Conduction Velocity Research Articles

Exploring pathogenic pathways in carpal tunnel syndrome: sterile inflammation and oxidative stress.

The main objective of the current study was to find the association between oxidative stress, inflammatory markers, and electrophysiological profile with symptom severity in patients of carpal tunnel syndrome (CTS). Thirty-two carpal tunnel syndrome patients and 32 controls were included in the study. Boston CTS questionnaire along with plasma oxidative stress markers including superoxide dismutase, malondialdehyde, and nitric oxide and inflammatory markers including IL-6 and TNF-α were compared with the electrophysiological parameters derived from nerve conduction studies. Statistical significance of the levels between groups was calculated using unpaired-t test after checking for normality with D'Agostino & Pearson omnibus normality test. We found that the median nerve conduction velocity was prolonged, amplitude was decreased, while the levels of oxidative stress markers like malondialdehyde (MDA), superoxidase dismutase (SOD), and nitric oxide (NO) were increased in CTS patients compared to controls. Inflammatory markers like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were also increased in CTS patients. We found that plasma SOD and TNF-α correlated well with the median motor amplitude. There was no other significant correlation between oxidative stress markers and inflammatory markers with nerve conduction studies or disease severity. Patients with mild disease also showed lesser levels of SOD, NO, IL-6, and TNF-α markers than patients with severe disease. CTS is probably a disease of sterile inflammation and disbalance of oxidative stress, with higher inflammatory and oxidative stress markers pointing to a more severe disease.

Impacts of DCM-linked gating pore currents on the electrophysiological characteristics of hiPSC-CM monolayers

BackgroundVariants of the SCN5A gene, which encodes the NaV1.5 cardiac sodium channel, have been linked to arrhythmic disorders associated with dilated cardiomyopathy (DCM). However, the precise pathological mechanisms remain elusive. The present study aimed to elucidate the pathophysiological consequences of the DCM-linked Nav1.5/R219H variant, which is known to generate a gating pore current, using patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) cultured in monolayers. MethodsVentricular- and atrial-like hiPSC-CM monolayers were generated from DCM patients carrying the R219H SCN5A variant as well as from healthy control individuals. CRISPR-corrected hiPSC-CMs served as isogenic controls. Simultaneous optical mapping of action potentials (APs) and calcium transients (CaTs) was employed to measure conduction velocities (CVs) and AP durations (APDs) and served as markers of electrical excitability. Calcium handling was evaluated by assessing CaT uptake (half-time to peak), recapture (tau of decay), and durations (TD50 and TD80). A multi-electrode array (MEA) analysis was conducted on hiPSC-CM monolayers to measure field potential (FP) parameters, including corrected Fridericia FP durations (FPDc). ResultsOur results revealed that CVs were significantly reduced by more than 50 % in both ventricular- and atrial-like hiPSC-CM monolayers carrying the R219H variant compared to the control group. APDs were also prolonged in the R219H group compared to the control and CRISPR-corrected groups. CaT uptake, reuptake, and duration were also markedly delayed in the R219H group compared to the control and CRISPR-corrected groups in both the ventricular- and the atrial-like hiPSC-CM monolayers. Lastly, the MEA data revealed a notably prolonged FPDc in the ventricular- and atrial-like hiPSC-CMs carrying the R219H variant compared to the control and isogenic control groups. ConclusionsThese findings highlight the impact of the gating pore current on AP propagation and calcium homeostasis within a functional syncytium environment and offer valuable insights into the potential mechanisms underlying DCM pathophysiology.

Enhancing OpenEP: atrial conduction velocity and conduction velocity heterogeneity quantification through EP Workbench

Abstract Background Alterations in atrial conduction velocity have been implicated in the pathogenesis of atrial arrhythmias, with conduction velocity thought to be slower and more heterogeneous in areas promoting atrial fibrillation. However, clinical studies of conduction velocity are challenging since there are no available platforms that provide researchers and clinicians with the ability to quantify conduction velocity and analyse conduction heterogeneity from electroanatomic mapping data. Purpose In this paper we sought to address these limitations by enhancing the OpenEP Python library by (1) automating calculations using previously-published conduction velocity estimation algorithms; (2) providing an interactive graphical representing of conduction velocity and conduction heterogeneity and (3) implementing a histogram analysis tool to quantify conduction velocity and enable the identification of slow conduction regions. Method Two well-known and previously published methods for calculating cardiac conduction velocity, Triangulation and polynomial surface fitting, were implemented. Conduction velocity estimation was improved further by excluding regions with wave collisions and focal discharges. These regions were identified using the divergence of conduction velocity vector fields, with positive divergence representing focal sources and negative divergence representing areas of collision. Finally, calculated conduction velocities using electrogram data were interpolated over the surface mesh via Radial Basis Function (RBF) interpolation method. All algorithms were implemented in the OpenEP Python library (openep-py), with visualisation tools provided in the complementary graphical interface, EP Workbench. Results An extensible "Analysis" feature was created in openep-py, to provide conduction velocity and divergence calculations which are fully customisable through the graphical interface based on user preferences. The EP Workbench desktop application displays resulting cardiac surface maps to depict calculated conduction velocity and divergence fields, together with conventional activation and voltage maps (Figure 1). The histogram analysis tool can be used to identify regions of slow conduction velocity from electroanatomic mapping data. Using a threshold of <0.3m/s, two slow conducting channels are visualised on the posterior wall of a test case (Figure 2). The tool is not specific to conduction velocity and may also be used to quantify other data types in EP Workbench. Finally, computed conduction velocity and divergence values and surface maps are stored in the standard OpenEP data structure, allowing further analysis following data export. Conclusion We have extended OpenEP to provide a comprehensive set of tools for conduction velocity calculation and analysis which will facilitate investigation of the structural and functional basis of conduction velocity alterations in disease states.

Conduction velocity-based functional substrate mapping during atrial fibrillation (AF) enhances identification of AF drivers compared to mapping during sinus rhythm

Abstract Background Conduction velocity (CV) heterogeneity is known to play a role in the initiation and maintenance of atrial fibrillation (AF) [1,2]. CV has been shown to decrease with cycle lengths (CLs) <600ms in low voltage areas (LVAs) [3,4], and with CLs <300ms in non-LVAs [4]. Yet, the impact of rhythm and CL on voltage-independent, CV-based atrial substrate mapping remains uncertain. Purpose This study evaluates CV differences based on mapping protocol and explores the relationship between CV and AF pathologic conduction patterns (PCPs) identified through global, non-contact, charge density mapping (CDM) [5]. Methods CDM was performed in twelve patients with persistent AF, presenting for de novo ablation. All mapping was performed prior to any ablation. Sinus rhythm (SR) CV was assessed during atrial pacing at two CLs (380ms and 800ms). To mitigate the impact of wavefront direction, pacing was performed at three sites: mid coronary sinus, left atrial appendage, and right atrial appendage. AF CV was determined from a 20-second continuous recording of global propagation. PCPs were identified as: focal firing (FF), rotational propagation (Localised Rotational Activation [LRA]), and pivoting propagation (Localised Irregular Activity [LIA]) [5]. Patients’ left atrial geometries consisted of approximately 3000 vertices, facilitating paired comparisons of spatial data. At each vertex, values for median CV dependent on mapping protocol and frequency of PCPs were utilised for analysis. Variables are presented as mean±standard deviation, median (interquartile range), and count (percentage) as appropriate. All analyses were performed using R (version 4.1.2). CV distributions were compared using the Analysis of Variance test. Results Mean age was 64±12 years, eight (67%) were male, median time since AF diagnosis was 3.1 (2-3.5) years, and median CHA2DS2-VASc score was 2 (2-4). Median CV across our cohort was significantly lower during AF than SR with either long or short CL pacing (0.37mm/ms vs 0.66mm/ms vs 0.61mm/ms, p<0.001). Histograms of CV vs left atrial surface area demonstrated similar distributions for both CLs. However, there was poor overlap with AF, which was prominently skewed towards slower CVs (Figure 1). Slower CVs during AF were associated with an increased frequency of PCPs (Figure 2), particularly FF with CVs <0.2mm/ms, and LRA and LIA with CVs <0.4mm/ms. This association was absent during SR. Conclusions Rhythm has a significant impact on CV-based functional substrate mapping. Slower CVs observed during AF likely result from the presence of CLs shorter than 300ms, which impact both LVA and non-LVA areas. Crucially, areas of slow CV during AF were associated with the location of PCPs. Mapping performed during AF may improve identification of areas where functional remodelling has preceded structural. Such areas, characterised by CV heterogeneity, may serve as promising targets for catheter ablation.Figure 1.Figure 2.

Non-invasive mapping of atrial slow-conduction areas and validation by endocardial isochronal mapping to predict atrial fibrillation recurrence after ablation

Abstract Background Atrial arrythmogenic substrate is a key determinant of arrhythmia recurrence after pulmonary vein isolation (PVI), and reduced conduction velocities have been linked to adverse outcome. However, a non-invasive method to assess such electrical substrate is not available to date. Purpose We have developed and validated a non-invasive mapping system based on electrocardiographic imaging (ECGi) to assess local conduction velocities and their predictive value regarding 12-months arrhythmia-free survival following PVI. Methods A novel ECGi-based non-invasive mapping system obviating the need of additional CT- or CMR-imaging was developed. 52 consecutive patients scheduled for AF ablation (PVI-only) and 19 healthy controls were prospectively included and local left and right atrial conduction velocities determined in sinus rhythm through non-invasive mapping. In 36 of the patients high density endocardial mapping was performed to define areas of slow conduction based on isochronal late activation maps. AF ablation patients were systematically followed and monitored for 12 months post ablation. Results Mean ECGi-determined atrial conduction velocities were significantly lower in AF patients (54% paroxysmal) than in healthy controls (1.45±0.15 vs. 1.64±0.15 m/s; p<0.0001). Differences were even more pronounced in a regional analysis (Fig. 1A). In this analysis we focused only on the segment with the slowest average conduction velocity in a given patient, i.e. the region that was most likely to harbour arrhythmogenic substrate. Multivariable regression analyses and c-statistics found this average conduction velocity of the „slowest" segment (AUC 0.74) to predict 12-months arrhythmia recurrence after PVI better than previously proposed non-invasive predictors including left atrial size (AUC 0.71) or the left atrial extent of late gadolinium enhancement (MRI) (AUC 0.70). A ROC analysis found a regional conduction velocity threshold of 0.78 m/s to best discriminate PVI responders from non-responders. Patients without slow-conduction areas (mean conduction velocity <0.78 m/s) showed significantly higher 12-months arrhythmia-free survival than those with one or more slow-conduction areas (88.9% versus 48.0%, p=0.002) (Fig. 1B). For validation we compared slow-conduction areas determined by non-invasive mapping with slow-conduction areas as defined by invasive isochronal mapping. Interrater reliability testing revealed good agreement between non-invasive mapping-determined slow-conduction areas and those defined by isochronal mapping (kappa 0.63, Fig. 2). Conclusions ECGi-based non-invasive mapping reliably identifies areas of slow conduction. The presence of ECGi-determined slow-conduction areas well discriminates PVI-responders from non-responders. Such non-invasive assessment of electrical arrhythmogenic substrate may guide treatment strategies and could be a step towards personalised AF therapy.Figure 1Figure 2

Spatial relationship between left peri-atrial fat with underlying arrhythmogenic substrate in patients with atrial fibrillation - innocent bystander or culprit?

Abstract Introduction Peri-atrial fat may have pro-inflammatory and pro-fibrotic effects on atrial myocardium and increase the risk of developing atrial fibrillation. Consistent with prior evidence, we have previously shown that peri-atrial fat volume, but not fat attenuation (an imaging biomarker of inflammation), was associated with prevalent atrial fibrillation. Whether this association is secondary to "outside-to-inside" tissue cross talk with local adverse electrical remodelling of adjacent atrial cardiomyocytes is not known. Purpose In this novel proof of concept study, we aimed to identify a spatial relationship between left peri-atrial fat and potentially arrhythmogenic substrate (low voltage areas and slow conduction pathways) in the left atrial myocardium. Methods Contrast-enhanced cardiac computed tomography (CT) imaging and electroanatomic mapping, during coronary sinus pacing, were performed pre-ablation in atrial fibrillation patients (n=27). The left atrium and surrounding peri-atrial fat were segmented and quantified using seg3D2 and CEMRGapp. We performed registration of the electroanatomic map onto the CT-derived left atrial mesh using OpenEP and EP Workbench. Mean fat volume and attenuation around each electroanatomic point (within a 3mm radial region of interest) were correlated with local voltage and conduction velocity. Results A total of 24,839 electroanatomic points were registered onto the 3D CT-derived left atrial mesh, with a median of 935 points (range 673 to 1150) per patient. The average bipolar voltage and conduction velocity in the left atrium was 1.92±1.91 mV and 0.66±0.47 ms-1 respectively. In comparison to areas with little/no surrounding periatrial fat (Quartile 1, ≤0.93 mm3 fat per electroanatomic point), areas with the highest burden of fat (Quartile 4, ≥17.6 mm3) had significantly lower bipolar voltage (1.69±1.7 vs 2.09±2.0 mV, p<0.001) and conduction velocity (0.627±0.43 vs 0.700±0.47 ms-1, p<0.001). However, the overall correlation between periatrial fat volume with bipolar voltage (r=-0.06, p<0.001) and conduction velocity (r=-0.07, p<0.001) was weak. High, not low, fat attenuation (Quartile 4; >-46.5HU vs Quartile 1; ≤-75.5HU) was associated with increased bipolar voltage (2.23±2.1 vs 1.63±1.6 mV) and conduction velocity (0.703±0.42 vs 0.623±0.39 ms-1 respectively). Conclusion There is a weak correlation between periatrial fat and localized adverse electrical remodelling. The relationship between fat attenuation and electrophysiological properties was inverted. These findings confirm an association between peri-atrial fat burden but call question as to whether peri-atrial fat inflammation is implicated in atrial fibrillation pathogenesis.

Source-sink mismatch and conduction block: simulation study

Abstract Background Source-sink mismatch is one of the key concepts in arrhythmia mechanism such as relationship between pulmonary veins and the left atrium in atrial fibrillation. We sought to find the condition for conduction block in various geometries. Methods To simulate cardiac atrial tissue, the finite element method was used to discretize the governing equation in a 2D mesh. We evaluated under the following conditions: 6 sizes of source width (0.1, 0.2, 0.3, 0.4, 0.5 and 0.6 mm), 64 types of angle (θ) at the junction (30-330 degrees), 3 conditions of conduction velocity (CV) (x0.5, x0.75, and x1 of normal CV of atrial myocardium). Results Conduction block was not observed with source width > 0.5 mm in any settings. In reduced CV condition, conduction block was not observed in θ < 300 degrees when source width > 0.3 mm. The higher CV, conduction block was observed in the narrower θ. In cases of CV of x1.0 and x0.75, conduction block was observed in θ < 180 degrees when source width < 0.3 mm. The smaller source width, conduction block was observed in the narrower θ. The wider θ, the easier conduction block occurred. Conclusion Conditions for conduction block due to source-sink mismatch are as follows: smaller source width, higher CV, and wider θ. Source with width > 0.5 mm may not be associated with source-sink mismatch in the atrial tissue. CV slowing by antiarrhythmic drugs can be effective in the aspect of source-sink mismatch.

Heterogenous atrial conduction in patients with hypertrophic cardiomyopathy and atrial fibrillation

Abstract Background/Introduction Hypertrophic cardiomyopathy (HCM) is characterised by myocardial thickening, fibrosis, and disarray, affecting both ventricles and atria. This pathology extends to atrial tissue, potentially influencing conductivity and contributing to arrhythmias, notably atrial fibrillation (AF). Pulmonary vein isolation to treat AF in HCM patients yields less satisfactory results compared to other patient groups. Improved understanding of the pathophysiology of AF in HCM patients could improve treatment stratification and delivery. Purpose This study aims to analyse atrial conduction properties in HCM patients with AF, compared to age, body mass index and sex-matched control patients. Methods Pre-ablation electroanatomic mapping data from 10 HCM patients and a matched control group of patients with structurally normal hearts undergoing AF ablation was retrospectively analysed. All patients underwent pre-ablation electroanatomic mapping during proximal coronary sinus pacing. This data was analysed using OpenEP software to quantify voltage mapping, conduction velocity and wave collision points. Conduction velocity was calculated using both plane fitting and triangulation methods. Wave collisions were identified by calculating the percentage of points with conduction velocity field divergence values less than -1.5. Results HCM patients exhibited significantly reduced mean left atrial bipolar voltage and greater low voltage burden <0.5mV than matched control patients (1.43mV vs. 2.14mV, p=0.0177; and 38.28% vs. 15.68%, p<0.0001), (Figure 1A and B). Wave collision points were significantly more prevalent in the HCM group (5.4% vs. 1.6%, p=0.0004), indicating more heterogeneous conduction (Figure 1C). Figure 2 shows example of divergence map with local electrograms around wave collision points. Both methods of quantifying conduction velocity showed comparable results. While average conduction velocity showed no statistically significant difference (plane fitting method - 0.61m/s in HCM group vs. 0.64m/s in control group, p = 0.465; triangulation method - 0.61m/s in HCM group, 0.64m/s in control group, p=0.393), a trend toward lower velocities in HCM patients was observed (Figure 1D and 1E). Conclusion HCM patients demonstrate significantly lower bipolar voltage and significantly greater low voltage areas than matched control patients. Atrial conduction in patients with HCM is significantly more heterogenous than matched control patients. These findings highlight marked conduction abnormalities in HCM patients which are likely to contribute to AF pathogenesis.

Charge-density mapping to evaluate non-pulmonary vein substrate in patients with paroxysmal atrial fibrillation: the ACUPRED study

Abstract Background/introduction Pulmonary veins (PV) electrical isolation (PVI) is the main ablation strategy for the treatment of paroxysmal atrial fibrillation (AF), since the description of PV triggers. However, non-PV substrate and triggers in AF are not a negligible clinical issue. Indeed, in up to 22% of patients with AF recurrence after PVI, all PV are found isolated. Non-PV triggers can be demonstrated in up to 10-15% of non-selected patients at first AF ablation and non-PV substrate has been related to functional slow conduction and fibrosis also in paroxysmal AF. Purpose The aim of this study is to evaluate non-PV substrate (slow conduction) and triggers with charge-density (CD) mapping in patients with paroxysmal AF. Methods All patients, were prospectively enrolled in 2023. Inclusion criteria for the study were: 1) paroxysmal AF patients undergoing PVI procedure with a single-shot device and 2) CD mapping pre- and post- PVI. CD mapping was performed during CS proximal pacing at cycle length (CL) 600 ms and CS proximal pacing at CL 300 ms, pre- and post- PVI. Conduction velocity (CV) magnitude (in cm/s) and vector (direction and sense) were calculated offline for each CD map for all anatomical vertices. Reduction map was defined as the map of CV magnitude difference between CL 600 ms and CL 300 ms, Figure 1. Refraction map was defined as the map of CV direction difference between CL 600 ms and CL 300 ms, Figure 1. Non-PV substrate was defined at pre-PVI maps as: 1) slow conduction (<30 cm/s) at CL 600 ms or CL 300 ms, or 2) difference in CV magnitude (>25 cm/s) at reduction map, a marker of functional slow conduction (induced by fast pacing), or 3) difference in CV direction more than 90° between two neighboring vertices at refraction map, a marker of anisotropy, Figure 1. Non-PV triggers were defined as non-PV premature atrial contractions >10/min or inducing AF. Results A total of 43 patients (60.6 ± 11.2 years, 74.4% males) with paroxysmal AF undergoing first procedure PVI were analyzed. Non-PV substrate was found in 13 patients (30.2%). Non-PV triggers were found in 3 patients (6.9%), including one patient on the posterior wall near right PV antra and two patients on the posterior wall near the left PV antra. At a mean follow-up of 5.6 months, a total of 5 patients (11.6%) experienced a recurrence. Patients experiencing a recurrence had more frequently non-PV substrate (80.0% vs 23.7%, p=0.024) and lower CV magnitude at CL 600 ms pre-PVI (72.3 cm/s vs 83.1 cm/s, p=0.04). At survival analysis for 34 patients (79.1%) out of the 2 months blanking period, patients with non-PV substrate had lower freedom from AF recurrence (56% vs 90%, p=0.0028), Figure 2. Conclusion In patients with paroxysmal AF undergoing index PVI, non-PV substrate or triggers can be found in up to 37.1% of cases. Non-PV substrate is associated with worse arrhythmic prognosis.Figure 1Figure 2

Non-invasive assessment of the ventricular tachycardia isthmus during sinus rhythm

Abstract Background The ablation of ventricular tachycardias (VT) presents significant challenges due to the complex and time-consuming approaches involved in identifying arrhythmogenic regions. Combining non-invasive electrocardiographic imaging (ECGI) with endocardial mapping could potentially enhance the efficacy of interventions. Objective To evaluate the capability of ECGI in guiding operators towards areas of VT isthmuses during sinus rhythm. Methods Patients with scar-related VT, confirmed by late gadolinium enhancement cardiac magnetic resonance, were prospectively enrolled. We compared the areas of slowed conduction identified by ECGI with the VT sustaining regions identified endocardially. Simultaneous Electroanatomical Mapping (EAM) and ECGI mapping were performed during VT ablation procedures. In patients in whom a hemodynamically stable VT was maintained, the reentry circuit was mapped endocardially, and the ablation target was identified. The left ventricle was segmented into 9 regions, categorized as either VT-isthmus or non-VT isthmus based on EAM findings. Prior to ablation, local activation times (LAT) and conduction velocity (CV) ECGI sinus maps were computed. Slow conduction was quantified non-invasively by computing different ECGI metrics per region, including the mean and the standard deviation (SD) of LAT and CV, the regional Total Activation Time (rTAT) – time span between the earliest and latest activated nodes–, and the Slow Conduction Velocity (SCV) – the percentage of nodes where velocity falls below 60 cm/s -. Results The study included 20 consecutive patients with ischemic cardiomyopathy who were referred for VT ablation. A total of 21 regions linked to the VT isthmus were identified endocardially in 17 patients (age: 66.1±8.8 years, 94.1% male, left ventricular ejection fraction: 26.4±7.3%). Figure 1 illustrates the correlation between the VT circuit and the ECGI sinus map in two patients with extensive left ventricular fibrosis. ECGI metrics related to VT isthmuses exhibited a higher standard deviation in both LAT (18.1±2.0 vs 9.8±1.2 ms; p=0.001), and CV (50.4±4.7 vs 37.1±2.8 cm/s; p=0.011), and a greater percentage of nodes with slowed conduction (13.7±2.7 vs 7.4±1.6 %; p=0.029), compared to non-VT isthmus regions, Figure 2. Multivariate logistic regression analysis revealed that SD-LAT was the strongest predictor of VT isthmus localization. Conclusion ECGI has demonstrated the capability to pinpoint slowed conduction areas responsible for VT in sinus rhythm, showing promise in planning and guiding VT ablation strategies. This advancement paves the way for further research into using this non-invasive tool to improve risk stratification methods for ventricular arrhythmias.

Systematic right ventricular electrophysiologic evaluation in patients with repaired tetralogy of Fallot before pulmonary valve replacement

Abstract Introduction Adults with repaired tetralogy of Fallot (rToF) are prone to develop ventricular tachycardia (VT) in adulthood, due to reentry related to slowly conducting anatomical isthmuses (SCAI). Pulmonary valve replacement (PVR) in patients without history of VT, may lead to obliteration of unrecognized SCAI with subsequent catheter ablation failure; electrophysiologic study is thus recommended before PVR. A systematic evaluation of the topology of SCAI in this population is, however, scant. Methods Consecutive rToF patients undergoing PVR with native right ventricular outflow tract were studied with pre-PVR EPS. Electroanatomical mapping with systematic evaluation of all possible anatomical isthmuses (AI) with pacemapping, activation mapping in sinus/paced rhythm and bipolar voltage mapping was performed (AI1: anterior scar/patch to tricuspid annulus; AI2: anterior scar to pulmonary annulus; AI3: pulmonary annulus to ventricular septal defect – VSD- patch; AI4: VSD to tricuspid annulus). Conduction velocity (CV) across all documented AI was calculated (ratio between the distance among the nearest point with bipolar voltage >1.5 mV and their difference in activation timing). Ventricular programmed stimulation was performed at 2 sites (apex and outflow tract) with drive train ad 600/400 ms, up to three extrastimuli until refractoriness or induction, during baseline and isoproterenol infusion. Radiofrequency catheter ablation (RFCA) was performed in all patients with inducible VT and/or SCAI, aiming at conduction block across the SCAI validated with differential pacing. Results Between May 2023 and November 2023, 10 patients with rToF and 1 double outlet right ventricle were studied (73% males, age 46±10 years; 54% with a previous shunt, 46% with a previous transannular patch, 27% pulmonary valvotomy and infundibular boring; median age at surgery 4 years, interquartile range 3-6). EPS was positive for inducible VT in 4 patients (mean cycle length 297 ms, 3 with left bundle branch morphology and 1 right bundle branch morphology, all inferior axis) and polymorphic VT in 1. AI1 was present in 5 patients, AI2 in 5, AI3 in 7, AI 4 in 2. At least 1 SCAI was present in 7 patients (64%), 2 SCAI in 3 patients (43% of patients with SCAI; in every patient SCAI3+SCAI2 in 2 and SCAI 4 in 1 patient). There were no SCAI1; there were 3 SCAI 2 (mean CV 0.43 m/s), 4 SCAI 3 (mean CV 0.3 m/s), 1 SCAI 4 (CV 0.4 m/s). RFCA was performed in 8 patients; acute success was achieved in all patients, achieving bidirectional conduction block across treated SCAI and non-inducibility of VT. Conclusions SCAI are often present in rToF candidate to PVR and without clinical history of spontaneous VT, involving prevalently SCAI3 and SCAI2. Inducible VT is not sufficient as a marker of arrhythmic risk and SCAI should be better sought for. RFCA of SCAI with bidirectional conduction block is acutely highly efficacious.

Bioenergetics and mitochondrial deregulation underlie self-sustained persistency of atrial fibrillation in an ovine model

Abstract Background Atrial fibrillation (AF) often transitions from paroxysmal to more sustained forms in a 4-15/100 person-year range(1). It is well-recognized from both clinical and animal studies that some individuals undergo this transition much more readily than others, but the underlying mechanisms remain unclear. Purpose To identify potential differences in atrial bioenergetics between animals developing stable AF (AF-S) versus those resistant to this transition (AF-R) in a sheep AF-model. Methods AF was induced through repeated bursts of atrial tachystimulation (2). Stability of AF was monitored with telemetry. In-vivo electrophysiological remodeling was assessed via contact mapping. Metabolic and bioenergetic remodeling were evaluated using frozen left atrial appendage (LAA) tissues and isolated LAA mitochondria. Results AF-S sheep developed stable (>24-hour self-sustained) AF after 13 (range 5-22) days on average, whereas AF-R sheep failed to develop stable AF despite 120-day tachystimulation. Contact mapping and histological analysis revealed similar electro-anatomical remodeling in AF-S and AF-R groups, with the only significant difference observed in the decrease of activation time and conduction velocity in the AF-S atria. Both AF-S and AF-R animals displayed a notable increase in mitochondrial mass. Proteomic analysis showed significant differences in metabolism-related proteins and pathways between AF-S and AF-R, in particular concerning the anaplerotic supplementation of the tricarboxylic acid cycle at the level of α-ketoglutarate. Furthermore, compared to AF-R, AF-S LAA exhibited a 45% increase in succinate content, and a 23% decrease in ATP and Creatine Phosphate (PCr) content, suggesting a pathological metabolic alteration linked to a bioenergetic default. AF-S mitochondria presented abnormal succinate-oxidation, associated with a significant 20% decrease in ATP-synthesis rate, 22% increase in ROS-production, mitochondrial-membrane hyperpolarization, and decreased Complex I/II specific activity ratio. AF-S mitochondria alterations were prevented by complex I inhibitor S1QEL1.1, hinting to a participation of mitochondrial ROS into the mechanism of AF stabilization. In vivo acute intravenous perfusion of succinate in rats made them more susceptible to more frequent (OR 35 CI=[1.63-449.80]) and longer AF episodes upon treansesophageal stimulation; this vulnerability to AF was prevented by intraperitoneal pretreatment with SQEL1.1. Conclusions Resistance to AF-stabilization is associated with specific bioenergetic remodeling. These findings provide new mechanistic insights into AF-resistance and might open avenues for novel therapeutic strategies for AF-management.

A novel method to identify critical isthmus of right atrial reentrant tachycardia; Functional substrate mapping characteristics during sinus rhythm

Abstract Background Right atrial tachycardia (AT) is a frequent rhythm disorder in patients with atrial scar mainly due to surgical incisions or congenital heart diseases. Despite the mounting evidence about AT mechanisms and types, data is scarce regarding the conduction properties as well as functional characteristics of atrial substrate during sinus rhythm that has role in the maintenance of the tachycardia. Purpose We sought to evaluate the relationship between the functional substrate mapping (FSM) characteristics of right atrium and the critical isthmus (CI) of re-entrant ATs in patients with underlying atrial scar. Methods Among patients with the history of right AT who underwent catheter ablation with 3-D mapping were retrospectively enrolled. Voltage map and isochronal late activation mapping (ILAM) were created during sinus / paced rhythm using multielectrode catheters to detect deceleration zones (DZ). Subsequently AT was induced with programmed stimulation and activation mapping was performed to detect CI of the tachycardia. Atrial tachyarrhythmia (ATa) recurrence was defined as detection of atrial fibrillation or AT (≥ 30 s) during the follow-up. Results A total of 24 patients [mean age: 46 ±15, gender: 13 (54 %) female] with right AT were included. A total of 37 ATs were mapped [16 (43.2%); localized reentry, 21 (56.7%), macroreentry]. Atrial low voltage zones comprised 23.3 ± 13.0 % of total right atrium. The mean value of bipolar voltage, EGM duration and conduction velocity during sinus rhythm corresponding to CI of ATs were 0.18 ± 0.10 mV, 121.7 ± 29.4 ms, 0.06 ± 0.04 m/s and, respectively. Total number of DZs per chamber was 1.1 ± 0.3, which were all located in the low-voltage zone (<0.5 mV) detected by high density mapping. All CIs of non- cavo-tricuspid-isthmus (CTI) dependent reentry were colocalized with DZs detected during FSM. The positive predictive value of DZs to detect CI of inducible ATs is 80.8%. During the mean follow-up of 11.7 ± 8.1 months, freedom from ATa was 87.5%. Conclusion Although, CTI-dependent macroreentry is the most common mechanism in patients with RA scar, our findings demonstrated the relevance of FSM to predict non-CTI dependent ATs. Conduction slowing manifested as DZs with continuous-fragmented signal morphology may guide to tailor ablation strategy in case of underlying RA scar.

Effects of different types of fibrotic remodelling in areas of low voltage on atrial fibrillation dynamics: an in-silico study

Abstract Background Personalized computational models include the effects of personalised anatomy and atrial fibrillation (AF) remodelling in a framework that can be used to investigate patient-specific AF mechanisms and test treatment response, but modelling fibrosis remains an unresolved matter. The interpretation of regions exhibiting low voltage in electroanatomic mapping data at different pacing rates also remain unclear. However, these occurrences are correlated with fibrotic remodelling. We aimed to use patient-specific simulations to investigate the effects of fibrosis type on AF properties by modelling conduction velocity slowing, changes in ionic channels, and replacement fibrosis, incorporated in regions of low voltage identified through omnipolar mapping at different pacing rates. Methods Local activation times (LATs) voltage and geometry data were obtained from patients undergoing ablation for persistent AF. LATs were collected in sinus rhythm with coronary sinus pacing at pacing interval (PIs) of 250ms and 600ms. For a total of 10 cases, personalised anatomical models were constructed for electrophysiology simulations, and analysed using an automated pipeline in python. For conductivity models, areas with peak omnipolar voltage (OV) below 0.5mV were assigned low conduction velocity. To incorporate ionic changes, the ionic properties were altered in fibrotic regions (peak OV < 0.5mV). In the simulations where replacement fibrosis was included through a probabilistic percolation method, percolation was modelled by using random number generator to probabilistically remove elements of low voltage. Pulmonary vein isolation was simulated in each model after 5s of AF, and wavefront propagation patterns were analysed to quantify the number of rotational areas or areas of wavefront break-up in 7 anatomical segments. Results The models with conductivity fibrotic remodelling demonstrated rotational drivers in more than two LA anatomical segments for both CS250ms pacing rate and CS600ms pacing rate across all 10 cases. The anterior wall exhibited the largest degree of rotational activity in 7 out of 10 cases for CS250ms pacing rate and in 9 out of 10 cases for CS600ms pacing rate (Figure A). The combination of percolation and conductivity remodelling also exhibited rotational activity on the anterior wall in 9 out of 10 cases at CS250ms pacing rate, and 7 out of 10 cases for CS600ms pacing rate. For the simulations where replacement fibrosis was included (percolation), both the roof and anterior wall exhibited the largest degree of rotational activity in 5 out of 10 cases at CS250ms pacing rate; while at CS600ms pacing rate, the posterior walled exhibited the majority of rotational activity in 7 cases (Figure B). All fibrosis models containing ionic changes terminated in more than half of the 10 cases for both pacing rates (CS250ms and 600). Conclusion The impact of low voltage on fibrotic remodelling causes complex effects on AF dynamics.

The right atrium affects in silico arrhythmia vulnerability in both atria

Abstract Introduction The role of the right atrium (RA) in atrial fibrillation (AF) has long been overlooked. Computer models of the atria can aid in assessing how the RA influences arrhythmia vulnerability and in studying the role of RA drivers in the induction of AF, both aspects challenging to assess in living patients. It remains unclear if incorporating the RA influences the reentry inducibility of the model. As personalized ablation strategies rely on non-inducibility criteria, the adequacy of left atrium (LA)-only models for developing such ablation tools is uncertain. Aim To evaluate the effect of incorporating the RA in 3D patient-specific computer models on arrhythmia vulnerability. Methods Imaging data from 8 subjects were obtained to generate patient-specific computer models. We created 2 models for each subject: a monoatrial with only the LA and a biatrial with both the RA and LA. We considered 3 different states of substrate remodeling: healthy (H), mild (M), and severe (S). The Courtemanche cellular model was modified from control conditions to a setup representing AF-induced remodeling [1] with 0%, 50%, and 100% changes for H, M, and S, respectively. Conduction velocity was set to 1.2, 1.0, and 0.8m/s for each remodeling state. Fibrosis extent corresponded to Utah 2 (5-20%) and Utah 4 (>35%) stages [2] for M and S, while the H state was modeled without fibrosis. Arrhythmia vulnerability was assessed by virtual S1S2 pacing from different points separated by 2cm using openCARP [3]. A point was classified as inducing arrhythmia if reentry was maintained for at least 1s. The vulnerability ratio was defined as the number of inducing points divided by the number of stimulation points. The mean tachycardia cycle length (TCL) was assessed at the stimulation site. We compared LA vulnerability ratios in monoatrial and biatrial models. Results Incorporating the RA increased the mean LA vulnerability ratio by 115.8% (0.19±0.13 to 0.41±0.22, p=0.033) in state M and 29.0% in state S (0.31±0.14 to 0.40±0.15, p=0.219) as illustrated in Figure 1. No arrhythmia was induced in the H models. RA inclusion increased the TCL of LA reentries by 5.5% (186.9±13.3ms to 197.2±18.3ms, p=0.006) in scenario M and decreased it by 7.2% (224.3±27.6ms to 208.2±34.8ms, p=0.010) in scenario S. RA inclusion increased LA inducibility revealing 5.5±3.0 new points per patient in the LA for the biatrial model, which did not induce reentry in the monoatrial model. Conclusions LA arrhythmia vulnerability in a biatrial model differs from that in a monoatrial model. Incorporating the RA in patient-specific computational models unmasked potential inducing points in the LA. The RA had a substrate-dependent effect on reentry dynamics, altering the TCL of LA-induced reentries. Our results provide evidence for an important role of the RA in the maintenance and induction of arrhythmia in patient-specific computational models, thus suggesting the use of biatrial models.

Functional substrate mapping characteristics during sinus rhythm predicts critical isthmus of scar related atrial tachycardia

Abstract Background Atrial tachycardia (AT) is a common rhythm disorder in patients with underlying atrial scar due to previous atrial surgery or valvular heart disease. Data is scarce about the role of functional characteristics or conduction properties during sinus rhythm that may have role in the critical isthmus (CI) of re-entry. Purpose We aimed to evaluate the relationship between the functional substrate mapping (FSM) characteristics of right and left atrium and the CI of re-entrant ATs in patients with atrial low-voltage areas. Methods A total of 95 [mean age: 57 ± 13, gender: 57 (60%) female] symptomatic patients with history of left and right AT who underwent catheter ablation with 3-D high-density mapping were enrolled. Isochronal late activation mapping were created during sinus/paced rhythm to detect deceleration zones (DZ). After induction of AT, activation mapping was performed in all patients. Results In 95 patients, 96 left-ATs [49 (51%) ATs were macroreentry and 47 (49%) ATs were localized reentry] and 40 right-ATs [24 (60%) ATs were macroreentry and 16 (40%) ATs were localized reentry] were mapped. Atrial low voltage zones comprised 23.3 ± 13.0 % of total right atrium and 33.3 ± 21.2 % of total left atrium. The mean value of bipolar voltage, EGM duration, and conduction velocity during sinus rhythm corresponding to CI of ATs were 0.17 ± 0.10 mV, 121 ± 39 ms, and 0.09 ± 0.06 m/s, respectively. Total number of DZs were 125 and all CIs of reentry were colocalized with DZs detected during FSM. The positive predictive value of DZs to detect CI of inducible ATs is 87.2%. Freedom from ATa was 76.8% at 12 months follow-up. Conclusion Our findings demonstrated the utility of FSM during sinus rhythm to predict the successful termination sites for ATs. These areas displayed continuous-fragmented signal morphology in correlation with the CI of AT detected during activation mapping.

P.063 Refractory pediatric CIDP converting to full recovery with rituximab

Background: Chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) is a rare, acquired polyneuropathy, especially in children, affecting the peripheral nervous system. It most commonly presents in a symmetric, proximal and distal, sensorimotor fashion. Immunosuppression and immunomanipulation are treatment modalities. We present a case of a 14 year old male with severe progressive CIDP who became refractory to steroid and IVIg but responded to Rituximab. Methods: Case presentation: A 14-year-old male with a history of asymmetric quadriparesis was diagnosed with CIDP. He had an initial partial response to IVIG and prednisone but then rapidly became refractory to even weekly IVIG and prednisone. Rituximab was therefore started. Results: Within 12 weeks his strength improved from quadriplegia to walker-assisted gait. By 22 weeks he achieved independent ambulation. His JAMAR hand grip increased from 0 to 28 kg. His worst recordable median conduction velocity (CV) improved from a nadir (MRC 0/5) of 14% of normal to 52% at full recovery (MRC 5/5). Conclusions: This case highlights several important clinical points. Dramatic improvement is possible in cases of quadriplegic CIDP. Strength recovery is not linearly related to CV recovery. There appears to be a role for polytherapy.

Neural control of ventricular electrophysiology: the role of the posterior descending ganglionated plexus

Abstract Background The autonomic nervous system plays an integral role in cardiac physiology. While the atrially located ganglionated plexus have been studied in several species, there is limited knowledge regarding the functional characterization of ventricular ganglionated plexus. Purpose The aim of the present study was to assess the role of the posterior descending ganglionated plexus (PD-GP) for neural control of ventricular electrophysiology. Methods First, to investigate whether the mouse may be useful as an animal model, a review of whole-mount immunohistological stained murine hearts (n=43) was conducted. Second, functional studies were performed in an ex-vivo retrograde-perfused porcine model (n=3) at baseline (pacing with a cycle length of 600 ms), during PD-GP high-frequency and local nicotine stimulation (Figure 1A). Wave propagation characteristics were determined by epicardial activation mapping. Activation recovery intervals (ARIs) were analyzed with a multi-electrode sock placed around the epicardium (Figure 1B). Finally, morphological analysis of explanted human hearts was conducted to determine the potential of translation into clinical practice. Results In murine hearts, ventricular ganglionated plexus were present in only 10% of hearts. In porcine hearts, dispersion of conduction velocity was increased during PD-GP high-frequency (8.52±2.24 radian vs. 2.79±0.89 radian; p=0.018) and nicotine stimulation (19.79±6.49 radian vs. 2.79±0.89 radian; p=0.044) compared to paced rhythm (Figure 1C). High-frequency stimulation prolonged ARIs in the posterior (257.8±6.7 ms vs. 244.8±1.9 ms; p=0.044) and basal (258.1±4.2 ms vs. 244.8±1.9 ms; p=0.039) right ventricle compared to the posterior left ventricle, while nicotine did not affect ARIs (right ventricle: 255.7±29.0 ms vs. left ventricle: 245.0±29.3 ms; p=0.677) (Figure 1D). Analysis of explanted human hearts confirmed the presence of the PD-GP in close relationship to the posterior descending coronary artery within epicardial adipose tissue (Figure 2). Conclusions While we demonstrate functional relevance of the PD-GP in explanted porcine hearts, important species-related differences might exist.Ex-vivo retrograde-perfused swine modelAnalysis of explanted human hearts

Angiotensin II-mediated oxidative stress increased the vulnerability of ventricular arrhythmia in cardiac hypertrophy rabbit model, which is suppressed by CaMKII inhibitor

Abstract Objectives Angiotensin system is a major cause of heart failure and arrhythmia. Despite a lack of direct evidence that oxidative stress causes ventricular arrhythmia, reversal of oxidative stress is considered a plausible therapy. This study evaluated the Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor could suppress arrhythmia in cardiac hypertrophy rabbit model. Methods Angiotensin II (Ang II) or saline was administrated for 2 weeks via osmotic minipumps implanted subcutaneously in the midclavicular region. Hearts were perfused, mapped optically to analyze action potential durations (APD), and restitution kinetics, and tested for VF vulnerability. The intracellular calcium dynamics were measured in cardiomyocyte treated with Ang II (10 ng/ml) for 1 hours. Results In Ang II rabbit groups, 2(30%) rabbits died and had ventricular arrhythmia and hearts had enlarged left ventricle, longer APD90, slower conduction velocity (CV; P<0.01 versus control) and higher levels of transcripts for CaMKII, PLB, RyR2 (P<0.05 versus control). N-acetylcysteine treatment reversed the transcripts for APD90 and CV (P<0.01). Programmed stimulation triggered VF in Ang II (n=5/6) and Ang II + saline (n=4/6), but not in control (n=0/10, P<0.01). Cardiomyocyte induced with Ang II showed increased spontaneous Ca2+ release (Ca2+ Wave Frequency; 1.0±0.0 vs. 5.1±0.5, p=0.001, Ca2+ Amplitude; 1.0±0.0 vs. 1.3±0.1, p=0.001) with control. CaMKII inhibitor reversed the change of Ca2+. Conclusion The Ang II group had an increased incidence of arrhythmia caused by increased phosphorylation of Ca2+ handling proteins. These changes were partially reversed by CaMKII inhibition.

Relationships between the global symptom score and electrophysiological findings after surgical release for carpal tunnel syndrome: Indications and outcomes.

Regarding surgical indications for carpal tunnel syndrome (CTS), the hypothesis that the recovery processes of subjective symptoms differ among pain, sensory, and motor symptoms and correlate with recovery in objective nerve conduction studies was examined in the present study. The global symptom score (GSS) is a method used to assess clinical outcomes and covers subjective symptoms, including pain (pain and nocturnal awakening), sensory (numbness and paresthesia), and motor (weakness/clumsiness) symptoms. The relationships between long-term changes in GSS and recovery in nerve conduction studies were investigated. Forty patients (40 hands) were included (mean age 65years; 80% female; 68% with moderate CTS: sensory nerve conduction velocity < 45m/s and motor nerve distal latency > 4.5ms). Pain and nocturnal awakening rapidly subsided within 1month after surgery and did not recur in the long term (median 5.6years). Paresthesia significantly decreased 3months after surgery and in the long term thereafter. Weakness/clumsiness significantly decreased at 1year. Sensory nerve distal latency, conduction velocity, and amplitude significantly improved 3months and 1year after surgery, and correlated with nocturnal awakening in the short term (3months) in moderate CTS cases. The patient satisfaction rate was 91%. Rapid recovery was observed in pain and nocturnal awakening, of which nocturnal awakening correlated with the recovery of sensory nerve conduction velocity. Patients with pain symptoms due to moderate CTS may benefit from surgical release.