Atrial Conduction Research Articles

Total Atrial Conduction Time as a Predictor of Atrial Fibrillation Recurrence: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis aims to evaluate the predictive value of total atrial conduction time (TACT) assessed by tissue Doppler echocardiography (PA-TDI) in atrial fibrillation (AF) recurrence in patients following a rhythm-control strategy. A systematic approach following Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines was applied in electronic databases (Pubmed, Cochrane Library, and Web of Science), supplemented by scanning through studies' references. TACT was compared using a random-effects model and presented as a difference in means (MD). The primary endpoint was AF recurrence. Seven publications were included in this systematic review. The mean age of the patients ranged from 55 years to 72 years. Prolonged TACT was associated with AF recurrence [MD, 23.12 msec; 95% confidence interval (CI), 11.54-34.71; I2 = 95%]. Subgroup analysis showed that prolonged TACT was strongly associated with AF recurrence in persistent AF cohorts undergoing electrical cardioversion (MD, 26.56; 95% CI, 15.51-37.6; I2 = 86%), while in patients with paroxysmal AF (PAF) undergoing catheter ablation, the results were not statistically significant (MD, 11.48; 95% CI, -1.19 to 24.14; I2 = 90%). The summary area under the curve (sAUC) using a random-effects model was 0.89 (95% CI, 0.80-0.99). TACT is a valuable echocardiographic parameter that can predict AF recurrence in patients following a rhythm-control strategy. Protocol registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022353018.

Left atrial conduction times and regional velocities in persistent atrial fibrillation patients with and without fibrotic atrial cardiomyopathy

Despite the progress in understanding left atrial substrate and arrhythmogenesis, only little is known about conduction characteristics in atrial fibrillation patients with various stages of fibrotic atrial cardiomyopathy (FACM). This study evaluates left atrial conduction times and conduction velocities based on high-density voltage and activation maps in sinus rhythm (CARTO®3 V7) of 53 patients with persistent atrial fibrillation (LVEF 60% (55–60 IQR), LAVI 39 ml/m2 (31–47 IQR), LApa 24 ± 6 cm2). Measurements were made in low voltage areas (LVA ≤ 0.5 mV) and normal voltage areas (NVA ≥ 1.5 mV) at the left atrial anterior and posterior walls. Maps of 28 FACM and 25 no FACM patients were analyzed (19 FACM I/II, 9 FACM III/IV, LVA 14 ± 11 cm2). Left atrial conduction time averaged to 110 ± 24 ms but was shown to be prolonged in FACM (119 ms, + 17%) when compared to no FACM patients (101 ms, p = 0.005). This finding was pronounced in high-grade FACM (III/IV) (133 ms, + 31.2%, p = 0.001). In addition, the LVA extension correlated significantly with the left atrial conduction time (r = 0.56, p = 0.002). Conduction velocities were overall slower in LVA than in NVA (0.6 ± 0.3 vs. 1.3 ± 0.5 m/s, -51%, p < 0.001). Anterior conduction appeared slower than posterior, which was significant in NVA (1 vs. 1.4 m/s, -29%, p < 0.001) but not in LVA (0.6 vs. 0.8 m/s, p = 0.096). FACM has a significant influence on left atrial conduction characteristics in patients with persistent atrial fibrillation. Left atrial conduction time prolongs with the grade of FACM and the quantitative expanse of LVA up to 31%. LVAs show a 51% conduction velocity reduction compared to NVA. Moreover, regional conduction velocity differences are present in the left atrium when comparing anterior to posterior walls. Our data may influence individualized ablation strategies.

Novel pathogenic variant in LMNA gene identified in a six-generation family causing atrial cardiomyopathy and associated right atrial conduction arrhythmias.

To characterize the cardiac phenotype associated with the novel pathogenic variant (c.1526del) of LMNA gene, which we identified in a large, six-generation family. A family tree was constructed. The clinical data of living and deceased family members were collected. DNA samples from 7 family members were analyzed for LMNA mutations using whole-exome high-throughput sequencing technology. The clinical presentation of pathogenic variant carriers was evaluated. In this six-generation family (n = 67), one member experienced sudden death at the age of 40-years-old. Three pathogenic variant carriers were identified to possess a novel heterozygous deletion mutation in LMNA gene (HGVS: NM_170707.4, c.1526del) located at exon 9 of LMNA chr1:156137145, which creates a premature translational stop signal (p.Pro509Leufs*39) in the LMNA gene and results in an mutant lamin A protein product. The main symptoms of the pathogenic variant carriers were palpitation, fatigue, and syncope, which typically occurred around 20-years-old. AV-conduction block and non-sustained ventricular tachycardia were the first signs of disease and would rapidly progress to atrial standstill around 30-years-old. Significant right atrial enlargement and bicuspid aortic valve malformation was also commonly seen in patients who carried this pathogenic variant. The pathogenic variant of c.1526del p.P509Lfs*39 was a frameshift deletion located at exon 9 of LMNA chr1:156137145 and causes severe right atrial enlargement, sick sinus syndrome, atrial standstill, ventricular tachycardia, and bicuspid aortic valve malformation. Our findings expand the phenotypic spectrum of novel LMNA gene mutations.

Effect of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors and their combination on left atrial strain and arterial function

Abstract Funding Acknowledgements Type of funding sources: None. Background We investigated the effects of insulin, glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and their combination on left atrial function of patients with type 2 diabetes mellitus and we searched for a relation with arterial function. Patients and methods A total of 201 patients (59,5±9,1 year old, 161 male) with type 2 diabetes mellitus treated with metformin were randomized to insulin (n= 50 served as controls), liraglutide (n=51), empagliflozin (n=50) or their combination (GLP-1RA+SGLT- 2i) (n= 50) as add-on. We measured at baseline and 6 months posttreatment: (a) perfused boundary region of the sublingual arterial microvessels (marker of endothelial glycocalyx thickness), (b) pulse wave velocity (PWV) and central systolic blood pressure, (c) global left ventricular Longitudinal strain, (d) left atrial strain. Results Six months after intervention, all patients improved left atrial reservoir strain (GLP1RA 30,7±9,3 vs 33,9±9,7%, p = 0,011/SGLT2i 30±8,3 vs 32,3±7,3%, p = 0,04/ GLP1&amp;SGLT2i 29,1±8,7 vs 31,3±8,2, p = 0,007) in comparison with controls (33±8,3% vs 32,8±7,4, p = 0,829). Also, patients treated with GLP1RA and their combination improved left atrial conduction strain (p&amp;lt;0.05). GLP-1RA or GLP-1RA+SGLT-2i provided a greater improvement in GLS compared with insulin or SGLT-2i (controls –18,5±3,9% vs − 19,1±3%, p = 0,202/GLP1RA –18,2±4,1% vs –19,1±3,5%, p = 0,03/SGLT2i –19±4,1% vs − 19,1±3,8%, p = 0,764/GLP1&amp;SGLT2i –16,7±3,9% vs –17,5±4,3%, p = 0,026). SGLT-2i or GLP-1RA and SGLT-2i showed a greater decrease of PWV (Controls 12,06±3,02 vs 11,62±2,79 m/sec, p = 0,142/ GLP1 11,54±2,91 vs 11,45±2,52 m/sec, p = 0,822/ SGLT2 11,86±2,51 vs 11,33±2,28 m/sec, p = 0,047/ GLP1&amp;SGLT2 12,01±2,46 vs 10,85±1,79 m/sec, p = 0,021) and central and brachial systolic blood pressure than insulin or GLP-1RA. At baseline, there was a correlation of LA reservoir strain with PWV (r =−0,209, p = 0,008), central SBP (r =−0,151, p = 0,030), EF (r=0,214, p = 0,004), GLS (r =−0,279, p = 0,009). At 6 months follow up, there was a correlation of LA reservoir strain with PWV (r=0,217, p = 0,003), central SBP (r =0,214, p = 0,004), EF (r=–0,221, p = 0,049), GLS (r =0,275, p = 0,014). Conclusions Treatment with GLP-1RA, SGLT-2i, and their combination for 6 months showed a greater improvement of left atrial function compared to insulin treatment in parallel with improvement arterial and myocardial function.

Arrhythmias in patients with cardiac amyloidosis

Cardiac amyloidosis is characterized by the extracellular deposition of fibrillar proteins in various heart parts, which can lead to restrictive heart failure and cardiac arrhythmias. In many cases, the incidence of both atrial and ventricular arrhythmias and conduction disorders is high and underestimated. The clinical picture often manifests itself only at the time of extensive involvement of the muscular and conduction system of the heart. Secondary to amyloid infiltration, bradyarrhythmias, and conduction disorders can occur, however, the timing of pacemaker implantation remains unclear. Many commonly used drugs may be poorly tolerated by patients with cardiac amyloidosis.

Atrial contractile and electrical remodeling is associated with more complex conduction patterns in patients without history of atrial fibrillation: a high-density epicardial mapping study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This work was supported by the Netherlands Heart Foundation (CVON2014-09, RACE V Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodelling, and Vascular Destabilisation in the Progression of AF), the European Union (ITN Network Personalized Therapies for Atrial Fibrillation: a translational network: PersonalizeAF, grant 860974, CATCH ME: Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly, No. 633196). Background Early atrial remodeling refers to a concept where atrial structural, functional, and electrophysiological changes may be present without clinical manifestation of atrial arrhythmias. (1) However, it is currently unknown how electrophysiological and functional atrial properties are related, especially in the early stages of atrial remodeling. Purpose To investigate the relationship between electrophysiological properties of the atria, determined by intraoperative high-density epicardial mapping after AF-induction, and echocardiographic and electrocardiographic parameters in patients without a history of AF undergoing cardiac surgery. Methods All patients underwent functional and electrophysiological analysis of both atria using preoperative transthoracic echocardiography, electrocardiography, and intraoperative biatrial high-density epicardial mapping. Postoperatively, all patients were continuously monitored for occurrence of new-onset postoperative AF (POAF). In addition to univariable and multivariable analysis, cluster analysis was performed to identify distinct clusters of subjects for epicardial mapping parameters. Results The study population consisted of 38 patients undergoing coronary artery bypass grafting, isolated aortic valve replacement, or the combination of both. All patients completed 1-year continuous rhythm monitoring and 19 patients (50%) developed POAF. There was a greater number of waves/cycle (4.57±1.55 vs. 3.98±1.63, p=0.04) and breakthrough (BT) waves/cycle (1.16±0.58 vs. 0.88±0.60, p=0.01) in the RA compared to the LA (Figure 1). Also, there was a lower conduction velocity (CV) in the RA than in the LA (0.71±0.10m/s vs 1.19±0.36m/s, p&amp;lt;0.01) (Figure 1). Average waves/cycle were significantly correlated with reduced P-wave duration and P-wave amplitude (Spearman’s rho=-0.32, p=0.04, and Spearman’s rho=-0.32, p=0.04, respectively). Also, there was significant negative correlation between LA booster function and LA waves/cycle (Spearman’s rho=-0.55, p&amp;lt;0.01). Survival analysis revealed that older age, lower P-wave amplitude, reduced LA booster function, and increased RA waves/cycle were associated with increased occurrence of POAF (Figure 2). Cluster analysis was performed for RA and LA epicardial mapping parameters, which identified 2 distinct clusters: cluster 1 consisted of patients with more complex atrial electrical conduction patterns, and cluster 2 less complex atrial electrical conduction patterns. Multivariable analysis showed that reduced LA booster function was independently associated with a cluster representing more complex atrial electrical conduction patterns in the LA (OR=1.13, 95% CI: 1.02-1.25, p=0.02). Conclusion In patients without a history of AF, reduced LA contractile function and lower P-wave amplitude are associated with more complex electrical conduction patterns in acutely induced AF, potentially representing an early step in the atrial remodeling process.

Double rhythm mapping for coherent electrophysiological substrate characterization in atrial fibrillation patients

Abstract Funding Acknowledgements Type of funding sources: None. Background Atrial fibrillation (AF) progresses with a cascade of combined structural, functional, and systemic dysfunctions. Electro-anatomical maps are employed to investigate pro-arrhythmic areas, characterized by abnormal electrical properties. However, single rhythm maps provide only a partial reconstruction: rhythm and wavefront directionality might mask some of these areas. Purpose To demonstrate that the combined quantitative analysis of different rhythm maps (i.e., parallel sinus rhythm and paced maps) could allow consistent identification of structural and functional defects sustaining AF. Methods Thirty AF clinical procedures have been performed with mapping system support. In particular, a sinus rhythm activation map and a paced map have been created with a multipolar catheter exploiting the parallel mapping feature by setting an extra beat (pacing interval = ERP + 40 ms) every three sinus beats. Areas of abnormal conduction have been identified and a comparison of electrophysiological biomarkers (EGMs voltage and fractionation) among the two rhythms has been performed. Results This comparative analysis allowed us to identify both structural and functional electrophysiological phenomena. Specifically, we distinguished: (i) abnormal conduction zones confirmed in both maps, both characterized by signal fractionation and a lower voltage (0,56 ± 0,18 mV) with respect to healthy atrial tissue (2,40 ± 0,41 mV), and (ii) abnormal conduction zones visible in only one of the two maps. In the latter, we distinguished whether the absence of the phenomena was due to wavefront orthogonality to the diseased area (revealed in paced rhythm thanks to a change in wavefront direction) or due to the presence of a functional phenomenon induced by the pacing. In the first group signal fractionation has been detected in both rhythms and a lower voltage has been found (1,79 ± 1,1 mV) with respect to normal conduction zones (3,26 ± 0,98 mV), while in functional cases EGMs fractionation has been identified only in paced maps and no significant difference has been observed in terms of voltage. Conclusion Double rhythm mapping provides a more robust characterization of atrial abnormal conduction phenomena. In fact, it allowed the distinction of true structural dysfunctions from dynamic (functional) ones thanks to the different wavefront directionality and rhythm. Moreover, the structural defects have been confirmed by EGMs analysis, which revealed both low voltage amplitude and high fractionation, characteristics that have not been reported in functional cases.

Omnipolar mapping improves substrate characterization and critical isthmus identification in atypical atrial flutters

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Characterizing atrial substrate and conduction properties is crucial to treat complex arrhythmias during catheter ablations. Unipolar and bipolar electrogram signals are routinely used with significant limits due to low detailed mapping, the impact of poor contact and far-field electrical signals. Moreover, signals morphology is dependent on the relative orientation of the catheter inter-electrode axis to the direction of activation. Omnipolar signals try to overcome this direction-dependence by using three adjacent electrodes to infer directional information about the local electric field. Purpose We compared omnipolar mapping (OM) signals with the traditional high-density bipolar mapping (BM) ones. Methods All the procedures were performed using a high-density grid-designed mapping catheter. The atypical left atrial flutters were mapped using both OM and BM configuration. All the analysis about voltage and potential duration are related to the entire left atrial surface excluding pulmonary veins. Results Ten atypical atrial flutters were mapped in the left atrium in seven patients (median age 70 y, 5 males). OM identified 7 double loops and 3 triple loops while BM identified 7 double loops, 2 triple loops and 1 single loop, missing 2 critical circuits (an example is shown in figure 1) Significant differences were present also in potentials amplitude (peak-to-peak voltage amplitude) in the critical isthmus with OM higher than BM (OM median 0.22 mV IQR [0.16 – 0.30] vs BM median 0.19 mV IQR [0.13 – 0.24], P= 0.002). Dense scar area (defined as voltage amplitude &amp;lt;0.05 mV) identified with OM was smaller compared to BM (1.3 cm2 IQR [0.13-1.73] vs 1.7 cm2 IQR [0.23-3.10]; P= 0.06). OM showed longer signal duration (+10.1%) compared to BM in the entire left atrium and in particular the mean signal duration in the critical isthmus (OM median 79.1 ms IQR [70.7 – 88.9] vs BM median 62.5 ms IQR [55.2 – 85.2], P= 0.006). Percentage of tachycardia cycle lenght (TCL) mapped at the critical isthmus (maximum signal duration at the isthmus/ TCL) was greater with OM than BM (OM mean 60% ± 11%, BM mean 54% ± 12% (P= 0.02)(a summary of the results are shown in table 1). Conclusions OM identifies higher amplitude and longer signal duration especially in the critical isthmus region also reducing the extension of dense scar area. This finding may be crucial in the definition of complex and localized reentrant activities, leading to a faster and more precise catheter ablation.

The relationship of plasma catestatin concentrations with the extension of left atrial fibrosis

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Atrial fibrosis is increasingly considered an important part of vulnerable substrates, with an essential function in the induction of left atrial (LA) conduction abnormalities underlying the transition from paroxysmal (PAF) to persistent atrial fibrillation (PeAF), contributing to disease continuation. A substantial number of studies suggest a correlation between atrial fibrosis and low voltage zones (LVZ) (1). Previous studies have shown that catestatin (CST) regulates cardiac remodeling. The CST inhibition of catecholamine inhibits the Ang II-induced cell proliferation, and the extracellular matrix (ECM) downregulation to protect the heart from fibrosis produces similar results inhibition of catecholamine and the regulation of the beta-adrenergic receptors (β-ARs) (2). From the results, it is clear that CST inhibits cardiac fibrosis by regulating nitric oxide (NO) and the reactive oxygen species (ROS) pathways via inhibiting catecholamine release and influencing the production of the downstream molecule (2). Purpose This study investigated the potential association of serum catestatin level and LA fibrosis in AF patients. Methods The current study enrolled 18 consecutive patients with PeAF who had undergone bipolar voltage mapping of the left atrium before catheter ablation. The proportion of the mapped LA surface exhibiting low voltage (&amp;lt;0.5mV) was expressed as a percentage of the overall mapped LA surface area. In all participants, fasting laboratory tests were drawn at admission. The primary outcome measure of the current study was the association of serum CST and low-voltage zones (%LVZ ≥ 10% as a reference for severe LVZ). Results The patient characteristics were summarized in Table 1. The LA was mildly dilated, and the median %LVZ was 4 (IQR 0.75-31.25). The lower degree of cardiac fibrosis (LVZ &amp;lt; 10%) is significantly associated with higher levels of catestatin compared to severe LVZ &amp;gt;10% (8.6 (interquartile range-IQR 4.6 – 25.0) vs. 21.9 (IQR 11.1-100.0), p= 0.040)(Figure 1). Conclusion The higher catestatin level was associated with the lower extension of atrial fibrosis (low LA voltage zones).

Voltage characterization of abnormal conduction zones in patients affected by atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: None. Background In case of persistent atrial fibrillation (AF), atrial substrate assumes a dominant role in sustaining the arrhythmia. Recent studies prove that low voltage areas (LVA, Voltage Amplitude &amp;lt; 0,5 mV) represent an additional target for ablation of AF patients. Purpose The purpose of this study is to analyse whether structural atrial conduction abnormalities (i.e., pivot sites and slow conduction corridors) may occur outside low voltage areas. Methods The study is based on the retrospective analysis of 31 consecutive maps of patients undergoing AF ablation (16 paroxysmal and 15 persistent cases). The clinical procedures have been performed with the support of a mapping system. Sinus rhythm activation maps and bipolar maps used for this analysis have been created with a multipolar mapping catheter. Map points were only acquired when the electrode was in contact with the endocardial tissue to avoid misleading voltage amplitude information. Slow conduction corridors and pivot sites have been analysed. At these sites, EGMs characterization included voltage amplitude (mV), signal duration (ms) and fractionation. Results The average value of EGMs amplitude reported at pivot sites and slow conduction zones, respectively, amounted to 2,08 ± 0,63 mV and 2,1 ± 0,66 mV in paroxysmal cases. In persistent cases, there were slight decreased values to 1,95 ± 0,93 mV and 1,89 ± 0,89 mV. Characterization at pivot sites documented a mean duration value of 45,4 ± 4,64 ms and 49,93 ± 5,51 ms in paroxysmal and persistent patients, respectively, while in slow conduction zones 41,53 ± 7,94 ms and 49,04 ± 6,41 ms have been reported. As for fractionation, more than five deflections per signal have been identified in all abnormal conduction areas. Conclusion Our study proves that functional electrophysiological phenomena can occur outside low voltage areas, even in persistent cases. According to this analysis, not all LVA represent the correct target for catheter ablation, encouraging the development of further methods for investigation of atrial substrate.

Performance of atrial conduction velocity algorithms: a comparative in-silico study

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Background Atrial conduction velocity is a key determinant of re-entry. Measurement of conduction velocity from electroanatomic mapping data is challenging due to sparsity, distribution, and uncertainty of measurements. Several mathematical methods have been proposed to address these challenges but their relative sensitivity to the typical uncertainty of clinical data is unknown. Furthermore, prior clinical studies utilising these algorithms provide conflicting results. Purpose To assess the performance of conduction velocity methods (triangulation, planar fitting, and radial basis function interpolation) for the calculation of atrial conduction velocity. Method Atrial activation was simulated with known conduction velocity using the monodomain model, Courtemanche cell model and atrial geometry derived from cardiac magnetic resonance imaging with mapped fibre orientations. The model was paced from the pulmonary veins, the mid coronary sinus, and the insertion of Bachmann's bundle. Reconstructed electroanatomic maps were used for conduction velocity calculation in OpenEP[1]. To test the robustness of algorithms to electrogram sampling density, simulated sampling densities were reduced from 16.45 to 8.43 points/cm2 (1950-1000 points/map). To test the robustness to uncertainty in local activation time assignment, random uniform noises with the maximum amplitude of ± 20ms was added to the local activation times from simulations. Mean squared velocity error was calculated using the differences between the ground truth and estimated conduction velocities. Result In electroanatomic maps recreated with high electrogram sampling density (16.45 points/cm2), planar fitting showed a slightly higher error compared to triangulation and the radial basis function methods (0.16 ± 0.03 m/s, 0.11 ± 0.01 m/s and 0.12 ± 0.03 m/s, respectively, P &amp;lt; 0.05). As mapping density was decreased, the relative performance of the planar fitting method increased and in low-density maps (13.5 to 8.43 points/cm2) the planar fitting method resulted in the lowest error. When local activation times were accurately assigned, all methods performed well. However, when uncertainty in local activation time assignment increased, conduction velocities calculated using planar fitting had a significantly lower error compared to those calculated with the triangulation and radial basis function methods (0.19 ± 0.03 m/s, 0.36 ± 0.04 and 0.29 ± 0.04 m/s, respectively, P &amp;lt; 0.05). Conclusion This study highlights the importance of spatial and temporal accuracy for the assessment of conduction velocity. At high electroanatomic mapping sampling densities (&amp;gt;16.9 points/cm2), all methods performed well. Below 13.5 points/cm2 (~1600 points per map), the planar fitting method outperformed the triangulation and radial basis function methods. The differential effects of clinical measurement uncertainty on the accuracy of each method may explain the conflicting results of prior studies.

Comparison of various tools for diagnosis of an atrial cardiomyopathy for outcome prediction after pulmonary vein isolation in patients with persistent atrial fibrillation - What is the Holy Grail?

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Medtronic Background Atrial cardiomyopathy (ACM) is associated with an increased risk for new-onset atrial fibrillation (AF), progression from paroxysmal to persistent AF-forms and higher arrhythmia recurrence rates after PVI. Therefore, the current ESC guidelines on AF recommend to characterize the underlying ACM to better inform and treat AF patients. Over the past decade, various diagnostic tools were established to diagnose an ACM by analyzing left atrial (LA) structure, and LA electrical and mechanical function. Aim To compare head-to-head electroanatomical mapping (EAM) to assess LA low-voltage substrate (LVS), late gadolinium enhancement (LGE)-MRI to analyse LGE-extent, body surface electrocardiograpghic imaging (ECGI) to measure total atrial conduction time (TACT), digital ECG to analyse amplified p-wave duration (aPWD), and TTE to quantify LA emptying fraction (LA-EF) and LA strain (LAS) regarding ACM diagnosis and outcome prediction after PVI in a homogenous study population. Methods Thirty-six ablation-naive patients (65±9years, 86% male) with persistent AF undergoing PVI were electrically cardioverted prior to PVI and all analyses were performed in sinus rhythm. LGE-MRI, ECGI using a 252-electrode-array, digital ECG and TTE were conducted one day prior to PVI. Subsequently, a high-density LA voltage map (2124±490 sites) was acquired followed by circumferential PVI. MRI-post-processing-analyses were performed by two independent expert laboratories (Marrek for Utah and Adas3D medical for the image-intensity-ratio(IIR)-method). Analysis of aPWD and LAS during reservoir (LASr), conduit (LAScd) and contraction phase (LASct) were performed automatically. Arrhythmia recurrence was recorded within 12 months. Relevant ACM was defined as presence of a LA-LVS≥2cm2 at 0.5mV, a LGE-extent≥20% using the Utah method, a LA-EF&amp;lt;34%, a LASr&amp;lt;23.5%, a LAScd&amp;lt;13.4%, and a LASct&amp;lt;5.4% as described previously. For the IIR-, ECGI-, and automatically measured aPWD-methods, ROC analyses were performed to find the optimal threshold for diagnosis of a relevant ACM as defined in EAM (LA-LVS≥2cm2 at 0.5mV) due to a lack of a predefined threshold. Results A LGE-extent of ≥12% using an IIR cut-off of 1.20, a TACT≥148ms and an automatically measured aPWD≥140ms predicted a relevant ACM as defined in EAM with a sensitivity of 76% and a specificity of 60% for LGE IIR 1.20, a sensitivity of 95% and a specificity of 93% for TACT, and a sensitivity of 86% and a specificity of 80% for aPWD, respectively. Arrhythmia recurrence was significantly higher in patients with a LA-LVS≥2cm2 at 0.5mV, a LGE-extent≥12% at 1.20IIR, a TACT≥148ms, an aPWD≥140ms, a LA-EF&amp;lt;34% and a LASct&amp;lt;5.4%. Conclusion ACM can be diagnosed using EAM, LGE-MRI, ECGI, ECG and TTE and is associated with an increased arrhythmia recurrence rate after PVI. However, only measurement of aPWD in digital ECG, and LA-EF and LAS in TTE are easy, cost-effective, non-invasive methods without any risk for complications.

C4 DOUBLE RHYTHM MAPPING FOR COHERENT ELECTROPHYSIOLOGICAL SUBSTRATE CHARACTERIZATION IN ATRIAL FIBRILLATION PATIENTS

Abstract Background Atrial fibrillation (AF) progresses with a cascade of combined structural, functional, and systemic dysfunctions. Electro–anatomical maps are employed to investigate pro–arrhythmic areas. However, single rhythm maps provide only a partial reconstruction: rhythm and wavefront directionality might mask some of these areas. Purpose. To demonstrate that the combined quantitative analysis of different rhythm maps (i.e., parallel sinus rhythm and paced maps) could allow consistent identification of structural and functional defects sustaining AF. Methods Thirty AF clinical procedures have been performed with mapping system support. In particular, a sinus rhythm activation map and a paced map have been created with a multipolar catheter by setting an extra beat every three sinus beats. Areas of abnormal conduction have been identified and a comparison of electrophysiological biomarkers (EGMs voltage and fractionation) among the two rhythms has been performed. Results This comparative analysis allowed us to identify both structural and functional electrophysiological phenomena. Specifically, we distinguished: (i) abnormal conduction zones confirmed in both maps, both characterized by signal fractionation and a lower voltage (0,56 ± 0,18 mV) with respect to healthy atrial tissue (2,40 ± 0,41 mV), and (ii) abnormal conduction zones visible in only one of the two maps. In the latter, we distinguished whether the absence of the phenomena was due to wavefront orthogonality to the diseased area (revealed thanks to a change in wavefront direction) or due to the presence of a functional phenomenon induced by the pacing. In the first group signal fractionation has been detected in both rhythms and a lower voltage has been found (1,79 ± 1,1 mV) with respect to normal conduction zones (3,26 ± 0,98 mV), while in functional cases EGMs fractionation has been identified only in paced maps and no significant difference has been observed in terms of voltage. Conclusion Double rhythm mapping provides a more robust characterization of atrial abnormal conduction phenomena which better represent AF electrical substrate. It allows the distinction of true structural dysfunctions from dynamic ones thanks to the different wavefront directionality and paced rhythm. Moreover, the structural defects have been confirmed by EGMs analysis, which revealed both low voltage amplitude and high fractionation, characteristics that have not been reported in functional cases.

P57 VOLTAGE CHARACTERIZATION OF ABNORMAL CONDUCTION ZONES IN PATIENTS AFFECTED BY ATRIAL FIBRIALLATION

Abstract Background In case of persistent atrial fibrillation (AF), atrial substrate assumes a dominant role in sustaining the arrhythmia. Recent studies prove that low voltage areas (LVA, Voltage Amplitude &amp;lt; 0,5 mV) represent an additional target for ablation of AF patients. Purpose. The purpose of this study is to analyse whether structural atrial conduction abnormalities (i.e., pivot sites and slow conduction corridors) may occur outside low voltage areas. Methods The study is based on the retrospective analysis of 31 consecutive maps of patients undergoing AF ablation (16 paroxysmal and 15 persistent cases). The clinical procedures have been performed with the support of a mapping system. Sinus rhythm activation maps and bipolar maps used for this analysis have been created with a multipolar mapping catheter. Map points were only acquired when the electrode was in contact with the endocardial tissue to avoid misleading voltage amplitude information. Slow conduction corridors and pivot sites have been analysed. At these sites, EGMs characterization included voltage amplitude (mV), signal duration (ms) and fractionation. Results The average value of EGMs amplitude reported at pivot sites and slow conduction zones, respectively, amounted to 2,08 ± 0,63 mV and 2,1 ± 0,66 mV in paroxysmal cases. In persistent cases, there were slight decreased values to 1,95 ± 0,93 mV and 1,89 ± 0,89 mV. Characterization at pivot sites documented a mean duration value of 45,4 ± 4,64 ms and 49,93 ± 5,51 ms in paroxysmal and persistent patients, respectively, while in slow conduction zones 41,53 ± 7,94 ms and 49,04 ± 6,41 ms have been reported. As for fractionation, more than five deflections per signal have been identified in all abnormal conduction areas. Conclusion Our study proves that functional electrophysiological phenomena can occur outside low voltage areas, even in persistent cases. According to this analysis, not all LVA represent the correct target for catheter ablation, encouraging the development of further methods for investigation of atrial substrate.

PO-01-142 ACUTE ATRIAL DILATION INCREASES REFRACTORY PERIOD AND CONDUCTION ABNORMALITIES: EVIDENCE FROM IN-VIVO MAPPING AND IN-VITRO LIVING ATRIAL SLICES

Atrial dilation shows strong clinical association with atrial fibrillation (AF) and its proarrhythmic nature is confirmed by various studies. However, previous (animal) models reproducing acute dilation yielded in conflicting effects on the functional refractory period (FRP). Shortcomings of previous studies included lack of in-human measurements, high-density mapping, atrial conduction characterization and titration of dilation. To evaluate the effect of acute atrial dilation on human atrial refractoriness and conduction with a two-way approach of in-vivo high-density mapping and in-vitro living atrial slices. Epicardial mapping with a 192-electrode array (inter-electrode distance 2.0 mm) was performed in 4 patients undergoing mitral valve surgery, without history of right atrial (RA) dilation and AF. Mapping was performed on the mid RA during baseline and overloaded conditions (echocardiographic RA diameter increase 10-20%) by positioning patients in Trendelenburg. Atrial FRP and conduction were evaluated with programmed extrastimulation, consisting of a S1-sequence with cycle length (CL) of 400ms followed by S2 stimuli of 300ms with decrements of 20ms. In addition, 23 living myocardial slices (LMS) (thickness: 300μm) were produced from RA left-over material from cardiac surgeries and cultured under electromechanical stimulation (diastolic preload 1mN, electrical stimulation 1.0Hz). These LMS were overloaded with 10–40% extra uniaxial lengthening for evaluation of FRP and early aftercontractions (EAC). FRP significantly increased during acute dilation both in in-vitro LMS (211±49 vs. 271±34ms, p=0.01) and during in-vivo electrophysiological mapping (255±30 vs. 280±23ms, p=0.042). FRP further increased with increasing dilation and EAC were more present in dilated LMS (Table 1). During acute dilation, S2 pacing (CL: 300ms) resulted in an increase in total activation time (TAT) (31 (29–39) vs. 67 (49–82) ms), conduction block (0.6 (0.0–3.0) vs. 12.9 (8.4-16.7)%) and total length of conduction block (2 (0–9) vs. 48 (21–72) mm). Moreover, the S2 stimulus with shortest coupling interval showed even more abnormalities in atrial conduction during dilation compared to baseline (Table 1). This first in-human study showed an unambiguous increase in atrial FRP and frequency-dependent conduction abnormalities during acute atrial dilation. These observations provide novel insights in the enhanced vulnerability for the development of AF in patients with dilated atria.Tabled 1Table 1In-vivo: EP mappingBaselineDilationRA Ø (cm)4.6 ± 1.05.6 ± 1.2CVP (mmHg)8 ± 418 ± 8FRP (ms)255 ± 30280 ± 23S1 400 msTAT (ms)34 (32 – 41)44 (40 – 52)CV (cm/s)85.5 (81.1 – 86.1)80.9 (77.7 – 83.8)CB (%)1.5 (1.1 – 2.1)3.1 (1.7 – 4.4)Length CB (mm)7 (5 – 9)16 (9 – 22)S2 300 msTAT (ms)31 (29 – 39)67 (49 – 82)CV (cm/s)82.1 (75.3 – 86.0)68.9 (61.6 – 79.8)CB (%)0.6 (0.0 – 3.0)11.7 (5.6 – 16.7)Length CB (mm)2 (0 – 9)48 (21 – 72)S2 with shortest coupling intervalTAT (ms)49 (41 – 61)82 (75 – 84)CV (cm/s)72.2 (67.0 – 78.3)66.7 (61.6 – 73.2)CB (%)6.0 (2.9 – 11.3)12.9 (8.4 – 16.7)Length CB (mm)30 (11 – 49)53 (33 – 72)In-vitro: LMSBaselineDilationAcute 20% (n=10)FRP (ms)211 ± 49271 ± 34EAC (%)0%50%Titration (n=13)10%20%30%40%FRP (ms)241 ± 46263 ± 68278 ± 63297 ± 75330 ± 79 Open table in a new tab

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.

BS-452682-4 EFFECTS OF CHRONIC ANGIOTENSIN CONVERTING ENZYME INHIBITION ON ATRIAL FUNCTION AND ARRHYTHMOGENESIS IN AGED AND FRAIL MICE

Aging is associated atrial remodeling and increased susceptibility to atrial fibrillation (AF); however, aging-dependent changes can be variable. Frailty measures health status independent of chronological age, can be quantified using a frailty index (FI) and can account for heterogeneity in aging individuals. Angiotensin converting enzyme inhibition (ACEi) can impact frailty however its effects on AF and atrial remodeling are unknown. To determine the effects of chronic ACEi on atrial structure, function, and arrhythmogenesis in aged and frail mice. Wildtype mice were treated with the ACEi enalapril (20 mg/kg/day) or placebo for 6 months starting at 75 weeks of age. Mice aged 10-15 weeks were used as young controls. Mice were used in intracardiac electrophysiology, high resolution optical mapping, patch-clamping, and histology. ACEi reduced FI in aged mice (0.24 vs 0.36; n=27-31; P<0.05) without altering blood pressure. AF susceptibility was increased in aged vs young mice (100 vs 17%; n=6; P<0.05) and reduced in ACEi vs aged mice (43 vs 100%; n=6-7; P<0.05). P wave duration was reduced in ACEi vs aged mice (27.4 vs 32.5 ms; n=7; P<0.05), showed variability within age/treatment groups, and was correlated and graded by FI (R=0.91; n=20; P<0.05). Optical mapping revealed an age dependent reduction in atrial conduction velocity (CV; 35.3 vs 40.2 cm/s; n=6-9; P<0.05) while ACEi improved CV in aged mice (37.7 vs 35.3 cm/s; n=6-9; P=0.05). CV was also correlated with FI score (R=0.72; n=24; P<0.05). Patch-clamp studies in isolated left atrial (LA) myocytes identified a reduction in action potential upstroke velocity (Vmax; 150.8 vs 165.4 V/s; n=18-32; P<0.05) that was associated with a reduction in peak sodium current (INa; -38.3 vs -52.1 pA/pF; n=7-19; P<0.05) in aged vs young mice. INa was increased in ACEi vs aged (-47.2 vs -38.3 pA/pF; n=14–19; P=0.09) and not different (P=0.62) vs young mice. Importantly, Vmax (R=0.32; n=73; P<0.05) and INa (R=0.5; n=36; P < 0.05) were graded by FI. LA fibrosis was increased in aged mice vs young (10.8 vs 3.9%; n=5-8; P<0.05), reduced in ACEi vs aged mice (8.9 vs 10.8%; n=5-8; P<0.05), and strongly correlated with FI (R=0.89; n=19; P<0.05). ACEi reduced frailty in aging mice and attenuated age-related AF and atrial remodeling. Aging was associated with substantial variability within groups. Frailty was a strong predictor of changes atrial function in aging mice including after ACEi treatment, independent of chronological age.

Late sodium current in synergism with Ca2+/calmodulin-dependent protein kinase II contributes to β-adrenergic activation-induced atrial fibrillation.

Atrial fibrillation (AF) is frequently associated with β-adrenergic stimulation, especially in patients with structural heart diseases. The objective of this study was to determine the synergism of late sodium current (late INa) and Ca2+/calmodulin-dependent protein kinase (CaMKII)-mediated arrhythmogenic activities in β-adrenergic overactivation-associated AF. Monophasic action potential, conduction properties, protein phosphorylation, ion currents and cellular trigger activities were measured from rabbit-isolated hearts, atrial tissue and atrial myocytes, respectively. Isoproterenol (ISO, 1-15 nM) increased atrial conduction inhomogeneity index, phospho-Nav1.5 and phospho-CaMKII protein levels and late INa by 108%, 65%, 135% and 87%, respectively, and induced triggered activities and episodes of AF in all hearts studied (p < 0.05). Sea anemone toxin II (ATX-II, 2 nM) was insufficient to induce any atrial arrhythmias, whereas the propensities of AF were greater in hearts treated with a combination of ATX-II and ISO. Ranolazine, eleclazine and KN-93 abolished ISO-induced AF, attenuated the phosphorylation of Nav1.5 and CaMKII, and reversed the increase of late INa (p < 0.05) in a synergistic mode. Overall, late INa in association with the activation of CaMKII potentiates β-adrenergic stimulation-induced AF and the inhibition of both late INa and CaMKII exerted synergistic anti-arrhythmic effects to suppress atrial arrhythmic activities associated with catecholaminergic activation. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

PO-02-245 THE IMPACT OF PULSED FIELD ABLATION ON CONDUCTION VELOCITY OVER TIME

Pulsed field ablation (PFA) is an emerging technology that has both reversible and irreversible effects. However, the time course of reversibility of atrial conduction velocity after PFA has not been well characterized. To determine changes in conduction velocity over time after PFA Nine pigs were studied. The Medtronic PVAC GOLD catheter was placed in the superior vena cava (SVC), right atrium (RA), left atrial appendage (LAA) and left pulmonary vein (LPV). One and four trains at 1000 V and 1500V were delivered at these four sites in a random fashion. Activation mapping was done at baseline and 10-20 minute intervals post ablation using ESI mapping system. Conduction velocity was obtained between a site of entry and exit identified by wavefront propagation in the scar at the 5-minute time point post ablation. Regional conduction slowing was defined as <31 cm/s and recovery was studied at 120 minutes time point. Recovery was defined as 50% recovery of baseline conduction velocity compared to the 5 minutes time point. The baseline conduction velocity was >100 cm/s across all experimental conditions. At 1000V x 1 and 1000V x 4 application, the average velocity was 21[HDM1] ±9 cm/s and 44 ±30 cm/s respectively. At 1500V x 1 and 1500V x 4 application, the average velocity was 27 ±16 cm/s and 33 ±15 cm/s respectively. The lowest conduction velocity occurred at the 5-minute time point (31 cm/s (5-100 cm/s). At 1000V x 1 and 1000V x 4 application, 2/8 and 2/8 animals recovered conduction at 120 min respectively. At 1500V x 1 and 1500V x 4, 1/8 animals and 0/8 animals recovered conduction at 120 min respectively. Median time to conduction recovery was 72 min (25-160 min). (Figure 1) Recovery of conduction is observed post PFA, more often with lower voltage ablations in this porcine model. The time course of conduction velocity recovery exceeds the standard clinical post ablation wait time suggesting that retesting for conduction block 20 min post ablation may be of limited value.

MP-453085-1 CALORIC RESTRICTION ATTENUATES SINOATRIAL NODE AND ATRIAL ARRHYTHMOGENESIS IN AGED AND FRAIL MICE

Atrial fibrillation (AF) and sinoatrial node (SAN) dysfunction are highly prevalent in elderly individuals; however, aging is also highly heterogenous. This heterogeneity has led to the concept of ‘frailty’, a state of increased vulnerability to adverse health outcomes in aging. Mild caloric restriction (CR; reducing caloric intake without malnutrition) can preserve cardiac function and improve frailty (healthspan); however, the effects of late-onset CR on SAN/atrial function in aging mice are unknown. To determine if CR affects frailty and SAN/atrial structure, function and arrhythmogenesis in aging mice. At 56 weeks of age, C57BL/6 mice were placed on either 25% CR or control diet ad libitum. Frailty scores were measured every 4 weeks for 24 weeks, at which point atrial and SAN function was studied using intracardiac electrophysiology, optical mapping, and histology. Young control mice (12 weeks) were used to account for differences in aging. Following 24 weeks of 25% CR, mice exhibited reduced frailty scores compared to the aged control diet (0.207±0.006 vs. 0.273±0.007, n=17-23; P<0.0001). Aged CR mice demonstrated lower AF inducibility (5/16, 31% vs. 12/18, 67%; P<0.05) compared to aged controls, as well as reduced corrected SAN recovery times (27.3±4.5 vs. 42.2±7.1, n=8-15; P<0.05). SAN recovery times in aged CR mice were similar to young mice (27.3±4.5 vs. 24.2.3±6.9, n=13-15; P>0.05). Due to substantial heterogeneity within groups, no difference in P-wave duration (PWD) was observed between groups. However, PWD (R2=0.15, P<0.01) and SAN recovery time (R2=0.19, P<0.0001) were each correlated with FI such that these fell along a continuum regardless of age or diet. Atrial conduction velocities were increased in CR mice compared to aged controls (51.1±2.4 vs. 19.2±2.7, n=5-7; P<0.0001), comparable to young controls (51.1±2.4 vs. 46.3±1.8, n=6-7; P>0.05). Atrial interstitial fibrosis was decreased in aged CR mice compared to aged controls (7.9±0.6 vs. 13.0±2.1, n=3; P<0.05), again comparable to young mice (7.9±0.6 vs. 5.0±0.2, n=3; P>0.05). Both conduction velocity (R2=0.32; P<0.01) and atrial fibrosis (R2=0.81; P<0.0001) showed a strong correlation to frailty score regardless of age or diet. Late-onset CR reduces frailty, improves SAN and atrial structure/function, and attenuates arrhythmogenesis in aging mice. These changes were strongly correlated, and often better predicted, by frailty compared to chronological age.