurement of atrial voltage, refractory periods (ERP) over three drive trains (600, 450 and 300ms) and local conduction velocity (CV) with subsequent assessment of ERP and CV restitution. Structural remodelling was assessed through non-invasive quantification of fibrosis using cardiac MRI (CMR). Origin of ectopy was evaluated invasively using isoprenaline infusion and non-invasively using 24-hour Holter monitoring. Comparison was made to normal heart controls. Results Meta-analysis Meta-analysis of 25 studies found that percutaneous closure was associated with a weak reduction in atrial arrhythmias only in patients &amp;gt;40 years old (OR 0.777, 95% CI 0.616-0.979, P = 0.032). Electrical Remodelling On invasive assessment (21 ASDs; 21 controls), proportion of right atrial low voltage (&amp;lt;0.5mV) and scar (&amp;lt;0.05mV) was greater in ASD vs control patients (P = 0.02 and P = 0.039). In ASD patients, these parameters were greater in the right atrium vs the left atrium (P = 0.002 and P = 0.01). Right atrial ERP restitution slopes were steeper in ASD vs control patients (P = 0.016). Maximum right atrial CV and CV restitution slopes were greater in ASD vs control patients (P= 0.005 and P &amp;lt; 0.001 respectively) and CV decrement occurred at longer coupling intervals in the right atrium in ASD patients (P = 0.015). Structural Remodelling On CMR assessment (36 ASDs; 36 controls), bi-atrial fibrosis was greater in ASD vs control patients (P &amp;lt; 0.001). In ASD patients right atrial fibrosis was burden greater in patients with vs without atrial arrhythmias (P = 0.034). Arrhythmia Triggers On 24-hour Holter monitoring and during invasive isoprenaline infusion right and left atrial ectopy was equally prevalent in ASD vs control patients. Conclusion This study highlights the importance of right atrial electrical dysfunction to the occurrence of arrhythmias in ASD patients with extensive right atrial remodelling (fibrosis, low voltage, steeper ERP and CV restitution) seen in ASD patients compared to normal heart controls. From the results of the meta-analysis it appears that percutaneous closure alone is insufficient to treat arrhythmias in ASD patients. Given the predominance of right atrial remodelling, right-sided ablation as an adjunct to conventional left-sided ablation should be investigated as a strategy to treat atrial arrhythmias in these patients. Abstract Figure.

16-24: Identification of Heterogeneous Intra-Atrial Conduction Delay in Paroxysmal AF Patients by Dynamic Electrophysiological Characterization

Purpose of the Study: Although atrial fibrillation (AF) is classified by arrhythmia duration, the presentation, clinical course and response to treatment vary widely within paroxysmal AF (PAF) patients. We hypothesized that variable electrical remodeling exists between PAF patients, resulting in intra-atrial conduction delay which could be identified using a novel programmed stimulation technique. Methods Used: In 15 PAF patients undergoing index PVI, high density LA contact mapping using a 20 pole Pentaray catheter was performed during pacing from two atrial sites (BCL 470ms, S1S2 350ms to atrial ERP in -2% steps). Regional atrial conduction delay (S1S2delay), activation dispersion, and AF vulnerability were measured. Computer modeling was used to interrogate the mechanism of conduction delay. Summary of Results: Conduction delay showed a bimodal distribution (peaks for HRA / CS pacing 275 ± 11 / 271 ± 11ms and 326 ± 13 / 319 ± 16ms) and patients with inducible AF were characterized by increased activation dispersion (ΔLAT 672 ± 41ms vs 542 ± 17ms, P = 0.0446, Fig). Action potential remodeling across the population could explain observed variation in conduction delay, but resulted in insufficient conduction velocity restitution variation (3.7 ± 0.5ms-1/s vs 2.3 ± 0.5 ms-1/s, P = 0.1926) to explain the activation dispersion seen in AF-inducible patients.

Pharmacological inhibition of IK1 by PA-6 in isolated rat hearts affects ventricular repolarization and refractoriness.

The inwardly rectifying potassium current (IK 1) conducted through Kir2.X channels contribute to repolarization of the cardiac action potential and to stabilization of the resting membrane potential in cardiomyocytes. Our aim was to investigate the effect of the recently discovered IK 1 inhibitor PA‐6 on action potential repolarization and refractoriness in isolated rat hearts. Transiently transfected HEK‐293 cells expressing IK 1 were voltage‐clamped with ramp protocols. Langendorff‐perfused heart experiments were performed on male Sprague–Dawley rats, effective refractory period, Wenckebach cycle length, and ventricular effective refractory period were determined following 200 nmol/L PA‐6 perfusion. 200 nmol/L PA‐6 resulted in a significant time‐latency in drug effect on the IK 1 current expressed in HEK‐293 cells, giving rise to a maximal effect at 20 min. In the Langendorff‐perfused heart experiments, PA‐6 prolonged the ventricular action potential duration at 90% repolarization (from 41.8 ± 6.5 msec to 72.6 ± 21.1 msec, 74% compared to baseline, P < 0.01, n = 6). In parallel, PA‐6 significantly prolonged the ventricular effective refractory period compared to baseline (from 34.8 ± 4.6 msec to 58.1 ± 14.7 msec, 67%, P < 0.01, n = 6). PA‐6 increased the short‐term beat‐to‐beat variability and ventricular fibrillation was observed in two of six hearts. Neither atrial ERP nor duration of atrial fibrillation was altered following PA‐6 application. The results show that pharmacological inhibition of cardiac IK 1 affects ventricular action potential repolarization and refractoriness and increases the risk of ventricular arrhythmia in isolated rat hearts.

Low-Level Electrical Stimulation of Aortic Root Ventricular Ganglionated Plexi Attenuates Autonomic Nervous System–Mediated Atrial Fibrillation

ObjectivesThis study investigated the effect of electrical stimulation of aortic root ventricular ganglionated plexi (GP) on atrial fibrillation (AF) inducibility. BackgroundThe ventricular GP are interconnected with atrial GP to govern heart function, although the effect of ventricular GP modification on control of AF remains unknown. MethodsEffective refractory periods (ERPs) of test pulmonary veins (PVs) were measured at baseline and during high-level (HL-ES) and low-level (LL-ES) electrical stimulation of the aortic root GP. The arrhythmogenic threshold of acetylcholine and isoproterenol was determined at baseline and during HL-ES and LL-ES. Moreover, AF was induced at PVs by programmed electrical stimulation after HL-ES or LL-ES. Immunohistochemistry staining was performed to examine the autonomic activity from aortic root GP to the PVs. ResultsCompared with the baseline group, HL-ES of aortic root GP significantly shortened atrial ERP (95 ± 13 ms vs. 122 ± 9 ms) and PV ERP (104 ± 11 ms vs. 131 ± 12 ms); decreased the threshold concentration of AF by both acetylcholine (1.3 ± 0.2 μmol/l vs. 3.2 ± 0.3 μmol/l) and isoproterenol (0.3 ± 0.1 μmol/l vs. 1.3 ± 0.2 μmol/l); and increased the AF-inducing rate from PVs (90% vs. 30%). In contrast, LL-ES of the GP prevented the shortening of ERP and PV ERP to 125 ± 10 ms and 133 ± 11 ms, respectively; increased threshold levels of acetylcholine and isoproterenol to 5.7 ± 0.4 μmol/l and 3.2 ± 0.3 μmol/l; and decreased the AF-inducing rate to 5%. We also found that the biotinylated dextran amine–containing varicose fibers projected directly from the aortic root GP to the left PVs. ConclusionsThese findings suggest that autonomic innervations of left PVs partly originated from aortic root ventricular GP. Moreover, LL-ES of aortic root ventricular GP suppressed AF inducibility and arose from PVs mediated by the autonomic nervous system.

ASSA13-03-6 Effects of Renal Sympathetic Denervation on the Development of Atrial Fibrillation Substrates in Dogs with Pacing-Induced Heart Failure

<h3>Objective</h3> We examined the role of renal denervation on the inducibility of AF in dogs with pacing-induced HF. <h3>Background</h3> Atrial fibrillation (AF) and heart failure (HF) are common interrelated conditions that are associated with renin-angiotensin-aldosterone system activity. <h3>Methods and Results</h3> Nineteen dogs were randomised into sham-operated (7 dogs), HF (6 dogs) and HF+renal artery ablation (RAA, 6 dogs) groups. Sham-operated dogs were implanted with transvenous cardiac pacemakers without pacing. Dogs in the HF group were implanted with pacemakers and underwent right ventricular pacing for 3 weeks at 240 bpm to induce HF. The dogs in the HF+RAA group received double renal artery ablation. The dogs recovered for 8 weeks and underwent the same HF-inducing procedure. Compared to the baseline, the atrial dimensions increased and the right atrial ERP (131 ± 14 ms to 112 ± 12 ms, p = 0.02) decreased significantly after 3 weeks in the HF dogs but not the HF+RAA dogs. A greater number of AFs were induced in the HF dogs than the HF+RAA dogs (2.2 ± 0.6 vs. 0.3 ± 0.3, p = 0.03). The atrium from HF hearts revealed a large amount of fibrosis, whereas control and HF+RAA dogs showed minimal fibrous tissue. The levels of BNP, Ang II, TNF-α and expression of TGF-β and Cx43 in atrial tissue were increased in the HF dogs compared to the sham-operated and HF+RAA dogs. <h3>Conclusion</h3> RAA suppressed the atrial substrate remodelling and the AF vulnerability that was induced by long-term rapid ventricular pacing.

Abstract 9717: Hypertension-Induced Atrial Remodeling Promotes Atrial Fibrillation Stabilization Upon Tachyarrhythmia Onset

Background: Hypertension (HT) is a major risk factor for atrial fibrillation (AF) but the underlying mechanisms are poorly understood. We hypothesized that HT produces an AF-stabilizing influence that favors faster progresion of spontaneous AF-maintenance when atrial tachyarrhythmia (AT) begins. Methods: HT was induced in dogs (n=6) by left nephrectomy and right renal artery constriction (1K1C). Sham operated dogs with the same surgery but no nephrectomy or artery constriction (n=5) were controls. Beginning 28 days from surgery, AT-pacing (ATP, 600 bpm) was started for 7 days. Serial atrial ERP measurement and AF induction was performed at days 7, 14, 28, 29, 30, 32 and 35 from surgery. Final open chest EPS was performed at day 36. Results: Systolic blood pressure (SBP) of HT dogs increased beginning at day 7 post 1K1C surgery (baseline 128±4 mm Hg; 7-d 183±6*, 28-d 176±10* mmHg; * p&lt;0.01 vs. baseline). SBP of sham dogs remained constant (baseline 133±4 mm Hg; 7-d 128±3, 28-d 126±6 mmHg). Mean AF duration (10 Hz burst pacing induced) increased marginally in HT dogs pre-ATP (Figure), but substantially after 1 and 2 days ATP vs control. At open-chest EPS, there were no differences in AF vulnerability to premature extrastimuli (HT, 69±5% vs. Sham, 70±11%; p=NS), AF duration (HT, 1501±273 sec vs. Sham, 1458±342 sec; p=NS) or regional ERP heterogeneity. HT dogs showed increased atrial conduction heterogeneity (heterogeneity index in HT, 2.01±0.10 vs. sham, 1.50±0.08; p&lt;0.01), associated with significant downregulation of connexin (Cx) 43 expression (by 57% + , + p&lt;0.05) but no change in Cx40 expression. Heart to body weight ratio increased in HT (9.7±0.4 vs. 8.5±0.2 + ), reflecting LVH. Conclusions: HT alone produces modest AF promotion, but changes caused by HT accelerate AF stabilization once initiated, increasing vulnerability to prolonged AF. The AF-promoting effects of hypertension are related to conduction abnormalities, possibly caused by connexin downregulation.

Genetic treatment of heart rhythm disorders—where do we stand?

C d a i p p Groundbreaking discoveries on genetic loci that underlie arrhythmia syndromes, which commenced in the early 1990s, have immensely increased our understanding of these syndromes. These discoveries also rigorously changed daily clinical practice for cardiologists who were faced with the enquiries of presymptomatic family members of symptomatic individuals who were known with an arrhythmia syndrome. Now it has become possible to screen the genome for the risk of arrhythmias or even sudden death and, understandingly, this took a flight. Still, the holy grail of genetic discoveries in disease is in its therapeutic applicability and that promise is indeed coming our way. For example, in Duchenne muscular dystrophy, the increasing knowledge of the diseased locus has recently led to therapeutic gene therapy in a relatively small number of patients in whom the diseased exon was selectively bypassed. For rrhythmia syndromes, we are still in a preclinical phase, ut efforts to find curative options by means of genetic herapy are growing. Currently, genetic therapy for atrial brillation and bradycardia/conduction disease seems to dominate the field, but ventricular arrhythmias in ischemic conditions are also thoroughly investigated (for a recent review, see, eg, Boink and Rosen). The first in-human studies into the use of gene therapy in heart failure are even underway. In this issue of HeartRhythm, Soucek and colleagues from Heidelberg, Germany, presnt to us their preclinical work on genetic therapy for atrial brillation. Delay of atrial repolarization is considered one pproach to genetic therapy for atrial fibrillation, as coninuing propagation or reentry of fibrillation waves can be mpeded by prolonging the atrial effective refractory period ERP). The main currents responsible for the atrial ERP are outward potassium currents: IKr, IKur, IKs, and IK1. In their tudy, Soucek et al focused on suppressing the IKr current y means of introducing an engineered gene that encodes an Kr-suppressing (dominant-negative) protein into the atria of pigs with the use of an adenovirus vector. Their aim was to

Effects of Ibutilide on Inhibiting Heart Rate and Rapidly Terminating Atrial Flutter in Canine

Ibutilide is a newer class-III antiarrhythmic agent approved for clinical use. We sought to investigate its electrophysiological effects in canines and also the underlying mechanism of conversion of atrial flutter (AFL). For this purpose, 15 male mongrel dogs were anesthetized, intubated with tracheal tube, and heart was exposed and connected to electrodes. Electrophysiologic variables were measured with and without ibutilide (10-min infusion-dose: 0.10mg/kg; 30-min later, maintaining dose: 0.01mg/min) which included heart rate, conduction of intra- and inter-atrium, conduction ratio of isthmus, and ERP. Ibutilide had a significant inhibitory effect on sinus atrial node, peak response time was 20-30min, and heart rate returned to the baseline after 2h. One canine had 5s sinus pause, and the other had 2:1 atrioventricular conduction post-administration. Atrial, ventricular, and pulmonary vein ERP was significantly prolonged (P<0.05). No significant differences were observed regarding conduction of intra-atrium, inter-atrium, and isthmus. It was, therefore, concluded that ibutilide had suppressive effect on sinus atrial and atrioventricular nodes. Ibutilide rapidly terminated AFL due to the reentrant wave front's inability to proceed as the refractory period was protracted and hence caused the whole excitable gap of the reentrant circuit to be affected by refractoriness.

The Impact of Age on the Electrophysiological Characteristics and Different Arrhythmia Patterns in Patients with Wolff-Parkinson-White Syndrome

Information about the impact of age on the electrophysiological characteristics of accessory pathways (APs) in patients with Wolff-Parkinson-White (WPW) syndrome remains limited. A total of 1,885 consecutive patients (mean age 43 ± 17 years, male 61.5%) with WPW syndrome who were referred to the tertiary center for an electrophysiological study and radiofrequency catheter ablation were investigated. The patients were divided into 4 groups based on their age (Group 1: <20; Group 2: 20-39; Group 3: 40-59; Group 4: ≧60 years old). With age, more left-sided APs (53.2%, 67.7%, 71.7%, 75.7%, P < 0.001) and a longer duration of the arrhythmia (4.3 ± 2.8 years, 10.1 ± 7.0 years, 12.4 ± 10.9 years, 14.0 ± 12.4 years, P < 0.001) were noted. The incidence of concealed APs (53.5%, 53.0%, 57.8%, 60.9%, P = 0.01), and orthodromic atrioventricular (AV) reentrant tachycardia (92.4%, 94.2%, 96.5%, 96.3%, P = 0.023) increased with age. The tachycardia cycle length, antegrade (275.5 ± 42.2 ms, 286.7 ± 62.7 ms, 302.5 ± 66.5 ms, 315.2 ± 80.2 ms, P < 0.001) and retrograde AP effective refractory periods (APERPs) (254.0 ± 42.5 ms, 263.3 ± 51.8 ms, 274.5 ± 100.5 ms, 292.7 ± 57.0 ms, P < 0.001), atrial ERP, antegrade AV node effective refractory period (AVNERP), and ventricular effective refractory period (VERP) lengthened as the age increased. The incidence of decremental APs, multiple APs, and a catecholamine response were similar. The duration of the catheter ablation, total fluoroscopy time, acute success rate, complication rate, and incidence of a secondary procedure were similar between the different age groups. The electrophysiological characteristics and pattern of the arrhythmic attack associated with the AP changed with age.

Riluzole Provides Insights into the Mechanisms of Ischaemic and Ischaemia-reperfusion Arrhythmias

Introduction: Primary pulmonary hypertension (PPH) is associated with RVH and RA enlargement. Little is known of the direct atrial effects of chronic stretch due to ventricular hypertrophy in humans. We performed electrophysiologic (EP) and electroanatomic (EA) RA studies in pts with PPH and RVH without atrial arrhythmias. Methods: 18 pts with (age: 52± 19 y) and without (age: 43± 14 y p= 0.3) PPHunderwent detailed EP and EAmapping. We measured atrial ERP, SNRT, conduction times (CT) and velocities (CV), regional low voltage and scar (bipolar voltage < 0.5mV and< 0.05mV, respectively) and serum markers of collagen turnover(P1NP). Results: (Table) PPH was associated with increased: RA pressure(4± 2 vs. 1± 1 in controls, p= 0.03); RVSP (61± 9mmHgvs. 23± 2mmHg in controls,p< 0.001). PPH wasassociatedwithprolongationofERPandSNRT, reduction in mean voltage, regional low voltage and atrial scarring together with slowing of global and regional conduction. Collagen turnover was increased in PPH (P1NP 171± 284 vs. controls 56± 39, p= 0.1). Conclusions: RVH secondary to PPH is associated with atrial remodelling characterised by (i) ERP prolongation, (ii) diffuse conduction slowing with evidence of marked regional abnormalities (iii) reduced tissue voltage and frank scar. These changes may in part be responsible for the increased propensity to AA’s observed with chronic atrial stretch secondary to ventricular hypertrophy.

Lipopolysaccharide Induces Atrial Arrhythmogenesis via Down-Regulation of L-Type Ca2+ Channel Genes in Rats

Septic shock has been reported as an independent risk factor for atrial fibrillation (AF), however, the mechanism remains unknown. We investigated whether lipopolysaccharide (LPS) could alter cardiac ion channel gene expression, thereby leading to atrial arrhythmogenesis. LPS (2.5 mg/kg) was injected intraperitoneally into 10 week old Sprague-Dawley rats (n = 5). Hemodynamic data were obtained and the atrial appendages were removed after LPS injection (0, 3, 6, 12, and 24 hours) for an RNase protection assay for alpha1C, beta2, alpha1G, and SCN5A. An electrophysiological study in isolated perfused hearts was performed before and 12 hours after the LPS injection. Heart rate and body temperature were significantly increased (P < 0.05) and mean blood pressure was slightly decreased (P < 0.1) at 12 hours after LPS injection. The mRNA levels of the L-type calcium channel gene (beta2 and alpha1C) were significantly decreased at 6 and 12 hours after LPS injection. Atrial ERP became significantly shortened and the number of repetitive atrial responses induced by an extrastimulus were significantly increased after LPS injection. LPS induced the down-regulation of L-type calcium channel gene expression and ERP shortening, which might be a mechanism underlying sepsis-induced AF.