Atrial Electrophysiological Properties Research Articles

Pacing cycle length–dependent electrophysiologic changes in left atrium: Poor validity of using low-voltage area and slow conduction area under specific pacing cycle length as absolute substrates of atrial fibrillation

BackgroundPacing cycle length (PCL)–dependent changes in left atrial (LA) electrophysiologic properties have not been fully elucidated. ObjectiveWe aimed to elucidate these changes using a high-resolution mapping system. MethodsForty-eight patients underwent atrial fibrillation ablation with RHYTHMIA HDx. Paired LA maps under a baseline PCL (600 ms) and rapid PCL (300 ms) were acquired after pulmonary vein isolation under right atrial appendage pacing. The PCL-dependent change in the low-voltage area (LVA; area with <0.5 mV bipolar voltage), LA activation time (interval from first LA activation to wavefront collision at lateral wall), regional mean voltage, regional mean wave propagation velocity, and slow conduction area (area with <0.3 m/s wave propagation velocity) were quantitatively analyzed. ResultsUnder the rapid PCL, the total LVA was significantly increased (7.6 ± 9.5 cm2 vs 6.7 ± 7.6 cm2; P = .031), especially in patients with a 10 cm2 LVA on the baseline PCL map (21.5 ± 9.1 cm2 vs 18.1 ± 6.5 cm2; P = .013). The LA activation time was also prolonged (87.9 ± 16.2 ms vs 84.0 ± 14.0 ms; P < .0001). Although the rapid PCL did not decrease the regional mean voltage, it significantly decreased the regional mean wave propagation velocity and increased the slow conduction area in all measured regions. ConclusionLVA and slow conduction area can be emphasized by rapid PCL LA mapping. There may be poor validity in using these areas as absolute atrial fibrillation substrates without considering the PCL-dependent changes.

Characterization of conduction recovery and atrial electrophysiological properties after pulmonary vein isolation using pulsed field ablation

Abstract Background Pulsed field ablation (PFA) is a relatively new technology for isolation of pulmonary veins in patients with atrial fibrillation (AF). Data addressing reasons for recurrent atrial fibrillation despite primarily successful pulmonary vein isolation (PVI) using PFA are scarce, due to an up to date limited number of patients treated this way. Objective The aim of this study was to analyze electrophysiological characteristics of reconduction and / or left atrial substrate of patients referred to our center for Re-Do procedures for recurrent AF after an initial PVI using PFA. Methods 90 patients (mean age 66±9 years, 69 male (77%)) had been treated in our center from November 2021 to July 2023 with PVI using PFA. 9 (10%) of these patients were referred for Re-Do procedures. These were performed by radiofrequency ablation (RFA) using Carto system including high density mapping and high power / short duration (HPSD) ablation. We analyzed location of PV reconnection and low voltage areas (LVA) in the left atria. Results 7 out of 9 patients (77%) presented with reconnections of pulmonary veins. In one patient a single vein showed reconduction (RSPV), in 5 patients 2 veins were conducting (1x LSPV, 3x LIPV, 1 left sided common os (LCo), 1x RSPV, 3x RIPV). None of the patients showed 3 or 4 reconnected veins. Areas of reconduction in each vein were: LSPV 1x ridge, 1x posterior; LIPV 1x posterior, 1x anterior and posterior; LCo 1x posterior, RSPV 1x anterior, 2x carina, 1x anterior and posterior; RIPV 1x complete, 2x carina. In 7 patients a fibrotic atrial cardiomyopathy (FACM) was diagnosed via high density mapping of LVA’s. In 2 of these patients all 4 pulmonary veins were chronically isolated after the initial PVI. All patients except one (very small anterior LVA) with FACM ≥1 were treated with additional linear or encircling lesions according to the individual extent of the fibrotic areas. 2 patients had no LVA’s detectable. In one of those 2 patients 2 veins had reconnected. The other patient had chronically isolated veins (no proof of dormant conduction with adenosine) and no detectable non-PV-triggers under isoprenaline. Conclusion In the population of patients undergoing PVI using PFA in our center, only 10% had clinically relevant recurrences leading to the necessity of a Re-Do procedure. Most patients (77%) in this setting had reconnections of pulmonary veins. There is a tendency of posterior reconnections of the left pulmonary veins and reconnections of the carina of the right pulmonary veins, but the number of patients is too small to clearly define predilection sites that have to be paid attention to when using PFA. Additionally, left atrial substrate is an important problem in patients with recurrent AF despite primarily successful PVI and has to be considered and thoroughly addressed in Re-Do procedures.Reconnection of LSPV and anterior LVAAblation of RSPV and LSPV (posterior)

Left Atrial Electrophysiological Properties after Pulmonary Vein Isolation Predict the Recurrence of Atrial Fibrillation: A Cohort Study.

The aim of this work was to investigate left atrial electrophysiological properties for their ability to predict the recurrence of atrial fibrillation (AF) following pulmonary vein isolation (PVI). The study comprised 53 patients with AF [62 (interquartile range (IQR): 52-68) years old; 47.2% females]. High-density, three-dimensional electro-anatomic mapping using PentaRay was conducted during sinus rhythm in the left atrium (LA) immediately after PVI. LA conduction time, conduction velocity in predefined anterior and posterior routes, low voltage area percentage and distribution were assessed. The AF recurrence group had longer LA conduction time compared to the non-recurrence group [11 (IQR: 10-12) ms vs. 9 (IQR: 8-10) ms, p = 0.001). The percent low voltage area was greater in the recurrence group than the non-recurrence group [31.2 (IRQ: 7.1-49.3)% vs. 7.7 (IQR: 4.3-15.2)%, p = 0.008]. Multivariate Cox regression revealed that LA conduction time independently predicted AF recurrence following ablation over a median follow-up of 235 days [IQR: 154-382 days; hazard ratio (HR): 2.37, 95% confidence interval (CI): 1.08-5.23, p = 0.031]. The optimal cut-off for LA conduction time was 98 ms [area under curve (AUC): 0.926, sensitivity: 0.833, specificity: 0.894, p 0.01]. Kaplan-Meier analysis revealed that patients with a conduction time 98 ms had a higher rate of AF recurrence following ablation (p 0.001). Patients with longer LA conduction time after PVI had more frequent AF recurrence.

How sex affects the sinus rhythm heartbeat

BackgroundThere is increasing awareness of sex-specific differences in epidemiology and pathophysiology of atrial fibrillation (AF). It is, however, unknown whether males and females differ in atrial electrophysiological properties during sinus rhythm (SR). The aim of this study was therefore to investigate sex-based (regional) differences in electrophysiological properties during SR of the right (RA) and left (LA) atrium including Bachmanns Bundle (BB) and pulmonary vein region (PVA). MethodsIntra-operative, high resolution mapping during SR was performed in 53 matched females with males (without a history of AF), to measure lines of conduction block (CB), continuous conduction delay and block (cCDCB), conduction velocities (CV), total atrial activation times (TAT), unipolar potential voltages and percentage of low voltage areas (LVA). ResultsCompared to males, females have significantly 1) lower unipolar potential voltages and slower CV at both RA and BB, 2) more LVAs, CB and cCDCB lines and longer CB and cCDCB lines at the RA only (all P < 0.05). ConclusionsElectrophysiological properties of the atria during SR differ between males and females. These sex-based differences are particularly present at the RA and to a lesser degree at BB. In females, both the RA and BB contained more areas of conduction disorders and low voltage potentials. Future studies are required to investigate whether these areas play a role in sex-based differences in vulnerability to arrhythmias such as atrial fibrillation.

Patch‐clamping on isolated equine atrial cardiomyocytes to study atrial electrophysiological properties

Patch‐clamping on isolated equine atrial cardiomyocytes to study atrial electrophysiological properties

PO-02-208 CHARACTERIZATION OF ATRIAL ELECTROPHYSIOLOGICAL PROPERTIES IN PATIENTS WITH HYPERTROPHIC OBSTRUCTIVE CARDIOMYOPATHY

Atrial fibrillation (AF) occurs frequently in patients with hypertrophic obstructive cardiomyopathy (HOCM) and the success rate of pulmonary vein isolation in these patients is less effective compared to other populations. This may be explained by the presence of an extensive arrhythmogenic substrate in both atria due to a primary atrial myopathy, but electrophysiological properties of the right (RA) and left atrium (LA) have never been investigated. The aim of this study is to 1) quantify atrial electrophysiological properties during sinus rhythm and 2) to determine whether atrial electrogram morphology and conduction disorders differ between the RA and LA in patients with HOCM. Intra-operative epicardial mapping of both atria was performed in HOCM patients undergoing surgical myectomy. Conduction delay and/or block (CD, CB), unipolar electrograms characteristics (unipolar voltages, potential fractionation) and low voltage areas (LVA) were quantified during sinus rhythm. Fifteen patients (mean age: 50± 12 years) were included. Conduction disorders were found in both atria in all patients, but did not differ between the RA and LA (CD: 2.9 [1.9-3.6] % versus 2.6 [2.1-6.4] %, p=0.541; CB: 1.7 [0.9-3.1] % versus 1.5 [0.5-2.8] %, p=0.600; respectively). Though unipolar voltages histograms differed significantly between the RA and LA (Table 1), LVA were equally present in both RA and LA (RA: 4.7 % [1.6-7.7] % versus LA: 2.9 % [2.1-7.1] %, p=0.793). The magnitude of unipolar voltages of single- and complex fractionated potentials (SP, CFP) were higher in the LA compared to the RA (SP: P75 10.9 mV versus 7.3 mV, respectively; CFP: P75 3.7 mV versus 2.0 mV, respectively).(Table 1) CFP corresponded to LVA in only 18% of all LA sites compared to 36% of all RA sites. In patients with HOCM, the magnitude of unipolar voltages is considerably higher in the LA compared to the RA. Remarkably, fractionated potentials in both atria mainly contained high voltage deflections. Therefore, substrate modification strategies, consisting of low voltage or other electrogram morphology guided AF ablation strategies, should be disease-tailored in this population. The observed equal amount of conduction disorders and LVA in both atria support the concept of a primary atrial myopathy with a bi-atrial substrate in HOCM patients.

An atrial fibrillation-associated regulatory region modulates cardiac Tbx5 levels and arrhythmia susceptibility.

Heart development and rhythm control are highly Tbx5 dosage-sensitive. TBX5 haploinsufficiency causes congenital conduction disorders, whereas increased expression levels of TBX5 in human heart samples has been associated with atrial fibrillation (AF). We deleted the conserved mouse orthologues of two independent AF-associated genomic regions in the Tbx5 locus, one intronic (RE(int)) and one downstream (RE(down)) of Tbx5. In both lines, we observed a modest (30%) increase of Tbx5 in the postnatal atria. To gain insight into the effects of slight dosage increase in vivo, we investigated the atrial transcriptional, epigenetic and electrophysiological properties of both lines. Increased atrial Tbx5 expression was associated with induction of genes involved in development, ion transport and conduction, with increased susceptibility to atrial arrhythmias, and increased action potential duration of atrial cardiomyocytes. We identified an AF-associated variant in the human RE(int) that increases its transcriptional activity. Expression of the AF-associated transcription factor Prrx1 was induced in Tbx5RE(int)KO cardiomyocytes. We found that some of the transcriptional and functional changes in the atria caused by increased Tbx5 expression were normalized when reducing cardiac Prrx1 expression in Tbx5RE(int)KO mice, indicating an interaction between these two AF genes. We conclude that modest increases in expression of dose-dependent transcription factors, caused by common regulatory variants, significantly impact on the cardiac gene regulatory network and disease susceptibility.

Epicardial Adipose Tissue and Cardiac Arrhythmias: Focus on Atrial Fibrillation

Atrial Fibrillation (AF) is the most frequent cardiac arrhythmia and its prevalence increases with age. AF is strongly associated with an increased risk of stroke, heart failure and cardiovascular mortality. Among the risk factors associated with AF onset and severity, obesity and inflammation play a prominent role. Numerous recent evidence suggested a role of epicardial adipose tissue (EAT), the visceral fat depot of the heart, in the development of AF. Several potential arrhythmogenic mechanisms have been attributed to EAT, including myocardial inflammation, fibrosis, oxidative stress, and fat infiltration. EAT is a local source of inflammatory mediators which potentially contribute to atrial collagen deposition and fibrosis, the anatomical substrate for AF. Moreover, the close proximity between EAT and myocardium allows the EAT to penetrate and generate atrial myocardium fat infiltrates that can alter atrial electrophysiological properties. These observations support the hypothesis of a strong implication of EAT in structural and electrical atrial remodeling, which underlies AF onset and burden. The measure of EAT, through different imaging methods, such as echocardiography, computed tomography and cardiac magnetic resonance, has been proposed as a useful prognostic tool to predict the presence, severity and recurrence of AF. Furthermore, EAT is increasingly emerging as a promising potential therapeutic target. This review aims to summarize the recent evidence exploring the potential role of EAT in the pathogenesis of AF, the main mechanisms by which EAT can promote structural and electrical atrial remodeling and the potential therapeutic strategies targeting the cardiac visceral fat.

Clinical Relevance of Sinus Rhythm Mapping to Quantify Electropathology Related to Atrial Fibrillation.

Progression of AF is accompanied by structural and electrical remodelling, resulting in complex electrical conduction disorders. This is defined as electropathology and it increases with the progression of AF. The severity of electropathology, thus, defines the stage of AF and is a major determinant of effectiveness of AF therapy. As specific features of AF-related electropathology are still unknown, it is essential to first quantify the electrophysiological properties of atrial tissue and then to examine the inter- and intra-individual variation during normal sinus rhythm. Comparison of these parameters between patients with and without a history of AF unravels quantified electrophysiological features that are specific to AF patients. This can help to identify patients at risk for early onset or progression of AF. This review summarises current knowledge on quantified features of atrial electrophysiological properties during sinus rhythm and discusses its relevance in identifying AF-related electropathology.

Abstract 11005: Electrophysiological Remodelling of Right Atria in Atrial Fibrillation Sheep Model and Role of Succinate in Electrophysiological Properties

Introduction: Atrial fibrillation (AF) is the most common arrhythmia and is associated with deleterious remodelling processes. In AF patients, the plasmatic succinate content increases, indicating a potential role for metabolic remodelling in AF progression. Objective: To assess the impact of succinate on the electrophysiological properties of right atria (RA) in a persistent AF sheep model. Methods: Optical mapping experiments were performed in ex vivo RA from a burst pacing AF sheep model (SHAM=5; AF=5). The right coronary artery was perfused with Tyrode solution initially containing glucose (5.6mM), subsequently replaced by succinate (5mM). Action potential durations at 80% of repolarization (APD80) and mean conduction velocities (CV) were assessed from 2 to 5Hz pacing frequency and during sinus rhythm (SR). An S1S2 protocol was used to determine effective refractory period (ERP) and a burst pacing procotol (20Hz) to assess ex vivo AF vulnerability. Finally, an organ donation program allowed us to investigate these properties in a human RA from an AF patient. Results: SR frequency was higher in AF than SHAM sheep (2.0 vs. 1.6 Hz; p=0.19). Succinate perfusion decreased SR frequency by 18% in SHAM sheep (1.7 vs. 1.4 Hz; p=0.12) and by 43% in AF sheep (2.0 vs. 1.2 Hz; p=0.009). The ERP was lower in AF than SHAM sheep (184 vs. 210 ms; p=0.5) and succinate induced a significant increase of 136% in SHAM sheep (210 vs. 286 ms; p=0.06) and of 188% in AF sheep (184 vs. 346 ms; p=0.0008). Epicardial APD80 was lower when pacing at 2.5Hz in AF than SHAM sheep (165 vs. 197 ms ; p=0.3). Succinate increased APD80 in both SHAM and AF RA (191 to 224 ms; 165 to 231 ms) but its effect was more important in AF than SHAM sheep (148 vs. 117 %; p=0.1). Mean CV was slower in AF sheep than SHAM sheep (110 vs. 130 cm/s; p=0.47). Succinate slowed mean CV on AF sheep (110 vs. 76; p=0.4) but did not affect SHAM RA. In the human RA, APD80 (257 vs; 309 ms) and total activation time were increased by succinate. Conclusions: Our results indicate that succinate alters atrial electrophysiological properties, most likely through the associated ROS overproduction. Importantly, AF sheep showed an increased sensitivity to succinate perfusion. Preliminary data in a human RA are in line with these observations.

Isolated superfused rats atrial model for the investigation of atrial fibrillation mechanisms and treatment

Abstract Background One of the major barriers to an improved mechanistic understanding of atrial fibrillation (AF), and thus in the pipeline of drug development, has been a lack of appropriate tissue models, especially in small animals. Aim We propose an advanced anatomical ex-vivo model based on rat atria for acute assessment of AF susceptibility. This novel model could yield a better understanding of arrhythmia mechanisms as well as the development of potential therapeutic strategies for the prevention or termination of atrial arrhythmias. Methods Wistar rats atria (N=25) were isolated, flattened and pinned to a custom-made silicon plate. Atria were superfused with an oxygenized Tyrode's solution. Tissues were then loaded with a voltage-sensitive dye and mapped using a high-resolution optical mapping system. AF was induced with 1uM carbamylcholine (N=23) coupled with pacing maneuvers and treated with 30uM Vernakalant (N=10) or 10uM Flecainide (N=10). Finally, the feasibility of a new ablation technique (electroporation) was evaluated. Results Optical mapping results suggested that the superfusion procedure led to a fast atrial recovery. Sinus activity was conserved for all atria for a long period. All the anatomical landmarks were clearly visualized. The acquired optical signals were analyzed during sinus rhythm and pacing, which allowed the creation of detailed activation maps and measurements of action potential duration (APD) and conduction velocity (CV) at different pacing rates. The resulting APD restitution curves revealed electrical excitation at high pacing rates (cycle length between 50ms and 300ms) with a relatively flattened curve. AF was successfully induced and optically mapping confirmed the presence of reentrant activity. AF was successfully treated using Vernacalant and Flecainide. Finally, we demonstrated the feasibility of a new ablation approach (electroporation) for creation of a continuous linear lesion serving as a functional block. Conclusion The isolated superfused atria model, coupled with voltage-sensitive dyes, can be utilized for long-term high-resolution functional imaging of the atria during sinus rhythm, pacing and arrhythmogenic activity. This allows the study of the atrial electrophysiological properties, the mechanisms involved in AF initiation, perpetuation, and termination as well as the study of drug and new ablation modalities. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research Council (ERC) Spontaneous activation of isolated atria

Persistent atrial fibrillation ablation in cardiac laminopathy: Electrophysiological findings and clinical outcomes

Little is known about persistent atrial fibrillation (AF) ablation in patients with cardiac laminopathy (CLMNA). We aimed to characterize atrial electrophysiological properties and to assess the long-term outcomes of persistent AF ablation in patients with CLMNA. All patients with CLMNA referred in our center for persistent AF ablation were retrospectively included. Left atrial (LA) volume, left atrial appendage (LAA) cycle length, interatrial conduction delay, and LA voltage amplitude were analyzed during the ablation procedure. Sinus rhythm maintenance and LA contractile function were assessed during long-term follow-up. From 2011 to 2020, 8 patients were included. The mean age was 47 ± 14 years, and 3 patients (38%) were women. The LA volume was 205.8 ± 43.7 mL; the LAA AF cycle length was 250.7 ± 85.6 ms; and the interatrial conduction delay was 296.5 ± 110.1 ms. Large low-voltage areas (>50% of the LA surface; <0.5 mV electrogram) were recorded in all 8 patients. Two patients had inadvertent LAA disconnection during ablation. All A waves recorded by pulsed Doppler in sinus rhythm were <30 cm/s before and after AF ablation. Early arrhythmia recurrence was recorded in 7 patients (87%) (time to recurrence 4 ± 4 months; 1.5 procedures per patient). After a mean follow-up of 4.4 ± 3.2 years, 4 patients underwent implantable cardioverter-defibrillator therapy for life-threatening ventricular arrhythmia and 3 patients finally underwent heart transplantation. Patients with persistent AF afflicted by CLMNA exhibit severe LA impairment because of large low-voltage areas, prolonged conduction velocity, and reduced contractile function. Ablation procedures have a limited effect with a high recurrence rate.

Genetic Susceptibility to Atrial Fibrillation Is Associated With Atrial Electrical Remodeling and Adverse Post-Ablation Outcome.

This study sought to assess the atrial electrophysiological properties and post-ablation outcomes in patients with atrial fibrillation (AF) with and without the rs2200733 single nucleotide variant. The phenotype associated with chromosome 4q25 of the AF-susceptibility locus remains unknown. In this study, 102 consecutive patients (ages 61 ± 9 years, 64% male) with paroxysmal or persistent AF were prospectively recruited prior to ablation. Patients were genotyped for rs2200733 and high-density left atrial (LA) electroanatomic maps were created using a multipolar catheter during distal coronary sinus (CS) pacing at 600ms. Voltage, conduction velocity (CV), CV heterogeneity, and fractionated signals of 6 LA segments were determined. Arrhythmia recurrence was assessed by continuous device (51%) and Holter monitoring. Overall, 41 patients (40%) were single nucleotide variant carriers (38 heterozygous, 3 homozygous). A mean of 2,239 ± 852 points per patient were collected. Carriers had relatively increased CV heterogeneity (45.7 ± 7.5% vs. 35.9 ± 2.3%; p<0.001), complex signals (9.4 ± 2.9% vs 6.0 ± 1.2%; p=0.008), regional LA slowing, or conduction block (31.7 ± 8.2% vs. 17.9 ± 1.9%; p=0.013) particularly in the posterior and lateral walls. There were no differences in CV, voltage, atrial refractoriness, or sinus node function. At follow-up (median: 27months; range 19 to 31months), carriers had lower arrhythmia-free survival (51% vs. 80%; p=0.003). On multivariable analysis, carrier status was independently associated with CV heterogeneity (p=0.001), complex signals (p=0.002), and arrhythmia recurrence (p=0.019). These data provide the first evidence that the rs2200733-tagged haplotype alters LA electrical remodeling and is a determinant of long-term outcome following AF ablation. The molecular mechanisms underpinning these changes warrant further investigation.

Previous use of Statins and Atrial Electrical Remodeling in Patients with Cryptogenic Stroke.

In the general population the leading cause of cardioembolic stroke is atrial fibrillation (AF). A silent AF is also the possible cause of many cryptogenic strokes. P wave dispersion (PWD), a predictor of AF, has been proposed as a marker of silent AF occurrence in these strokes. PWD correlates with high-sensitive C-reactive protein levels reflecting the role of inflammation in promoting a slowed and inhomogeneous atrial conduction. Statins have a multitude of additional effects beyond lipid lowering, in particular anti-inflammatory effects that may influence atrial conduction. The aim of this study was to evaluate the effects of previous statin use on PWD in patients with cryptogenic stroke, in order to highlight a possible role for statins in preventing atrial conduction alterations that predispose to AF. We enrolled 131 patients (67 males, 64 females; mean age 69±13 years) with cryptogenic stroke. All patients underwent neuroimaging examination, arterial ultrasound examination, echocardiography and ECG. PWD was measured in all subjects. Patients previously treated with statins (n: 34) had lower PWD and P index values in comparison with no-statin group (41.7±12.2 vs 48.7±15.2 ms, p=0.01, and 14.2±3.7 vs 16.5±5.3 ms, p=0.02, respectively). Our results show lower PWD values in cryptogenic stroke patients previously treated with statins. These findings provide support to the hypothesis that statins may play a role in modulating atrial electrophysiological and structural properties, preventing the occurrence of a slowed and heterogeneous atrial conduction and finally, reducing the occurrence of AF.

In Silico Assessment of Efficacy and Safety of IKur Inhibitors in Chronic Atrial Fibrillation: Role of Kinetics and State-Dependence of Drug Binding.

Current pharmacological therapy against atrial fibrillation (AF), the most common cardiac arrhythmia, is limited by moderate efficacy and adverse side effects including ventricular proarrhythmia and organ toxicity. One way to circumvent the former is to target ion channels that are predominantly expressed in atria vs. ventricles, such as KV1.5, carrying the ultra-rapid delayed-rectifier K+ current (IKur). Recently, we used an in silico strategy to define optimal KV1.5-targeting drug characteristics, including kinetics and state-dependent binding, that maximize AF-selectivity in human atrial cardiomyocytes in normal sinus rhythm (nSR). However, because of evidence for IKur being strongly diminished in long-standing persistent (chronic) AF (cAF), the therapeutic potential of drugs targeting IKur may be limited in cAF patients. Here, we sought to simulate the efficacy (and safety) of IKur inhibitors in cAF conditions. To this end, we utilized sensitivity analysis of our human atrial cardiomyocyte model to assess the importance of IKur for atrial cardiomyocyte electrophysiological properties, simulated hundreds of theoretical drugs to reveal those exhibiting anti-AF selectivity, and compared the results obtained in cAF with those in nSR. We found that despite being downregulated, IKur contributes more prominently to action potential (AP) and effective refractory period (ERP) duration in cAF vs. nSR, with ideal drugs improving atrial electrophysiology (e.g., ERP prolongation) more in cAF than in nSR. Notably, the trajectory of the AP during cAF is such that more IKur is available during the more depolarized plateau potential. Furthermore, IKur block in cAF has less cardiotoxic effects (e.g., AP duration not exceeding nSR values) and can increase Ca2+ transient amplitude thereby enhancing atrial contractility. We propose that in silico strategies such as that presented here should be combined with in vitro and in vivo assays to validate model predictions and facilitate the ongoing search for novel agents against AF.

Effect of eicosapentaenoic acid and pitavastatin on electrophysiology and anticoagulant gene expression in mice with rapid atrial pacing.

Atrial remodeling is considered to be any persistent change in atrial structure or function, and is responsible for the development and perpetuation of atrial fibrillation (AF). Oxidative stress and intracellular pH regulation may also be linked to AF; however it remains unclear whether eicosapentaenoic acid (EPA) or statins have beneficial therapeutic effects. The aim of the present study was to investigate the effects of EPA and pitavastatin on the electrophysiology of and gene expressions in mice with rapidly-paced atria. Mice were treated with EPA (10 mg/g/day) or pitavastatin (30 ng/g/day) for 6 weeks, following which AF was simulated by 8-h atrial pacing at 1,800 bpm. The atrial electrophysiological properties and the expression of cardiac genes, potassium voltage-gated channel subfamily A member 5 (Kcna5), Kcn subfamily D member 2 (Kcnd2), Kv channel-interacting protein 2 (KChIP2), solute carrier family 9 member A1, thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI) were examined using reverse transcription-quantitative polymerase chain reaction. In control mice, significant atrial electrical remodeling was observed (P<0.05); however, treatment with either EPA or pitavastatin ameliorated these electrophysiological changes (P>0.05). mRNA levels of Kcnd2, KChIP2 and Kcna5 were significantly upregulated in control mice (P<0.05), whereas treatment with EPA or pitavastatin attenuated this upregulation (P>0.05). Administration of pitavastatin significantly reduced the downregulation of both TFPI and TM (P<0.05). EPA treatment attenuated the TFPI downregulation compared with control mice (P>0.05), however no significant effect on TM expression was observed. In addition, both EPA (P>0.05) and pitavastatin (P<0.05) suppressed the overexpression of endothelial nitric oxide synthase. This was also exhibited in Ras-related C3 botulinum toxin substrate 1 genes (P<0.01 for both treatments). In conclusion, the results of the present study suggested that EPA and pitavastatin are able to prevent atrial electrical remodeling, thrombotic states and oxidative stress in rapidly-paced murine atria.

Noninvasive Imaging of Human Atrial Activation during Atrial Flutter and Normal Rhythm from Body Surface Potential Maps.

BackgroundKnowledge of atrial electrophysiological properties is crucial for clinical intervention of atrial arrhythmias and the investigation of the underlying mechanism. This study aims to evaluate the feasibility of a novel noninvasive cardiac electrical imaging technique in imaging bi-atrial activation sequences from body surface potential maps (BSPMs).MethodsThe study includes 7 subjects, with 3 atrial flutter patients, and 4 healthy subjects with normal atrial activations. The subject-specific heart-torso geometries were obtained from MRI/CT images. The equivalent current densities were reconstructed from 208-channel BSPMs by solving the inverse problem using individual heart-torso geometry models. The activation times were estimated from the time instant corresponding to the highest peak in the time course of the equivalent current densities. To evaluate the performance, a total of 32 cycles of atrial flutter were analyzed. The imaged activation maps obtained from single beats were compared with the average maps and the activation maps measured from CARTO, by using correlation coefficient (CC) and relative error (RE).ResultsThe cardiac electrical imaging technique is capable of imaging both focal and reentrant activations. The imaged activation maps for normal atrial activations are consistent with findings from isolated human hearts. Activation maps for isthmus-dependent counterclockwise reentry were reconstructed on three patients with typical atrial flutter. The method was capable of imaging macro counterclockwise reentrant loop in the right atrium and showed inter-atria electrical conduction through coronary sinus. The imaged activation sequences obtained from single beats showed good correlation with both the average activation maps (CC = 0.91±0.03, RE = 0.29±0.05) and the clinical endocardial findings using CARTO (CC = 0.70±0.04, RE = 0.42±0.05).ConclusionsThe noninvasive cardiac electrical imaging technique is able to reconstruct complex atrial reentrant activations and focal activation patterns in good consistency with clinical electrophysiological mapping. It offers the potential to assist in radio-frequency ablation of atrial arrhythmia and help defining the underlying arrhythmic mechanism.

Acute effects of unilateral temporary stellate ganglion block on human atrial electrophysiological properties and atrial fibrillation inducibility

In experimental models, stellate ganglion block (SGB) reduces the induction of atrial fibrillation (AF), while data in humans are limited. The aim of this study was to assess the effect of unilateral SGB on atrial electrophysiological properties and AF induction in patients with paroxysmal AF. Thirty-six patients with paroxysmal AF were randomized in a 2:1 order to temporary, transcutaneous, pharmaceutical SGB with lidocaine or placebo before pulmonary vein isolation. Lidocaine was 1:1 randomly infused to the right or left ganglion. Before and after randomization, atrial effective refractory period (ERP) of each atrium, difference between right and left atrial ERP, intra- and interatrial conduction time, AF inducibility, and AF duration were assessed. After SGB, right atrial ERP was prolonged from a median (1st-3rd quartile) of 240 (220-268) ms to 260 (240-300) ms (P < .01) and left atrial ERP from 235 (220-260) ms to 245 (240-280) ms (P < .01). AF was induced by atrial pacing in all 24 patients before SGB, but only in 13 patients (54%) after the intervention (P < .01). AF duration was shorter after SGB: 1.5 (0.0-5.8) minutes from 5.5 (3.0-12.0) minutes (P < .01). Intra- and interatrial conduction time was not significantly prolonged. No significant differences were observed between right and left SGB. No changes were observed in the placebo group. Unilateral temporary SGB prolonged atrial ERP, reduced AF inducibility, and decreased AF duration. An equivalent effect of right and left SGB on both atria was observed. These findings may have a clinical implication in the prevention of drug refractory and postsurgery AF and deserve further clinical investigation.

Cardiac pacing in 21 patients with Emery-Dreifuss muscular dystrophy: a single-centre study with a 39-year follow-up.

Emery-Dreifuss muscular dystrophy (EDMD) is a genetic condition associated with cardiac arrhythmias. The patients typically develop early, asymptomatic bradyarrhythmia, which may lead to sudden death, preventable with a cardiac implantable electronic device (CIED). EDMD may be characterised by atrial electrical silence. Intra-operative electrophysiological evaluation of the myocardium helps ultimately determine the true nature of the disorder and select an appropriate CIED. To analyse permanent electrotherapy procedures in EDMD patients: atrial pacing limitations that stem from the electrophysiological properties of the myocardium and long-term follow-up of implanted devices. A total of 21 EDMD patients (mean age 29 ± 9 years) with a CIED implanted (1976-2014) due to bradyarrhythmia were included in the study. The implantation procedures and factors determining the CIED type selection were analysed. CIEDs were implanted in five women and in 16 men with EDMD types 1 and 2 (mean follow-up: 11 ± 8 years). Intra-operatively assessed atrial electrophysiology resulted in changing the planned CIED type during the procedure in three men with EDMD type 1. Eventually, we implanted: eight DDD, one VDD, 11 VVI, and one CD-DR device, with four of the patients' devices switched later from DDD to VVI mode in response to electrophysiological changes in the atria. Intra-operative assessment of atrial electrophysiological properties resulted in changing the planned DDD mode for VVI in 19% of patients with EDMD type 1. Progression of the underlying disease over a 39-year follow-up resulted in a later change of the initially selected pacing mode from DDD to VVI in 40% of cases.

Neuronally released vasoactive intestinal polypeptide alters atrial electrophysiological properties and may promote atrial fibrillation.

Vagal hyperactivity promotes atrial fibrillation (AF), which has been almost exclusively attributed to acetylcholine. Vasoactive intestinal polypeptide (VIP) and acetylcholine are neurotransmitters co-released during vagal stimulation. Exogenous VIP has been shown to promote AF by shortening action potential duration (APD), increasing APD spatial heterogeneity, and causing intra-atrial conduction block. The purpose of this study was to investigate the effects of neuronally released VIP on atrial electrophysiologic properties during vagal stimulation. We used a specific VIP antagonist (H9935) to uncover the effects of endogenous VIP released during vagal stimulation in canine hearts. H9935 significantly attenuated (1) the vagally induced shortening of atrial effective refractory period and widening of atrial vulnerability window during stimulation of cervical vagosympathetic trunks (VCNS) and (2) vagal effects on APD during stimulation through fat-pad ganglion plexus (VGPS). Atropine completely abolished these vagal effects during VCNS and VGPS. In contrast, VGPS-induced slowing of local conduction velocity was completely abolished by either VIP antagonist or atropine. In pacing-induced AF during VGPS, maximal dominant frequencies and their spatial gradients were reduced significantly by H9935 and, more pronouncedly, by atropine. Furthermore, VIP release in the atria during vagal stimulation was inhibited by atropine, which may account for the concealment of VIP effects with muscarinic blockade. Neuronally released VIP contributes to vagal effects on atrial electrophysiologic properties and affects the pathophysiology of vagally induced AF. Neuronal release of VIP in the atria is inhibited by muscarinic blockade, a novel mechanism by which VIP effects are concealed by atropine during vagal stimulation.