Gender-Based Differences in Atrial and Pulmonary Vein Substrate
Gender-Based Differences in Atrial and Pulmonary Vein Substrate
This study included 38 consecutive participants with no history of AF undergoing catheter ablation for supraventricular tachycardia (SVT) and 55 with symptomatic drug-refractory paroxysmal or persistent AF undergoing a first catheter ablation of AF. All underwent detailed atrial electroanatomic mapping studies. Patients with left ventricular (LV) systolic dysfunction (LV ejection fraction < 50%), flow-limiting coronary artery disease, severe obstructive sleep apnea or poorly controlled hypertension associated with significant LV hypertrophy on echocardiography (myocardial wall thickness > 1.1 cm) were excluded. All participants provided written informed consent before enrolment. The study protocol was approved by appropriate local Human Research and Ethics Committees.
The procedure was performed in the fasting state under general anesthesia. All antiarrhythmic medications were withheld for at least 5 half-lives before the procedure. Amiodarone was ceased at least 3 months prior. All patients underwent transthoracic echocardiography to define cardiac structure and function, and those with AF underwent transesophageal echocardiography on the day of the procedure to exclude LA thrombus.
A 10-pole catheter (2–5–2 mm interelectrode spacing) was positioned in the coronary sinus (CS) with the proximal bipole at the ostium and a 6-pole catheter was placed at the His-bundle/right ventricular recording position. In those in whom LA access was clinically indicated transseptal access was obtained with standard techniques, after which intravenous heparin was administered with a target activated clotting time of 350 seconds. An externally-irrigated 3.5 mm ablation catheter (2–5–2 mm interelectrode spacing; Biosense-Webster, Johnson & Johnson, Diamond Bar, CA, USA) was introduced into the atria in all participants, with an additional multipolar circular mapping catheter introduced into the LA in the AF cohort.
Bipolar intracardiac electrograms and 12-lead surface electrocardiograph (ECG) were recorded simultaneously on a computerized digital amplifier system (EPMed Systems, West Berlin, NJ, USA). Intracardiac electrograms were filtered between 30–500 Hz and the surface ECG was filtered between 0.05 and 40 Hz. All procedures were performed with the assistance of a 3-D electroanatomic mapping system (EnSite NavX, St. Jude Medical, St. Paul, MN, USA). In those undergoing catheter ablation of AF cardiac computerized tomography or magnetic resonance images acquired preoperatively were integrated into this system.
Using a methodology that we have reported in previous studies, detailed right atrial (RA), LA and PV electroanatomic maps were created. These were created during pacing from the distal CS at a constant 600 milliseconds cycle length so as to standardize the speed and direction of wavefront propagation. Electrical cardioversion, with a subsequent 10-minute waiting period, was used to terminate AF in those who presented to the electrophysiology laboratory in AF. The ablation catheter was used to collect electroanatomic data points, with all data collected prior to tissue ablation. Points were manually acquired after careful evaluation of tissue contact based on tactile catheter pressure, motion of the catheter during fluoroscopic imaging, the catheter icon-to-surface feature of the mapping system, and the presence of constant electrogram characteristics. Surface color projection with an interpolation fill threshold of 10 mm was used to ensure a minimum number of points in an even distribution throughout the LA. Each individual electrogram was manually verified offline. Points acquired following ectopic beats were excluded from the analysis.
Local bipolar voltage during paced rhythm was defined as the amplitude between the absolute peak positive and peak negative deflections of the electrogram. Bipolar voltage was annotated with the assistance of automated algorithms, followed by manual verification of each individual point. Appropriate time windows were applied during paced rhythm to exclude stimulus artifact and far-field ventricular electrograms. A baseline noise threshold of 0.05 mV was applied to exclude background system noise. Each chamber was considered globally, with mean voltage determined from all data points. Low-voltage zones were defined as those with bipolar voltage <0.5 mV, and the proportion of low-voltage signals in each chamber was calculated by dividing the number of low-voltage signals by the total number of data points.
Local activation time for each point on the map during distal CS pacing was annotated to the earliest sharp deflection. Total chamber activation time for the LA was determined from the pacing stimulus to the latest point of chamber activation and chamber activation time for the RA was determined by subtracting the earliest from the latest activation time. The surface area of each atrium was measured off-line using NavX system software and, to adjust for different chamber surface areas, an activation index was calculated:
Similarly, PV conduction time was determined by subtraction of the earliest from the latest activation time within each vein during stable pacing. PV muscle sleeve length was assessed by measuring the distance between the PV ostium (as defined by venography, 3-D mapping and local electrogram characteristics) to the disappearance of PV potentials distally within the vein. To allow for the effect of differing muscle sleeve lengths a conduction index was again calculated:
Complex fractionated electrograms (CFE) were defined as those with ≥3 deflections and >50 milliseconds duration or those with 2 separate deflections separated by an isoelectric interval. Analysis of signal complexity was performed globally for each chamber, with the percentage of complex signals calculated by dividing the number of complex signals by the total number of data points.
Effective refractory period (ERP) testing was performed after voltage and activation mapping. ERPs were measured at the posterior LA wall, the LA appendage (LAA), the proximal and the distal CS, and the left and right superior PVs using a pacing drive train of 8 beats followed by a single extra-stimulus commencing at a coupling interval of 150 ms and incrementing by 10 ms until local capture was demonstrated. The local ERP was defined as the longest extra-stimulus that failed to capture the pacing site. ERPs were measured at drive train cycle lengths of 600 and 450 milliseconds and were repeated at least twice at each site to ensure consistency.
All statistical analysis was performed using STATA software (version 12.1, StataCorp, College Station, TX, USA). Continuous variables are expressed as mean ± SD if normally distributed and otherwise as median (IQR), and categorical variables as number of subjects (%). Normality of distribution was tested with the Shapiro-Wilk method. Differences between group-averaged values were tested using Student's t-test for normally distributed data, and otherwise with the Mann–Whitney U-test. Categorical variable proportions are compared between groups with χ or Fisher's exact test as appropriate. Statistical significance was assessed at the 0.05 level.
Methods
This study included 38 consecutive participants with no history of AF undergoing catheter ablation for supraventricular tachycardia (SVT) and 55 with symptomatic drug-refractory paroxysmal or persistent AF undergoing a first catheter ablation of AF. All underwent detailed atrial electroanatomic mapping studies. Patients with left ventricular (LV) systolic dysfunction (LV ejection fraction < 50%), flow-limiting coronary artery disease, severe obstructive sleep apnea or poorly controlled hypertension associated with significant LV hypertrophy on echocardiography (myocardial wall thickness > 1.1 cm) were excluded. All participants provided written informed consent before enrolment. The study protocol was approved by appropriate local Human Research and Ethics Committees.
Electroanatomic Mapping Protocol
The procedure was performed in the fasting state under general anesthesia. All antiarrhythmic medications were withheld for at least 5 half-lives before the procedure. Amiodarone was ceased at least 3 months prior. All patients underwent transthoracic echocardiography to define cardiac structure and function, and those with AF underwent transesophageal echocardiography on the day of the procedure to exclude LA thrombus.
A 10-pole catheter (2–5–2 mm interelectrode spacing) was positioned in the coronary sinus (CS) with the proximal bipole at the ostium and a 6-pole catheter was placed at the His-bundle/right ventricular recording position. In those in whom LA access was clinically indicated transseptal access was obtained with standard techniques, after which intravenous heparin was administered with a target activated clotting time of 350 seconds. An externally-irrigated 3.5 mm ablation catheter (2–5–2 mm interelectrode spacing; Biosense-Webster, Johnson & Johnson, Diamond Bar, CA, USA) was introduced into the atria in all participants, with an additional multipolar circular mapping catheter introduced into the LA in the AF cohort.
Bipolar intracardiac electrograms and 12-lead surface electrocardiograph (ECG) were recorded simultaneously on a computerized digital amplifier system (EPMed Systems, West Berlin, NJ, USA). Intracardiac electrograms were filtered between 30–500 Hz and the surface ECG was filtered between 0.05 and 40 Hz. All procedures were performed with the assistance of a 3-D electroanatomic mapping system (EnSite NavX, St. Jude Medical, St. Paul, MN, USA). In those undergoing catheter ablation of AF cardiac computerized tomography or magnetic resonance images acquired preoperatively were integrated into this system.
Using a methodology that we have reported in previous studies, detailed right atrial (RA), LA and PV electroanatomic maps were created. These were created during pacing from the distal CS at a constant 600 milliseconds cycle length so as to standardize the speed and direction of wavefront propagation. Electrical cardioversion, with a subsequent 10-minute waiting period, was used to terminate AF in those who presented to the electrophysiology laboratory in AF. The ablation catheter was used to collect electroanatomic data points, with all data collected prior to tissue ablation. Points were manually acquired after careful evaluation of tissue contact based on tactile catheter pressure, motion of the catheter during fluoroscopic imaging, the catheter icon-to-surface feature of the mapping system, and the presence of constant electrogram characteristics. Surface color projection with an interpolation fill threshold of 10 mm was used to ensure a minimum number of points in an even distribution throughout the LA. Each individual electrogram was manually verified offline. Points acquired following ectopic beats were excluded from the analysis.
Voltage Mapping
Local bipolar voltage during paced rhythm was defined as the amplitude between the absolute peak positive and peak negative deflections of the electrogram. Bipolar voltage was annotated with the assistance of automated algorithms, followed by manual verification of each individual point. Appropriate time windows were applied during paced rhythm to exclude stimulus artifact and far-field ventricular electrograms. A baseline noise threshold of 0.05 mV was applied to exclude background system noise. Each chamber was considered globally, with mean voltage determined from all data points. Low-voltage zones were defined as those with bipolar voltage <0.5 mV, and the proportion of low-voltage signals in each chamber was calculated by dividing the number of low-voltage signals by the total number of data points.
Assessment of Conduction
Local activation time for each point on the map during distal CS pacing was annotated to the earliest sharp deflection. Total chamber activation time for the LA was determined from the pacing stimulus to the latest point of chamber activation and chamber activation time for the RA was determined by subtracting the earliest from the latest activation time. The surface area of each atrium was measured off-line using NavX system software and, to adjust for different chamber surface areas, an activation index was calculated:
Similarly, PV conduction time was determined by subtraction of the earliest from the latest activation time within each vein during stable pacing. PV muscle sleeve length was assessed by measuring the distance between the PV ostium (as defined by venography, 3-D mapping and local electrogram characteristics) to the disappearance of PV potentials distally within the vein. To allow for the effect of differing muscle sleeve lengths a conduction index was again calculated:
Signal Fractionation
Complex fractionated electrograms (CFE) were defined as those with ≥3 deflections and >50 milliseconds duration or those with 2 separate deflections separated by an isoelectric interval. Analysis of signal complexity was performed globally for each chamber, with the percentage of complex signals calculated by dividing the number of complex signals by the total number of data points.
Assessment of Refractoriness
Effective refractory period (ERP) testing was performed after voltage and activation mapping. ERPs were measured at the posterior LA wall, the LA appendage (LAA), the proximal and the distal CS, and the left and right superior PVs using a pacing drive train of 8 beats followed by a single extra-stimulus commencing at a coupling interval of 150 ms and incrementing by 10 ms until local capture was demonstrated. The local ERP was defined as the longest extra-stimulus that failed to capture the pacing site. ERPs were measured at drive train cycle lengths of 600 and 450 milliseconds and were repeated at least twice at each site to ensure consistency.
Statistical Analysis
All statistical analysis was performed using STATA software (version 12.1, StataCorp, College Station, TX, USA). Continuous variables are expressed as mean ± SD if normally distributed and otherwise as median (IQR), and categorical variables as number of subjects (%). Normality of distribution was tested with the Shapiro-Wilk method. Differences between group-averaged values were tested using Student's t-test for normally distributed data, and otherwise with the Mann–Whitney U-test. Categorical variable proportions are compared between groups with χ or Fisher's exact test as appropriate. Statistical significance was assessed at the 0.05 level.
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