Differences in atrial substrate localization using late gadolinium enhancement-magnetic resonance imaging, electrogram voltage, and conduction velocity: a cohort study using a consistent anatomical reference frame in patients with persistent atrial fibrillation.

AIMS: Electro-anatomical voltage, conduction velocity (CV) mapping, and late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) have been correlated with atrial cardiomyopathy (ACM). However, the comparability between these modalities remains unclear. This study aims to (i) compare pathological substrate extent and location between current modalities, (ii) establish spatial histograms in a cohort, (iii) develop a new estimated optimized image intensity threshold (EOIIT) for LGE-MRI identifying patients with ACM, (iv) predict rhythm outcome after pulmonary vein isolation (PVI) for persistent atrial fibrillation (AF). METHODS AND RESULTS: Thirty-six ablation-naive persistent AF patients underwent LGE-MRI and high-definition electro-anatomical mapping in sinus rhythm. Late gadolinium enhancement areas were classified using the UTAH, image intensity ratio (IIR >1.20), and new EOIIT method for comparison to low-voltage substrate (LVS) and slow conduction areas <0.2 m/s. Receiver operating characteristic analysis was used to determine LGE thresholds optimally matching LVS. Atrial cardiomyopathy was defined as LVS extent ≥5% of the left atrium (LA) surface at <0.5 mV. The degree and distribution of detected pathological substrate (percentage of individual LA surface are) varied significantly (P < 0.001) across the mapping modalities: 10% (interquartile range 0-14%) of the LA displayed LVS <0.5 mV vs. 7% (0-12%) slow conduction areas <0.2 m/s vs. 15% (8-23%) LGE with the UTAH method vs. 13% (2-23%) using IIR >1.20, with most discrepancies on the posterior LA. Optimized image intensity thresholds and each patient's mean blood pool intensity correlated linearly (R2 = 0.89, P < 0.001). Concordance between LGE-MRI-based and LVS-based ACM diagnosis improved with the novel EOIIT applied at the anterior LA [83% sensitivity, 79% specificity, area under the curve (AUC): 0.89] in comparison to the UTAH method (67% sensitivity, 75% specificity, AUC: 0.81) and IIR >1.20 (75% sensitivity, 62% specificity, AUC: 0.67). CONCLUSION: Discordances in detected pathological substrate exist between LVS, CV, and LGE-MRI in the LA, irrespective of the LGE detection method. The new EOIIT method improves concordance of LGE-MRI-based ACM diagnosis with LVS in ablation-naive AF patients but discrepancy remains particularly on the posterior wall. All methods may enable the prediction of rhythm outcomes after PVI in patients with persistent AF.

Spatial correlation of left atrial low voltage substrate in sinus rhythm versus atrial fibrillation: The rhythm specificity of atrial low voltage substrate.

INTRODUCTION: Improved sinus rhythm (SR) maintenance rates have been achieved in patients with persistent atrial fibrillation (AF) undergoing pulmonary vein isolation plus additional ablation of low voltage substrate (LVS) during SR. However, voltage mapping during SR may be hindered in persistent and long-persistent AF patients by immediate AF recurrence after electrical cardioversion. We assess correlations between LVS extent and location during SR and AF, aiming to identify regional voltage thresholds for rhythm-independent delineation/detection of LVS areas. (1) Identification of voltage dissimilarities between mapping in SR and AF. (2) Identification of regional voltage thresholds that improve cross-rhythm substrate detection. (3) Comparison of LVS between SR and native versus induced AF. METHODS: Forty-one ablation-naive persistent AF patients underwent high-definition (1 mm electrodes; >1200 left atrial (LA) mapping sites per rhythm) voltage mapping in SR and AF. Global and regional voltage thresholds in AF were identified which best match LVS < 0.5 mV and <1.0 mV in SR. Additionally, the correlation between SR-LVS with induced versus native AF-LVS was assessed. RESULTS: Substantial voltage differences (median: 0.52, interquartile range: 0.33-0.69, maximum: 1.19 mV) with a predominance of the posterior/inferior LA wall exist between the rhythms. An AF threshold of 0.34 mV for the entire left atrium provides an accuracy, sensitivity and specificity of 69%, 67%, and 69% to identify SR-LVS < 0.5 mV, respectively. Lower thresholds for the posterior wall (0.27 mV) and inferior wall (0.3 mV) result in higher spatial concordance to SR-LVS (4% and 7% increase). Concordance with SR-LVS was higher for induced AF compared to native AF (area under the curve[AUC]: 0.80 vs. 0.73). AF-LVS < 0.5 mV corresponds to SR-LVS < 0.97 mV (AUC: 0.73). CONCLUSION: Although the proposed region-specific voltage thresholds during AF improve the consistency of LVS identification as determined during SR, the concordance in LVS between SR and AF remains moderate, with larger LVS detection during AF. Voltage-based substrate ablation should preferentially be performed during SR to limit the amount of ablated atrial myocardium.

Amplified sinus-P-wave analysis predicts outcomes of cryoballoon ablation in patients with persistent and long-standing persistent atrial fibrillation: A multicentre study.

Introduction: Outcomes of catheter ablation for non-paroxysmal atrial fibrillation (AF) remain suboptimal. Non-invasive stratification of patients based on the presence of atrial cardiomyopathy (ACM) could allow to identify the best responders to pulmonary vein isolation (PVI). Methods: Observational multicentre retrospective study in patients undergoing cryoballoon-PVI for non-paroxysmal AF. The duration of amplified P-wave (APW) was measured from a digitally recorded 12-lead electrocardiogram during the procedure. If patients were in AF, direct-current cardioversion was performed to allow APW measurement in sinus rhythm. An APW cut-off of 150 ms was used to identify patients with significant ACM. We assessed freedom from arrhythmia recurrence at long-term follow-up in patients with APW ≥ 150 ms vs. APW < 150 ms. Results: We included 295 patients (mean age 62.3 ± 10.6), of whom 193 (65.4%) suffered from persistent AF and the remaining 102 (34.6%) from long-standing persistent AF. One-hundred-forty-two patients (50.2%) experienced arrhythmia recurrence during a mean follow-up of 793 ± 604 days. Patients with APW ≥ 150 ms had a significantly higher recurrence rate post ablation compared to those with APW < 150 ms (57.0% vs. 41.6%; log-rank p < 0.001). On a multivariable Cox-regression analysis, APW≥150 ms was the only independent predictor of arrhythmia recurrence post ablation (HR 2.03 CI95% 1.28-3.21; p = 0.002). Conclusion: APW duration predicts arrhythmia recurrence post cryoballoon-PVI in persistent and long-standing persistent AF. An APW cut-off of 150 ms allows to identify patients with significant ACM who have worse outcomes post PVI. Analysis of APW represents an easy, non-invasive and highly reproducible diagnostic tool which allows to identify patients who are the most likely to benefit from PVI-only approach.

3D mapping of phrenic nerve course for radiofrequency pulmonary vein isolation.

INTRODUCTION: Phrenic nerve (PN) injury is a rare but severe complication of radiofrequency (RF) pulmonary vein isolation (PVI). The objective of this study was to characterize the typical intracardiac course of the PN with a three-dimensional electroanatomic mapping system, to quantify the need for modification of the ablation trajectory to avoid delivering an ablation lesion on sites with PN capture, and to identify very circumscribed areas of common PNC on the routine ablation trajectory of a RF-PVI, allowing fast and effective PN screening for everyday usage. METHODS: We enrolled 137 consecutive patients (63 ± 9 years, 64% men) undergoing PVI. A detailed high output (20 mA) pace-mapping protocol was performed in the right (RA) and left atrium (LA) and adjacent vasculature. RESULTS: The right PN was most commonly captured in the superior vena cava at a lateral (50%) or posterolateral (23%) position before descending along the RA either straight (29%) or with a posterolateral bend (20%). In the LA, beginning deep within the right superior pulmonary vein (RSPV), the right PN is most frequently detectable anterolateral (31%), then descends to the lateral proximal RSPV (23%), and further towards the lateral antral region (15%) onto the medial LA wall (12%). To avoid delivering an ablation lesion on sites with PN capture, modification of ablation trajectory was necessary in 23% of cases, most commonly in the lateral RSPV antrum (81%). No PN injury occurred. CONCLUSION: PN mapping frequently reveals the close proximity of the PN to the ablation trajectory during PVI, particularly in the lateral RSPV antrum. Routine PN pacing should be considered during RF PVI procedures.

Validating left atrial fractionation and low-voltage substrate during atrial fibrillation and sinus rhythm-A high-density mapping study in persistent atrial fibrillation.

Background: Low-voltage-substrate (LVS)-guided ablation for persistent atrial fibrillation (AF) has been described either in sinus rhythm (SR) or AF. Prolonged fractionated potentials (PFPs) may represent arrhythmogenic slow conduction substrate and potentially co-localize with LVS. We assess the spatial correlation of PFP identified in AF (PFP-AF) to those mapped in SR (PFP-SR). We further report the relationship between LVS and PFPs when mapped in AF or SR. Materials and methods: Thirty-eight patients with ablation naïve persistent AF underwent left atrial (LA) high-density mapping in AF and SR prior to catheter ablation. Areas presenting PFP-AF and PFP-SR were annotated during mapping on the LA geometry. Low-voltage areas (LVA) were quantified using a bipolar threshold of 0.5 mV during both AF and SR mapping. Concordance of fractionated potentials (CFP) (defined as the presence of PFPs in both rhythms within a radius of 6 mm) was quantified. Spatial distribution and correlation of PFP and CFP with LVA were assessed. The predictors for CFP were determined. Results: PFPs displayed low voltages both during AF (median 0.30 mV (Q1-Q3: 0.20-0.50 mV) and SR (median 0.35 mV (Q1-Q3: 0.20-0.56 mV). The duration of PFP-SR was measured at 61 ms (Q1-Q3: 51-76 ms). During SR, most PFP-SRs (89.4 and 97.2%) were located within LVA (<0.5 mV and <1.0 mV, respectively). Areas presenting PFP occurred more frequently in AF than in SR (median: 9.5 vs. 8.0, p = 0.005). Both PFP-AF and PFP-SR were predominantly located at anterior LA (>40%), followed by posterior LA (>20%) and septal LA (>15%). The extent of LVA < 0.5 mV was more extensive in AF (median: 25.2% of LA surface, Q1-Q3:16.6-50.5%) than in SR (median: 12.3%, Q1-Q3: 4.7-29.4%, p = 0.001). CFP in both rhythms occurred in 80% of PFP-SR and 59% of PFP-AF (p = 0.008). Notably, CFP was positively correlated to the extent of LVA in SR (p = 0.004), but not with LVA in AF (p = 0.226). Additionally, the extent of LVA < 0.5 mV in SR was the only significant predictor for CFP, with an optimal threshold of 16% predicting high (>80%) fractionation concordance in AF and SR. Conclusion: Substrate mapping in SR vs. AF reveals smaller areas of low voltage and fewer sites with PFP. PFP-SR are located within low-voltage areas in SR. There is a high degree of spatial agreement (80%) between PFP-AF and PFP-SR in patients with moderate LVA in SR (>16% of LA surface). These findings should be considered when substrate-based ablation strategies are applied in patients with the left atrial low-voltage substrate with recurrent persistent AF.

Risk Stratification for Pacemaker Implantation after Transcatheter Aortic Valve Implantation in Patients with Right Bundle Branch Block.

BACKGROUND: Permanent pacemaker implantation (PPI) after transcatheter valve implantation (TAVI) is a common complication. Pre-existing right bundle branch block (RBBB) is a strong risk factor for PPI after TAVI. However, a patient-specific approach for risk stratification in this subgroup has not yet been established. METHODS: We investigated TAVI patients with pre-existing RBBB to stratify risk factors for PPI and 1-year-mortality by detailed analysis of ECG data, RBBB morphology and degree of calcification in the implantation area assessed by computed tomography angiography. RESULTS: Between 2010 and 2018, 2129 patients underwent TAVI at our institution. Among these, 98 pacemaker-naïve patients with pre-existing RBBB underwent a TAVI procedure. PPI, because of relevant conduction disturbances (CD), was necessary in 43 (43.9%) patients. PPI was more frequently indicated in women vs. men (62.1% vs. 32.8%, p = 0.004) and in men treated with a self-expandable vs. a balloon-expandable valve (58.3% vs. 26.5%, p = 0.035). ECG data (heart rhythm, PQ, QRS, QT) and RBBB morphology had no influence on PPI rate, whereas risk for PPI increased with the degree of calcification in the left septal His-/left bundle branch-area to a 9.375-fold odds for the 3rd tertile of calcification (1.639-53.621; p = 0.012). Overall, 1-year-mortality was comparable among patients with or without PPI (14.0% vs. 16.4%; p = 0.697). CONCLUSIONS: Patients with RBBB undergoing TAVI have a high risk of PPI. Among this subgroup, female patients, male patients treated with self-expandable valve types, patients with high load/degree of non-coronary LVOT calcification and patients with atrial fibrillation need enhanced surveillance for CD after procedure.

Echocardiographic and Electrocardiographic Determinants of Atrial Cardiomyopathy Identify Patients with Atrial Fibrillation at Risk for Left Atrial Thrombogenesis.

Objective: Atrial cardiomyopathy (ACM) is associated with development of AF, left atrial (LA) thrombogenesis, and stroke. Diagnosis of ACM is feasible using both echocardiographic LA strain imaging and measurement of the amplified p-wave duration (APWD) in digital 12-lead-ECG. We sought to determine the thresholds of LA global longitudinal strain (LA-GLS) and APWD that identify patients with AF at risk for LA appendage (LAA) thrombogenesis. Methods: One hundred and twenty-eight patients with a history of AF were included. Left atrial appendage maximal flow velocity (LAA-Vel, in TEE), LA-GLS (TTE), and APWD (digital 12-lead-ECG) were measured in all patients. ROC analysis was performed for each method to determine the thresholds for LA-GLS and the APWD, enabling diagnosis of patients with LAA-thrombus. Results: Significant differences in LA-GLS were found during both rhythms (SR and AF) between the thrombus group and control group: LA-GLS in SR: 14.3 ± 7.4% vs. 24.6 ± 9.0%, p < 0.001 and in AF: 11.4 ± 4.2% vs. 16.1 ± 5.0%, p = 0.045. ROC analysis revealed a threshold of 17.45% for the entire cohort (AUC 0.82, sensitivity: 84.6%, specificity: 63.6%, Negative Predictive Value (NPV): 94.3%) with additional rhythm-specific thresholds: 19.1% in SR and 13.9% in AF, and a threshold of 165 ms for APWD (AUC 0.90, sensitivity: 88.5%, specificity: 75.5%, NPV: 96.2%) as optimal discriminators of LAA-thrombus. Moreover, both LA-GLS and APWD correlated well with the established contractile LA-parameter LAA-Vel in TEE (r = 0.39, p < 0.001 and r = −0.39, p < 0.001, respectively). Conclusion: LA-GLS and APWD are valuable diagnostic predictors of left atrial thrombogenesis in patients with AF.

Machine Learning Using a Single-Lead ECG to Identify Patients With Atrial Fibrillation-Induced Heart Failure.

Aims: Atrial fibrillation (AF) and heart failure often co-exist. Early identification of AF patients at risk for AF-induced heart failure (AF-HF) is desirable to reduce both morbidity and mortality as well as health care costs. We aimed to leverage the characteristics of beat-to-beat-patterns in AF to prospectively discriminate AF patients with and without AF-HF. Methods: A dataset of 10,234 5-min length RR-interval time series derived from 26 AF-HF patients and 26 control patients was extracted from single-lead Holter-ECGs. A total of 14 features were extracted, and the most informative features were selected. Then, a decision tree classifier with 5-fold cross-validation was trained, validated, and tested on the dataset randomly split. The derived algorithm was then tested on 2,261 5-min segments from six AF-HF and six control patients and validated for various time segments. Results: The algorithm based on the spectral entropy of the RR-intervals, the mean value of the relative RR-interval, and the root mean square of successive differences of the relative RR-interval yielded an accuracy of 73.5%, specificity of 91.4%, sensitivity of 64.7%, and PPV of 87.0% to correctly stratify segments to AF-HF. Considering the majority vote of the segments of each patient, 10/12 patients (83.33%) were correctly classified. Conclusion: Beat-to-beat-analysis using a machine learning classifier identifies patients with AF-induced heart failure with clinically relevant diagnostic properties. Application of this algorithm in routine care may improve early identification of patients at risk for AF-induced cardiomyopathy and improve the yield of targeted clinical follow-up.

Electrocardiographic diagnosis of atrial cardiomyopathy to predict atrial contractile dysfunction, thrombogenesis and adverse cardiovascular outcomes.

Thromboembolism and stroke are dreaded complications in atrial fibrillation (AF). Established risk stratification models identify susceptible patients, but their discriminative properties are poor. Atrial cardiomyopathy (ACM) is associated to thromboembolism and stroke in smaller studies, but the modalities used for ACM-diagnosis (MRI and endocardial mapping) are unsuitable for widespread population screening. We aimed to investigate an ECG-based diagnosis of ACM using amplified p-wave analysis (APWA) for stratification of thromboembolic risk and cardiovascular outcome. In this case-control study, ACM-staging was performed using APWA on digital 12-lead sinus rhythm-ECGs in patients with LAA-thrombus and a propensity-score-matched control-cohort. Left atrial contractile function and thrombi were evaluated by transesophageal echocardiography (TEE). Outcome for MACCE including death was assessed using official registries and structured phone interviews. Left-atrial appendage [LAA]-thrombi and appropriate sinus rhythm-ECGs for ACM-staging were found in 109 of 4086 patients that were matched 1:1 to control patients without thrombus (218 patients in total). Both cohorts were comparable regarding cardiovascular risk factors, anticoagulants and CHA2DS2-VASC-score. ACM-stages 1 to 3 (equivalent to no, moderate and extensive ACM) were found in 63 (57.8%), 36 (33.0%) and 10 (9.2%) of patients without and 3 (2.8%), 23 (21.1%) and 83 (76.1%) of patients with LAA-thrombi. Atrial contractile function decreased from ACM-stages 1 to 3 (LAA-flow velocities 38 ± 16 cm/s, 31 ± 15 cm/s and 21 ± 12 cm/s; p < 0.0001), while the likelihood for LAA-thrombus increased (2.8%, 21.1% and 76.1%, p < 0.001). Multivariable analysis confirmed an independent odds ratio for LAA-thrombus of 24.6 (p < 0.001) per ACM-stage. Two-year survival free of stroke/TIA, hospitalization for heart failure, myocardial infarction or all-cause death was strongly reduced in ACM-stage 3 (53.8%) compared to no or moderate ACM (82.8% and 84.7%, respectively; p < 0.0001). Electrocardiographic diagnosis of ACM identifies patients with atrial contractile dysfunction and atrial thrombi at risk for adverse cardiovascular outcomes and death.

Determinants of fibrotic atrial cardiomyopathy in atrial fibrillation. A multicenter observational study of the RETAC (reseau européen de traîtement d'arrhythmies cardiaques)-group.

AIMS: Despite advances in interventional treatment strategies, atrial fibrillation (AF) remains associated with significant morbidity and mortality. Fibrotic atrial myopathy (FAM) is a main factor for adverse outcomes of AF-ablation, but complex to diagnose using current methods. We aimed to derive a scoring system based entirely on easily available clinical parameters to predict FAM and ablation-success in everyday care. METHODS: In this multicenter, prospective study, a new risk stratification model termed AF-SCORE was derived in 220 patients undergoing high-density left-atrial(LA) voltage-mapping to quantify FAM. AF-SCORE was validated for FAM in an external mapping-validation cohort (n = 220) and for success following pulmonary vein isolation (PVI)-only (without adjunctive left- or right atrial ablations) in an external outcome-validation cohort (n = 518). RESULTS: FAM was rare in patients < 60 years (5.4%), but increased with ageing and affected 40.4% (59/146) of patients ≥ 60 years. Sex and AF-phenotype had additional predictive value in older patients and remained associated with FAM in multivariate models (odds ratio [OR] 6.194, p < 0.0001 for ≥ 60 years; OR 2.863, p < 0.0001 for female sex; OR 41.309, p < 0.0001 for AF-persistency). Additional clinical or diagnostic variables did not improve the model. AF-SCORE (+ 1 point for age ≥ 60 years and additional points for female sex [+ 1] and AF-persistency [+ 2]) showed good discrimination to detect FAM (c-statistic 0.792) and predicted arrhythmia-freedom following PVI (74.3%, 54.7% and 45.5% for AF-SCORE ≤ 2, 3 and 4, respectively, and hazard ratio [HR] 1.994 for AF-SCORE = 3 and HR 2.866 for AF-SCORE = 4, p < 0.001). CONCLUSIONS: Age, sex and AF-phenotype are the main determinants for the development of FAM. A low AF-SCORE ≤ 2 is found in paroxysmal AF-patients of any age and younger patients with persistent AF irrespective of sex, and associated with favorable outcomes of PVI-only. Freedom from arrhythmia remains unsatisfactory with AF-SCORE ≥ 3 as found in older patients, particularly females, with persistent AF, and future studies investigating adjunctive atrial ablations to PVI-only should focus on these groups of patients.

Machine learning enables noninvasive prediction of atrial fibrillation driver location and acute pulmonary vein ablation success using the 12-lead ECG.

BACKGROUND: Atrial fibrillation (AF) is the most common supraventricular arrhythmia, characterized by disorganized atrial electrical activity, maintained by localized arrhythmogenic atrial drivers. Pulmonary vein isolation (PVI) allows to exclude PV-related drivers. However, PVI is less effective in patients with additional extra-PV arrhythmogenic drivers. OBJECTIVES: To discriminate whether AF drivers are located near the PVs vs extra-PV regions using the noninvasive 12-lead electrocardiogram (ECG) in a computational and clinical framework, and to computationally predict the acute success of PVI in these cohorts of data. METHODS: AF drivers were induced in 2 computerized atrial models and combined with 8 torso models, resulting in 1128 12-lead ECGs (80 ECGs with AF drivers located in the PVs and 1048 in extra-PV areas). A total of 103 features were extracted from the signals. Binary decision tree classifier was trained on the simulated data and evaluated using hold-out cross-validation. The PVs were subsequently isolated in the models to assess PVI success. Finally, the classifier was tested on a clinical dataset (46 patients: 23 PV-dependent AF and 23 with additional extra-PV sources). RESULTS: The classifier yielded 82.6% specificity and 73.9% sensitivity for detecting PV drivers on the clinical data. Consistency analysis on the 46 patients resulted in 93.5% results match. Applying PVI on the simulated AF cases terminated AF in 100% of the cases in the PV class. CONCLUSION: Machine learning-based classification of 12-lead-ECG allows discrimination between patients with PV drivers vs those with extra-PV drivers of AF. The novel algorithm may aid to identify patients with high acute success rates to PVI.

Easily available ECG and echocardiographic parameters for prediction of left atrial remodeling and atrial fibrillation recurrence after pulmonary vein isolation: A multicenter study.

BACKGROUND: The assessment of noninvasive markers of left atrial (LA) low-voltage substrate (LVS) enables the identification of atrial fibrillation (AF) patients at risk for arrhythmia recurrence after pulmonary vein isolation (PVI). METHODS: In this prospective multicenter study, 292 consecutive AF patients (72% male, 62 ± 11 years, 65% persistent AF) underwent high-density LA voltage mapping in sinus rhythm. LA-LVS (<0.5 mV) was considered as significant at 2 cm2  or above. Preprocedural clinical electrocardiogram and echocardiographic data were assessed to identify predictors of LA-LVS. The role of the identified LA-LVS markers in predicting 1-year arrhythmia freedom after PVI was assessed in 245 patients. RESULTS: Significant LA-LVS was identified in 123 (42%) patients. The amplified sinus P-wave duration (APWD) best predicted LA-LVS, with a 148-ms value providing the best-balanced sensitivity (0.81) and specificity (0.88). An APWD over 160 ms was associated with LA-LVS in 96% of patients, whereas an APWD under 145 ms in 15%. Remaining gray zones improved their accuracy by introduction of systolic pulmonary artery pressure (sPAP) of 35 mmHg or above, age, and sex. According to COX regression, the risk of arrhythmia recurrence 12 months following PVI was twofold and threefold higher in patients with APWD 145-160 and over 160 ms, compared to APWD under 145 ms. Integration of pulmonary hypertension further improved the outcome prediction in the intermediate APWD group: Patients with APWD 145-160 ms and normal sPAP had similar outcome than patients with APWD under 145 ms (hazard ratio [HR] 1.62, p = .14), whereas high sPAP implied worse outcome (HR 2.56, p < .001). CONCLUSIONS: The APWD identifies LA-LVS and risk for arrhythmia recurrence after PVI. Our prediction model becomes optimized by means of integration of the pulmonary artery pressure.

Comparison of Unipolar and Bipolar Voltage Mapping for Localization of Left Atrial Arrhythmogenic Substrate in Patients With Atrial Fibrillation.

Background: Presence of left atrial low voltage substrate in bipolar voltage mapping is associated with increased arrhythmia recurrences following pulmonary vein isolation for atrial fibrillation (AF). Besides local myocardial fibrosis, bipolar voltage amplitudes may be influenced by inter-electrode spacing and bipole-to-wavefront-angle. It is unclear to what extent these impact low voltage areas (LVA) in the clinical setting. Alternatively, unipolar electrogram voltage is not affected by these factors but requires advanced filtering. Objectives: To assess the relationship between bipolar and unipolar voltage mapping in sinus rhythm (SR) and AF and identify if the electrogram recording mode affects the quantification and localization of LVA. Methods: Patients (n = 28, 66±7 years, 46% male, 82% persistent AF, 32% redo-procedures) underwent high-density (>1,200 sites, 20 ± 10 sites/cm2, using a 20-pole 2-6-2 mm-spaced Lasso) voltage mapping in SR and AF. Bipolar LVA were defined using four different thresholds described in literature: <0.5 and <1 mV in SR, <0.35 and <0.5 mV in AF. The optimal unipolar voltage threshold resulting in the highest agreement in both unipolar and bipolar mapping modes was determined. The impact of the inter-electrode distance (2 vs. 6 mm) on the correlation was assessed. Regional analysis was performed using an 11-segment left atrial model. Results: Patients had relevant bipolar LVA (23 ± 23 cm2 at <0.5 mV in SR and 42 ± 26 cm2 at <0.5 mV in AF). 90 ± 5% (in SR) and 85 ± 5% (AF) of mapped sites were concordantly classified as high or low voltage in both mapping modes. Discordant mapping sites located to the border zone of LVA. Bipolar voltage mapping using 2 vs. 6 mm inter-electrode distances increased the portion of matched mapping points by 4%. The unipolar thresholds (y) which resulted in a high spatial concordance can be calculated from the bipolar threshold (x) using following linear equations: y = 1.06x + 0.26mV (r = 0.994) for SR and y = 1.22x + 0.12mV (r = 0.998) for AF. Conclusion: Bipolar and unipolar voltage maps are highly correlated, in SR and AF. While bipole orientation and inter-electrode spacing are theoretical confounders, their impact is unlikely to be of clinical importance for localization of LVA, when mapping is performed at high density with a 20-polar Lasso catheter.

Specific Electrogram Characteristics Identify the Extra-Pulmonary Vein Arrhythmogenic Sources of Persistent Atrial Fibrillation - Characterization of the Arrhythmogenic Electrogram Patterns During Atrial Fibrillation and Sinus Rhythm.

Identification of atrial sites that perpetuate atrial fibrillation (AF), and ablation thereof terminates AF, is challenging. We hypothesized that specific electrogram (EGM) characteristics identify AF-termination sites (AFTS). Twenty-one patients in whom low-voltage-guided ablation after pulmonary vein isolation terminated clinical persistent AF were included. Patients were included if short RF-delivery for <8sec at a given atrial site was associated with acute termination of clinical persistent AF. EGM-characteristics at 21 AFTS, 105 targeted sites without termination and 105 non-targeted control sites were analyzed. Alteration of EGM-characteristics by local fibrosis was evaluated in a three-dimensional high resolution (100 µm)-computational AF model. AFTS demonstrated lower EGM-voltage, higher EGM-cycle-length-coverage, shorter AF-cycle-length and higher pattern consistency than control sites (0.49 ± 0.39 mV vs. 0.83 ± 0.76 mV, p < 0.0001; 79 ± 16% vs. 59 ± 22%, p = 0.0022; 173 ± 49 ms vs. 198 ± 34 ms, p = 0.047; 80% vs. 30%, p < 0.01). Among targeted sites, AFTS had higher EGM-cycle-length coverage, shorter local AF-cycle-length and higher pattern consistency than targeted sites without AF-termination (79 ± 16% vs. 63 ± 23%, p = 0.02; 173 ± 49 ms vs. 210 ± 44 ms, p = 0.002; 80% vs. 40%, p = 0.01). Low voltage (0.52 ± 0.3 mV) fractionated EGMs (79 ± 24 ms) with delayed components in sinus rhythm ('atrial late potentials', respectively 'ALP') were observed at 71% of AFTS. EGMs recorded from fibrotic areas in computational models demonstrated comparable EGM-characteristics both in simulated AF and sinus rhythm. AFTS may therefore be identified by locally consistent, fractionated low-voltage EGMs with high cycle-length-coverage and rapid activity in AF, with low-voltage, fractionated EGMs with delayed components/ 'atrial late potentials' (ALP) persisting in sinus rhythm.

3D mapping for the identification of the fossa ovalis in left atrial ablation procedures: a pilot study of a first step towards an electroanatomic-guided transseptal puncture.

AIMS: Transseptal puncture (TP) for left atrial (LA) catheter ablation procedures is routinely performed under fluoroscopic guidance. To decrease radiation exposure and increase safety alternative techniques are desirable. The aim of this study was to assess whether right atrial (RA) electroanatomic 3D mapping can reliably identify the fossa ovalis (FO) in preparation of TP. METHODS AND RESULTS: Between May 2019 and August 2019, electroanatomic RA mapping was performed before TP in 61 patients with paroxysmal or persistent atrial fibrillation. Three electroanatomic methods for FO identification, mapping catheter-induced FO protrusion, electroanatomic-guided analysis, and voltage mapping, were evaluated and compared with transoesophageal echocardiography (TOE). Mapping catheter-induced FO protrusion was feasible in 60 patients (98%) with a mean displacement of 6.8 ± 2.5 mm, confirmed by TOE, and proofed to be the most valuable and easiest marker for FO identification. Electroanatomic-guided analysis localized the FO midpoint consistently in the lower half (43 ± 7%) and posterior (18.2 ± 4.4 mm) to a line between coronary sinus and vena cava superior. Analysis of RA voltage maps during sinus rhythm (n = 40, low-voltage cut-off value 1.0 and 1.5 mV) allowed secure FO recognition in 33% and 18%, only. A step-by-step approach, combining FO protrusion (first step) with anatomy criteria in case of protrusion failure (second step) would have allowed for the correct localization of a TP site within the FO in all patients. CONCLUSION: Right atrial electroanatomic 3D mapping prior to TP proofed to be a simple tool for FO identification and may potentially be of use in the safe and radiation-free performance of TP prior to LA ablation procedures.

Amplified P-wave duration predicts new-onset atrial fibrillation in patients with heart failure with preserved ejection fraction.

BACKGROUND: Atrial fibrillation (AF) increases morbidity and mortality in heart failure with preserved ejection fraction (HFpEF), yet identification of HFpEF-patients at risk for new-onset AF is challenging. Amplified P-wave duration (APWD) non-invasively detects arrhythmogenic atrial substrate with high accuracy. We hypothesized that APWD may help in the prediction of new-onset AF in HFpEF. METHODS: Patients with suspected HFpEF (n = 99, left ventricular ejection fraction > 50%, no evidence of valvulopathy, coronary artery disease, or non-cardiac dyspnea) underwent exercise testing with concomitant right-heart catheterization. Normal resting pulmonary capillary wedge pressure (PCWP; < 12 mmHg) with an increase during exercise > 25.5 mmHg/W/kg defined early HFpEF. Advanced HFpEF was diagnosed with PCWP > 12 mmHg at rest. Arrhythmogenic atrial substrate (defined as APWD > 150 ms) was investigated on digitized standard 12-lead ECGs and patients were followed for new-onset AF at 6-month intervals. RESULTS: Forty-seven patients had normal exercise haemodynamics and served as controls. Early and advanced HFpEF was diagnosed in 29 and 23 patients, respectively. Eighty-seven per cent of patients with advanced HFpEF had evidence of arrhythmogenic atrial substrate, (APWD 175 ± 29 ms vs. 132 ± 14 ms in controls, p < 0.0001), which was associated with a tenfold increased risk for new-onset AF during 4.6 years of follow-up (hazard ratio [HR] 9.684, 95% CI 2.61-35.89, p < 0.0001). Early HFpEF was neither related to APWD (p = 0.395), nor to a higher risk for AF (HR 3.44, 95% CI 0.57-20.72, p = 0.178). Importantly, the presence of arrhythmogenic substrate was independent of left atrial indexed volume. CONCLUSION: The analysis of amplified P-wave duration (APWD) allows for the prediction of new-onset AF in patients with advanced HFpEF.

Amplified sinus-P-wave reveals localization and extent of left atrial low-voltage substrate: implications for arrhythmia freedom following pulmonary vein isolation.

AIMS: Presence of arrhythmogenic left atrial (LA) low-voltage substrate (LVS) is associated with reduced arthythmia freedom rates following pulmonary vein isolation (PVI) in persistent atrial fibrillation (AF). We hypothesized that LA-LVS modifies amplified sinus-P-wave (APW) characteristics, enabling identification of patients at risk for arrhythmia recurrences following PVI. METHODS AND RESULTS: Ninety-five patients with persistent AF underwent high-density (>1200 sites) voltage mapping in sinus rhythm. Left atrial low-voltage substrate (<0.5 and <1.0 mV) was quantified in a 10-segment LA model. Amplified sinus-P-wave-morphology and -duration were evaluated using digitized 12-lead electrocardiograms (40-80 mm/mV, 100-200 mm/s). 12-months arrhythmia freedom following circumferential PVI was assessed in 139 patients with persistent AF. Left atrial low-voltage substrate was most frequently (84%) found at the anteroseptal LA. Characteristic changes of APW were related to the localization and extent of LA-LVS. At an early stage, LA-LVS predominantly located to the LA-anteroseptum and was associated with APW-prolongation (≥150 ms). More extensive LA-LVS involved larger areas of LA-anteroseptum, leading to morphological changes of APW (biphasic positive-negative P-waves in inferior leads). Severe LA-LVS involved the LA-anteroseptum, roof and posterior LA, but spared the inferior LA, lateral LA, and LA appendage. In this advanced stage, widespread LVS at the posterior LA abolished the negative portion of P-wave in the inferior leads. The delayed activation of the lateral LA and LA appendage produced the late positive deflections in the anterolateral leads, resulting in the "late-terminal P"-pattern. Structured analysis of APW-duration and -morphology stratified patients to their individual extent of LA-LVS (Grade 1: mean LA-LVS 4.9 cm2 at <1.0 mV; Grade 2: 28.6 cm2; Grade 3: 42.3 cm2; P < 0.01). The diagnostic value of APW-duration for identification of LA-LVS was significantly superior to standard P-wave-amplification (c-statistic 0.945 vs. 0.647). Arrhythmia freedom following PVI differed significantly between APW-predicted grades of LA-LVS-severity [hazard ratio (HR) 2.38, 95% confidence interval (CI) 1.18-4.83; P = 0.015 for Grade 1 vs. Grade 2; HR 1.79, 95% CI 1.00-3.21, P = 0.049 for Grade 2 vs. Grade 3). Arrhythmia freedom 12 months after PVI was 77%, 53%, and 33% in Grades 1, 2 and 3, respectively. CONCLUSION: Localization and extent of LA-LVS modifies APW-morphology and -duration. Analysis of APW allows accurate prediction of LA-LVS and enables rapid and non-invasive estimation of arrhythmia freedom following PVI.

Heart non-specific effector CD4+ T cells protect from postinflammatory fibrosis and cardiac dysfunction in experimental autoimmune myocarditis.

Heart-specific CD4+ T cells have been implicated in development and progression of myocarditis in mice and in humans. Here, using mouse models of experimental autoimmune myocarditis (EAM) we investigated the role of heart non-specific CD4+ T cells in the progression of the disease. Heart non-specific CD4+ T cells were obtained from DO11.10 mice expressing transgenic T cell receptor recognizing chicken ovalbumin. We found that heart infiltrating CD4+ T cells expressed exclusively effector (Teff) phenotype in the EAM model and in hearts of patients with lymphocytic myocarditis. Adoptive transfer experiments showed that while heart-specific Teff infiltrated the heart shortly after injection, heart non-specific Teff effectively accumulated during myocarditis and became the major heart-infiltrating CD4+ T cell subset at later stage. Restimulation of co-cultured heart-specific and heart non-specific CD4+ T cells with alpha-myosin heavy chain antigen showed mainly Th1/Th17 response for heart-specific Teff and up-regulation of a distinct set of extracellular signalling molecules in heart non-specific Teff. Adoptive transfer of heart non-specific Teff in mice with myocarditis did not affect inflammation severity at the peak of disease, but protected the heart from adverse post-inflammatory fibrotic remodelling and cardiac dysfunction at later stages of disease. Furthermore, mouse and human Teff stimulated in vitro with common gamma cytokines suppressed expression of profibrotic genes, reduced amount of α-smooth muscle actin filaments and decreased contraction of cardiac fibroblasts. In this study, we provided a proof-of-concept that heart non-specific Teff cells could effectively contribute to myocarditis and protect the heart from the dilated cardiomyopathy outcome.

Extent and spatial distribution of left atrial arrhythmogenic sites, late gadolinium enhancement at magnetic resonance imaging, and low-voltage areas in patients with persistent atrial fibrillation: comparison of imaging vs. electrical parameters of fibrosis and arrhythmogenesis.

AIMS: Atrial fibrosis contributes to arrhythmogenesis in atrial fibrillation and can be detected by MRI or electrophysiological mapping. The current study compares the spatial correlation between delayed enhancement (DE) areas to low-voltage areas (LVAs) and to arrhythmogenic areas with spatio-temporal dispersion (ST-Disp) or continuous activity (CA) in atrial fibrillation (AF). METHODS AND RESULTS: Sixteen patients with persistent AF (nine long-standing) underwent DE-magnetic resonance imaging (1.25 mm × 1.25 mm × 2.5 mm) prior to pulmonary vein isolation. Left atrial (LA) voltage mapping was acquired in AF and the regional activation patterns of 7680 AF wavelets were analysed. Sites with ST-Disp or CA were characterized (voltage, duration) and their spatial relationship to DE areas and LVAs <0.5 mV was assessed. Delayed enhancement areas and LVAs covered 55% and 24% (P < 0.01) of total LA surface, respectively. Delayed enhancement area was present at 61% of LVAs, whereas low voltage was present at 28% of DE areas. Most DE areas (72%) overlapped with atrial high-voltage areas (>0.5 mV). Spatio-temporal dispersion and CA more frequently co-localized with LVAs than with DE areas (78% vs. 63%, P = 0.02). Regional bipolar voltage of ST-Disp vs. CA was 0.64 ± 0.47 mV vs. 0.58 ± 0.51 mV. All 28 ST-Disp and 56 CA areas contained electrograms with prolonged duration (115 ± 14 ms) displaying low voltage (0.34 ± 0.11 mV). CONCLUSION: A small portion of DE areas and LVAs harbour the arrhythmogenic areas displaying ST-Disp or CA. Most arrhythmogenic activities co-localized with LVAs, while there was less co-localization with DE areas. There is an important mismatch between DE areas and LVAs which needs to be considered when used as target for catheter ablation.

Rapid improvement in left ventricular function after sinus rhythm restoration in patients with idiopathic cardiomyopathy and atrial fibrillation.

AIMS: Sinus rhythm restoration (SRR) in patients with atrial fibrillation (AF) and heart failure may improve systolic function and impact on consecutive clinical management, but time course and potential predictors of response to SRR are uncertain. METHODS AND RESULTS: We prospectively studied 50 consecutive patients who presented in heart failure with reduced ejection fraction (EF) and concomitant AF. After exclusion of valvular and coronary artery disease patients underwent electrical cardioversion. Serial echocardiography, cardiac magnetic resonance imaging (cMRI), and 24-h electrocardiograms were performed at baseline, and on Days 3 and 40 following SRR. Baseline left ventricular EF of the study population (76% male, age 69 ± 11 years) was 30 ± 7%. Sustained SRR (≥3 days) significantly improved EF (Day 3: 43 ± 7%, n = 46; Day 40: 53 ± 9%, n = 34; P < 0.001) as quantified by echocardiography. Comparable results were obtained using cMRI (baseline: 29 ± 8%; Day 3: 42 ± 9%). Three patients showed no response to SRR (EF improvement <15%). The percentage of patients meeting current criteria for implantable cardioverter-defibrillator (ICD) implantation for primary prevention dropped from 76% (n = 38) to 11% (n = 3) on Day 40 following SRR. No specific clinical or echocardiographic factor predicting improved EF after SRR could be identified. CONCLUSION: The majority of patients presenting with non-ischaemic, non-valvular heart failure with reduced EF and concomitant AF show a significant and rapid improvement in EF following SRR. An attempt at SRR and reassessment of the need for ICD implantation after 40 days may be warranted in all such patients.