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Abstract

Aims

To describe the extent and distribution of low voltage zones (LVZ) in a large cohort of patients undergoing ablation for paroxysmal and persistent atrial fibrillation (AF), and to explore baseline predictors of LVZ in these patients.

Methods and results

Consecutive patients who underwent a bipolar voltage map guided AF ablation, were enrolled. Voltage maps were conducted for each patient using 3-dimensional electroanatomical mapping system and LVZ were defined as areas of bipolar voltage < 0.5 mV. A total of 539 patients (309 male, age 65 ± 10 years) were included. Low voltage zones was present in 58 out of 292 patients with paroxysmal and 134 out of 247 persistent AF (P < 0.001). The area of LVZ was larger in patients with persistent as compare to paroxysmal AF, 5 cm2 (IQR 3-18.6) vs. 12.1 cm2 (IQR 3.6-28.5), P = 0.026, respectively. In the multivariate analysis age (OR 1.07, 95%CI 1.05-1.10, P < 0.001), female gender (OR 2.18, 95%CI 1.38-3.43, P = 0.001), sinoatrial node dysfunction (OR 3.90, 95%CI 1.24-12.21, P = 0.020), larger surface area of left atrium pr. cm2 (OR 1.01, 95%CI 1.00-1.02, P = 0.016), and persistent AF (OR 5.03, 95%CI 3.20-7.90, P<0.001) were associated with presence of LVZ.

Conclusion

In a large cohort of patients undergoing ablation for AF, the prevalence of LVZ was higher and LVZ areas larger in patients with persistent as compared with paroxysmal AF. The most frequent localization of LVZ was anterior wall, septum and posterior wall. Presence of LVZ was associated with higher age, female gender, larger LA surface area, and sinoatrial node dysfunction.

Bipolar voltage map, Low voltage zone, Localization of low voltage zone, Area of low voltage zone, Fibro-fatty infiltration, Sinoatrial node dysfunction, Atrioventricular conduction block, Atrial fibrillation

What's new?

  • The present study reports detailed characteristics of bipolar voltage of the left atrium, including areas of low voltage zones (LVZ), using 3 dimensional electro anatomical mapping in a large cohort (n = 539) of consecutive patients undergoing AF ablation.

  • Low voltage zones were more prevalent and larger in patients with persistent as compared to paroxysmal AF.

  • The most frequent localization of LVZ was anterior wall, septum and posterior wall.

  • Presence of LVZ was associated with higher age, female gender, larger LA surface area, and sinoatrial node dysfunction.

Introduction

In 1977, Evans and Shaw investigated eight patients with sinoatrial node dysfunction (SND) and demonstrated increased fibrosis or fatty infiltration in right atrium (RA) musculature in seven of these patients. It was the first study to demonstrate widespread fibro-fatty infiltration in the RA of patients with an atrial conduction abnormality.1

Later, post-mortem atrial biopsies showed fibrosis and fatty infiltration in patients with a history of atrial fibrillation (AF). And these histological findings were more extensive in patients with AF compared with patients without history of AF.2 Moreover, it has been demonstrated that atrial dilatation in AF patients is associated with fibro-fatty replacement of the atrial myocardium that both comprises the atrial walls and the major conduction routes.2 Further studies were carried out to explore the link between histological abnormalities and electrophysiological disorders, and up to date the vast majority of these studies is based on percutaneous biopsies of RA septum or surgically removed tissue samples of right or left atrial (LA) appendages and not on whole LA or RA wall specimens.3,4 Fibro-fatty transformation of atrial walls is believed to be the leading cause of deteriorated atrial conduction responsible for AF.3 Furthermore, fibro-fatty replacement of atrial tissue may increase the thrombogenicity and risk of stroke.5

Due to the limitations of fibrosis assessment based on histological specimens, alternative methods such as invasive mapping techniques as well as cardiac imaging have been introduced. Low voltage zones (LVZ) recorded in a bipolar electroanatomically guided voltage map in the LA has previously shown to be correlated with areas presenting delayed enhancement on magnetic resonance imaging scans.6 Even though this suggests that LVZ might represent fibro-fatty infiltration, there are no previous studies comparing LVZ and histology in the atria.

There are limited data on detailed distribution of LVZ in larger area of the atria and the relation between these LVZ and other conduction disorders. Therefore, the aim of the present study was to describe the extent and distribution of LVZ in a large cohort of patients with paroxysmal and persistent atrial fibrillation and to explore baseline predictors of LVZ in these patients. Furthermore, we wanted to compare LVZ in patients with and without conduction disturbances including SND and atrioventricular block (AVB).

Methods

Subjects

Consecutive patients with highly symptomatic AF, who underwent a bipolar voltage map guided AF ablation, were enrolled into the current study. Participants (18 to 75 years of age) had (i) paroxysmal or persistent symptomatic AF, and (ii) previously ineffective antiarrhythmic therapy. Exclusion criteria were: (i) any previous ablation procedure affecting the atria, (ii) previous surgery on heart, oesophagus or lungs, (iii) radiotherapy due to cancer in the thorax or previous receiving chemotherapy, (iv) known intracardiac or other thrombi, (v) pregnancy, (vi) left atrial (LA) diameters of >60 mm (transthoracic echocardiography, parasternal long axis), or (vii) contraindication for anticoagulation.

Baseline variables including conduction disturbances (SND and AVB) were collected before the ablation procedure. SND was defined as pauses over 3 s or persistent bradycardia <40 bpm. And AVB defined as first degree (PR > 220 ms), second degree (including atrioventricular conduction block mobitz type 2 or 2:1 block), and third degree (AV-dissociation).

All antiarrhythmic drugs were discontinued at least five half-lives prior to the study, including beta-blockers and digitalis, except amiodarone.

All patients gave written informed consent, and the investigational nature of the procedure was approved by the institutional review committee.

Assessment of LA bipolar voltage maps

Electrophysiological studies and ablations were carried out following our clinical routine.7 In brief, a bipolar voltage map was carried out simultaneously with LA reconstruction, guided by a three-dimensional electroanatomical (3D-EAM) system (CARTO3, Biosense Webster, Inc., Diamond Bar, CA, USA) using a 7-French catheter containing a deflectable decapolar circular mapping catheter of variable diameter size (15–25 mm) and 1 mm electrode/8 mm spacing (Lasso 2515 NAV Eco, Biosense Webster, Inc., Diamond Bar, CA, USA). Patients underwent a cardiac CT scan of the LA and pulmonary veins before the procedure, and the images were segmented in CARTOMEREG image integration (Biosense Webster, Inc., Diamond Bar, CA, USA) and compared with the 3D-EAM.

All points were taken in sinus rhythm. The CONFIDENSE Module (Biosense Webster, Inc., Diamond Bar, CA, USA) was employed to collect voltage points with continuous mapping using the following settings: 5% CL filtering, 3 ms LAT-stability, 3 mm position stability, and 1 mm density. For each mapping point, stable contact between the local atrial tissue and each paired electrodes of the Lasso catheter was required. Afterwards, a confirmation of LVZ was performed using an ablation catheter (ThermoCool SF, Biosense Webster, Inc., Diamond Bar, CA, USA). A stable contact between the local atrial tissue and the parallel-aligned tip of the ablation catheter was also required. Extra care was taken while collecting voltage points on the border of LVZ.

Sufficient quality of the acquired voltage points was verified by the physician performing the procedure from the following criteria: (i) identical P-wave morphology during the acquired mapping point and spontaneous sinus rhythm, (ii) identical activation sequences of the CS during the acquired mapping point and spontaneous sinus rhythm, (iii) identical cycle length during the acquired mapping point and spontaneous sinus rhythm, (iv) identical local bipolar electrograms acquired mapping points at the same spot for at least two beats, and (v) consistent differences of local activation time (local activation time at acquired point to proximal CS) for at least two beats. Recordings that did not meet all these criteria were deleted from the maps.

Bipolar voltage map analysis

The following areas were defined from the voltage map: (i) electrically silent areas: absence of recordable activity and no atrial capture during pacing with an output of 10 V/2 ms, (ii) LVZ: contiguous areas of bipolar voltage < 0.5 mV, and (iii) Normal voltage > 0.5 mV.

The LA was divided into 5 regions, i.e. septum, anterior, posterior, inferior, and lateral walls, omitting the LA appendage (LAA). Each region was further divided in to nine equally sized blocks. The median voltage value within each block and the area and localization of LVZ in each region was recorded and used for further analysis. In each predefined region at least 30 voltage-mapping points were collected and the voltage in one region was median of these measurements. The surface area in each predefined region was measured offline on the 3D reconstructed CT-model of the LA. The area of LVZ was measured within each region separately and presented in cm2. The landmarks, which were used to separate the LA surface into the five regions, are demonstrated in Figure 1.

Quantitative assessment of LA surface area and LVZ.
Figure 1

Quantitative assessment of LA surface area and LVZ.

Predefined landmarks were used for separating the LA surface into the 5 regions. Each region was further divided in to 9 equally sized blocks.

Landmark definitions: MA12, MA at 12 o'clock, MA4, MA at 4 o'clock, MA7, MA at 7 o'clock, MA11, MA at 11 o'clock, LS12, LSPV at 12 o'clock; RS12, RSPV at 12 o'clock; LI6, LIPV at 6 o'clock and RI6, RIPV at 6 o'clock.

Definition of surface regions: AW, Area among MA12, MA11, LS12 and RS12; S, Area among MA11, MA7, RI6 and RS12; IW, Area among LI6, RI6, MA7 and MA4; LW, Area among LI6, LS12, MA4 and MA12; PW, Area among LS12, RS12, LI6 and RI6.

MA, mitral annulus; LSPV, left superior pulmonary vein; LIPV, left inferior pulmonary vein; RSPV, right superior pulmonary vein; RIPV, right inferior pulmonary vein; AW, Anterior wall; S, Septum; IW, Inferior wall; LW, Lateral wall; PW, Posterior wall.

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Data management and statistical analysis

Continuous variables were tested for normal distribution using Shapiro–Wilk test. Data with normal distribution was presented as means ± SD and data without normal distribution was presented as median and inter-quartile range (IQR). Categorical variables were expressed with a number and percentage of patients.

Differences between continuous normally distributed data were tested for statistical significance using the t-test for independent samples. In the case of continuous data without a normal distribution a non-parametric test was used. Differences of categorical data were tested for statistical significance using χ2 or Fisher’s exact test where necessary. To test for predictors of LVZ we used multivariate binary logistic regression. Baseline variables that were significant (P < 0.05) in the univariate analysis were entered into the multivariate analysis. A P-value of <0.05 was considered significant. The data was collected and managed by the investigators (CP and YH) and all statistics were performed using the IBM SPSS Statistics v20 software.

Results

Patient characteristics and LA electro-anatomical mappings

A total 539 patients [309 male (57.3%), age 65 ± 10 years] with highly symptomatic AF [292 (54.2%) paroxysmal and 247 (45.8%), persistent] undergoing a bipolar voltage map guided AF ablation were consecutively included in the study from December 2014 to February 2016. At the time of the procedure 22 (4.1%) patients were diagnosed with SND and 26 (4.8%) patients with AVB. A pacemaker or ICD was previously implanted in 6 (27.3%) patients with SND and 15 (57.7%) patients with AVB. Further detailed data on patient characteristics in all patients and in patients with paroxysmal and persistent AF are presented in Table 1.

Table 1
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Patients’ characteristics

All patientsParoxysmal AFPersistent AFP-value
(N = 539)(N = 292)(N = 247)
Age (years)64.9 ± 10.164.3 ± 10.365.5 ± 9.80.186
BMI28.9 ± 5.528.4 ± 6.029.4 ± 4.80.024
Gender (male)309 (57.3%)159 (54.5%)150 (60.7%)0.142
Hypertension356 (66.0%)192 (65.8%)164 (66.4%)0.824
DM91 (16.9%)44 (15.1%)47 (19.0%)0.213
CAD38 (7.1%)13 (4.5%)25 (10.1%)0.010
RF18 (3.3%)6 (2.1%)12 (4.9%)0.070
ICM5 (0.9%)1 (0.3%)4 (1.6%)0.122
DCM9 (1.7%)2 (0.7%)7 (2.8%)0.052
SND22 (4.1%)11 (3.8%)11 (4.5%)0.681
AVB26 (4.8%)12 (4.1%)14 (5.7%)0.394
 AVB I21 (3.9%)10 (3.4%)11 (4.5%) 0.653
 AVB II1 (0.2%)0 (0.0%)1 (0.4%)
 AVB III4 (0.7%)2 (0.7%)2 (0.8%)
 Stroke22 (4.1%)13 (4.5%)9 (3.6%)0.637
CHA2DS2-VASc
 057 (10.6%)42 (14.4%)15 (6.1%) 0.032
 198 (18.2%)52 (17.8%)46 (18.6%)
 2152 (28.2%)86 (29.5%)66 (26.7%)
 3131 (24.3%)64 (21.9%)67 (27.1%)
 464 (11.9%)27 (9.2%)37 (15.0%)
 524 (4.5%)15 (5.1%)9 (3.6%)
 611 (2.0%)5 (1.7%)6 (2.4%)
 72 (0.4%)1 (0.3%)1 (0.4%)
All patientsParoxysmal AFPersistent AFP-value
(N = 539)(N = 292)(N = 247)
Age (years)64.9 ± 10.164.3 ± 10.365.5 ± 9.80.186
BMI28.9 ± 5.528.4 ± 6.029.4 ± 4.80.024
Gender (male)309 (57.3%)159 (54.5%)150 (60.7%)0.142
Hypertension356 (66.0%)192 (65.8%)164 (66.4%)0.824
DM91 (16.9%)44 (15.1%)47 (19.0%)0.213
CAD38 (7.1%)13 (4.5%)25 (10.1%)0.010
RF18 (3.3%)6 (2.1%)12 (4.9%)0.070
ICM5 (0.9%)1 (0.3%)4 (1.6%)0.122
DCM9 (1.7%)2 (0.7%)7 (2.8%)0.052
SND22 (4.1%)11 (3.8%)11 (4.5%)0.681
AVB26 (4.8%)12 (4.1%)14 (5.7%)0.394
 AVB I21 (3.9%)10 (3.4%)11 (4.5%) 0.653
 AVB II1 (0.2%)0 (0.0%)1 (0.4%)
 AVB III4 (0.7%)2 (0.7%)2 (0.8%)
 Stroke22 (4.1%)13 (4.5%)9 (3.6%)0.637
CHA2DS2-VASc
 057 (10.6%)42 (14.4%)15 (6.1%) 0.032
 198 (18.2%)52 (17.8%)46 (18.6%)
 2152 (28.2%)86 (29.5%)66 (26.7%)
 3131 (24.3%)64 (21.9%)67 (27.1%)
 464 (11.9%)27 (9.2%)37 (15.0%)
 524 (4.5%)15 (5.1%)9 (3.6%)
 611 (2.0%)5 (1.7%)6 (2.4%)
 72 (0.4%)1 (0.3%)1 (0.4%)

AF, atrial fibrillation; BMI, body mass index; DM, diabetes mellitus; CAD, coronary artery disease; RF, renal failure; ICM, ischaemic cardiomyopathy; DCM, dilative cardiomyopathy; SND, sinoatrial node dysfunction; AVB, atrioventricular block.

Table 1
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Patients’ characteristics

All patientsParoxysmal AFPersistent AFP-value
(N = 539)(N = 292)(N = 247)
Age (years)64.9 ± 10.164.3 ± 10.365.5 ± 9.80.186
BMI28.9 ± 5.528.4 ± 6.029.4 ± 4.80.024
Gender (male)309 (57.3%)159 (54.5%)150 (60.7%)0.142
Hypertension356 (66.0%)192 (65.8%)164 (66.4%)0.824
DM91 (16.9%)44 (15.1%)47 (19.0%)0.213
CAD38 (7.1%)13 (4.5%)25 (10.1%)0.010
RF18 (3.3%)6 (2.1%)12 (4.9%)0.070
ICM5 (0.9%)1 (0.3%)4 (1.6%)0.122
DCM9 (1.7%)2 (0.7%)7 (2.8%)0.052
SND22 (4.1%)11 (3.8%)11 (4.5%)0.681
AVB26 (4.8%)12 (4.1%)14 (5.7%)0.394
 AVB I21 (3.9%)10 (3.4%)11 (4.5%) 0.653
 AVB II1 (0.2%)0 (0.0%)1 (0.4%)
 AVB III4 (0.7%)2 (0.7%)2 (0.8%)
 Stroke22 (4.1%)13 (4.5%)9 (3.6%)0.637
CHA2DS2-VASc
 057 (10.6%)42 (14.4%)15 (6.1%) 0.032
 198 (18.2%)52 (17.8%)46 (18.6%)
 2152 (28.2%)86 (29.5%)66 (26.7%)
 3131 (24.3%)64 (21.9%)67 (27.1%)
 464 (11.9%)27 (9.2%)37 (15.0%)
 524 (4.5%)15 (5.1%)9 (3.6%)
 611 (2.0%)5 (1.7%)6 (2.4%)
 72 (0.4%)1 (0.3%)1 (0.4%)
All patientsParoxysmal AFPersistent AFP-value
(N = 539)(N = 292)(N = 247)
Age (years)64.9 ± 10.164.3 ± 10.365.5 ± 9.80.186
BMI28.9 ± 5.528.4 ± 6.029.4 ± 4.80.024
Gender (male)309 (57.3%)159 (54.5%)150 (60.7%)0.142
Hypertension356 (66.0%)192 (65.8%)164 (66.4%)0.824
DM91 (16.9%)44 (15.1%)47 (19.0%)0.213
CAD38 (7.1%)13 (4.5%)25 (10.1%)0.010
RF18 (3.3%)6 (2.1%)12 (4.9%)0.070
ICM5 (0.9%)1 (0.3%)4 (1.6%)0.122
DCM9 (1.7%)2 (0.7%)7 (2.8%)0.052
SND22 (4.1%)11 (3.8%)11 (4.5%)0.681
AVB26 (4.8%)12 (4.1%)14 (5.7%)0.394
 AVB I21 (3.9%)10 (3.4%)11 (4.5%) 0.653
 AVB II1 (0.2%)0 (0.0%)1 (0.4%)
 AVB III4 (0.7%)2 (0.7%)2 (0.8%)
 Stroke22 (4.1%)13 (4.5%)9 (3.6%)0.637
CHA2DS2-VASc
 057 (10.6%)42 (14.4%)15 (6.1%) 0.032
 198 (18.2%)52 (17.8%)46 (18.6%)
 2152 (28.2%)86 (29.5%)66 (26.7%)
 3131 (24.3%)64 (21.9%)67 (27.1%)
 464 (11.9%)27 (9.2%)37 (15.0%)
 524 (4.5%)15 (5.1%)9 (3.6%)
 611 (2.0%)5 (1.7%)6 (2.4%)
 72 (0.4%)1 (0.3%)1 (0.4%)

AF, atrial fibrillation; BMI, body mass index; DM, diabetes mellitus; CAD, coronary artery disease; RF, renal failure; ICM, ischaemic cardiomyopathy; DCM, dilative cardiomyopathy; SND, sinoatrial node dysfunction; AVB, atrioventricular block.

During the bipolar voltage mapping of the LA mean 658 ± 87 points were recorded in each patient. Median surface area was 103.2 cm2 (IQR: 86.2–119.5) and median amplitude of the recordings was 2.2 mV (IQR: 1.6–3.0). Detailed data from the electro-anatomical mapping are presented in Table 2. Areas of LVZ were detected in 189 (35.1%) patients and no patient presented areas with electrically silence. The surface area of the entire LA and each of the predefined regions were significantly larger in patients with LVZ as compared with patients without LVZ, and the median value of the bipolar amplitude of the entire LA and each of the predefined region were significantly lower in patients with LVZ as compared with patients without LVZ (Table 3).

Table 2
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Bipolar voltage map characteristics of LA and each predefined region in all patients

N = 539Surface area (cm2)Amplitude (mV)Incidence of LVZ (n, %)LVZ area (cm2) (n = 189)
LA103.2 (86.2–119.5)2.2 (1.6–3.0)189 (35.1%)10.0 (3.0–26.2)
AW16.0 (13.0–20.2)1.8 (1.2–2.6)128 (23.7%)7.6 (3.0–12.6)
Septum19.6 (15.1–24.4)1.7 (1.2–2.5)127 (23.6%)6.2 (2.0–12.7)
IW18.0 (14.0–22.3)2.4 (1.0–5.4)57 (10.6%)3.0 (1.8–6.4)
LW10.4 (8.1–13.5)2.6 (1.8–3.2)35 (7.2%)3.0 (2.0–10.0)
PW17.4 (13.9–21.4)2.2 (1.4–3.4)90 (16.7%)5.2 (2.0–11.0)
LAA19.9 (15.1–26.0)3.3 (2.2–6.0)3 (0.6%)2.2 (1.5–)
N = 539Surface area (cm2)Amplitude (mV)Incidence of LVZ (n, %)LVZ area (cm2) (n = 189)
LA103.2 (86.2–119.5)2.2 (1.6–3.0)189 (35.1%)10.0 (3.0–26.2)
AW16.0 (13.0–20.2)1.8 (1.2–2.6)128 (23.7%)7.6 (3.0–12.6)
Septum19.6 (15.1–24.4)1.7 (1.2–2.5)127 (23.6%)6.2 (2.0–12.7)
IW18.0 (14.0–22.3)2.4 (1.0–5.4)57 (10.6%)3.0 (1.8–6.4)
LW10.4 (8.1–13.5)2.6 (1.8–3.2)35 (7.2%)3.0 (2.0–10.0)
PW17.4 (13.9–21.4)2.2 (1.4–3.4)90 (16.7%)5.2 (2.0–11.0)
LAA19.9 (15.1–26.0)3.3 (2.2–6.0)3 (0.6%)2.2 (1.5–)

All data are presented as median and IQR.

AF, atrial fibrillation; LA, left atria; AW, anterior wall; IW, inferior wall; LW, lateral wall; PW, posterior wall; LAA, left atrial appendage; LVZ, low voltage zone.

Table 2
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Bipolar voltage map characteristics of LA and each predefined region in all patients

N = 539Surface area (cm2)Amplitude (mV)Incidence of LVZ (n, %)LVZ area (cm2) (n = 189)
LA103.2 (86.2–119.5)2.2 (1.6–3.0)189 (35.1%)10.0 (3.0–26.2)
AW16.0 (13.0–20.2)1.8 (1.2–2.6)128 (23.7%)7.6 (3.0–12.6)
Septum19.6 (15.1–24.4)1.7 (1.2–2.5)127 (23.6%)6.2 (2.0–12.7)
IW18.0 (14.0–22.3)2.4 (1.0–5.4)57 (10.6%)3.0 (1.8–6.4)
LW10.4 (8.1–13.5)2.6 (1.8–3.2)35 (7.2%)3.0 (2.0–10.0)
PW17.4 (13.9–21.4)2.2 (1.4–3.4)90 (16.7%)5.2 (2.0–11.0)
LAA19.9 (15.1–26.0)3.3 (2.2–6.0)3 (0.6%)2.2 (1.5–)
N = 539Surface area (cm2)Amplitude (mV)Incidence of LVZ (n, %)LVZ area (cm2) (n = 189)
LA103.2 (86.2–119.5)2.2 (1.6–3.0)189 (35.1%)10.0 (3.0–26.2)
AW16.0 (13.0–20.2)1.8 (1.2–2.6)128 (23.7%)7.6 (3.0–12.6)
Septum19.6 (15.1–24.4)1.7 (1.2–2.5)127 (23.6%)6.2 (2.0–12.7)
IW18.0 (14.0–22.3)2.4 (1.0–5.4)57 (10.6%)3.0 (1.8–6.4)
LW10.4 (8.1–13.5)2.6 (1.8–3.2)35 (7.2%)3.0 (2.0–10.0)
PW17.4 (13.9–21.4)2.2 (1.4–3.4)90 (16.7%)5.2 (2.0–11.0)
LAA19.9 (15.1–26.0)3.3 (2.2–6.0)3 (0.6%)2.2 (1.5–)

All data are presented as median and IQR.

AF, atrial fibrillation; LA, left atria; AW, anterior wall; IW, inferior wall; LW, lateral wall; PW, posterior wall; LAA, left atrial appendage; LVZ, low voltage zone.

Table 3
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Surface area and voltage amplitude in patients with and without low voltage zones

Surface area (cm2)
Amplitude (mV)
No LVZ (n = 350)LVZ (n = 189)P-valueNo LVZ (n = 350)LVZ (n = 189)P-value
LA98.9 (84.4–114.5)111.9 (94.3–126.5)<0.0012.6 (1.9–3.3)1.5 (1.2–2.2)<0.001
AW15.6 (12.9–20.1)16.4 (13.2–20.6)0.1212.1 (1.5–3.0)1.1 (0.6–1.8)<0.001
Septum18.5 (14.1–23.2)21.5 (16.1–25.5)<0.0012.0 (1.4–2.8)1.1 (0.8–1.8)<0.001
IW16.8 (13.4–21.4)19.9 (15.7–24.0)<0.0012.6 (2.0–3.7)1.9 (1.5–2.6)<0.001
LW10.0 (8.0–12.7)11.1 (8.5–14.5)<0.0012.8 (2.1–3.5)2.1 (1.4–2.7)<0.001
PW17.1 (13.4–20.8)18.5 (14.6–22.4)<0.0012.8 (1.7–3.8)1.5 (0.9–3.3)<0.001
LAA19.0 (14.3–25.3)20.6 (16.2–27.6)0.0303.9 (0.9–9.6)2.2 (0.5–6.5)<0.001
Surface area (cm2)
Amplitude (mV)
No LVZ (n = 350)LVZ (n = 189)P-valueNo LVZ (n = 350)LVZ (n = 189)P-value
LA98.9 (84.4–114.5)111.9 (94.3–126.5)<0.0012.6 (1.9–3.3)1.5 (1.2–2.2)<0.001
AW15.6 (12.9–20.1)16.4 (13.2–20.6)0.1212.1 (1.5–3.0)1.1 (0.6–1.8)<0.001
Septum18.5 (14.1–23.2)21.5 (16.1–25.5)<0.0012.0 (1.4–2.8)1.1 (0.8–1.8)<0.001
IW16.8 (13.4–21.4)19.9 (15.7–24.0)<0.0012.6 (2.0–3.7)1.9 (1.5–2.6)<0.001
LW10.0 (8.0–12.7)11.1 (8.5–14.5)<0.0012.8 (2.1–3.5)2.1 (1.4–2.7)<0.001
PW17.1 (13.4–20.8)18.5 (14.6–22.4)<0.0012.8 (1.7–3.8)1.5 (0.9–3.3)<0.001
LAA19.0 (14.3–25.3)20.6 (16.2–27.6)0.0303.9 (0.9–9.6)2.2 (0.5–6.5)<0.001

All data are presented as median and IQR.

AF, atrial fibrillation; LA, left atria; AW, anterior wall; IW, inferior wall; LW, lateral wall; PW, posterior wall; LAA, left atrial appendage; LVZ, low voltage zone.

Table 3
Open in new tab

Surface area and voltage amplitude in patients with and without low voltage zones

Surface area (cm2)
Amplitude (mV)
No LVZ (n = 350)LVZ (n = 189)P-valueNo LVZ (n = 350)LVZ (n = 189)P-value
LA98.9 (84.4–114.5)111.9 (94.3–126.5)<0.0012.6 (1.9–3.3)1.5 (1.2–2.2)<0.001
AW15.6 (12.9–20.1)16.4 (13.2–20.6)0.1212.1 (1.5–3.0)1.1 (0.6–1.8)<0.001
Septum18.5 (14.1–23.2)21.5 (16.1–25.5)<0.0012.0 (1.4–2.8)1.1 (0.8–1.8)<0.001
IW16.8 (13.4–21.4)19.9 (15.7–24.0)<0.0012.6 (2.0–3.7)1.9 (1.5–2.6)<0.001
LW10.0 (8.0–12.7)11.1 (8.5–14.5)<0.0012.8 (2.1–3.5)2.1 (1.4–2.7)<0.001
PW17.1 (13.4–20.8)18.5 (14.6–22.4)<0.0012.8 (1.7–3.8)1.5 (0.9–3.3)<0.001
LAA19.0 (14.3–25.3)20.6 (16.2–27.6)0.0303.9 (0.9–9.6)2.2 (0.5–6.5)<0.001
Surface area (cm2)
Amplitude (mV)
No LVZ (n = 350)LVZ (n = 189)P-valueNo LVZ (n = 350)LVZ (n = 189)P-value
LA98.9 (84.4–114.5)111.9 (94.3–126.5)<0.0012.6 (1.9–3.3)1.5 (1.2–2.2)<0.001
AW15.6 (12.9–20.1)16.4 (13.2–20.6)0.1212.1 (1.5–3.0)1.1 (0.6–1.8)<0.001
Septum18.5 (14.1–23.2)21.5 (16.1–25.5)<0.0012.0 (1.4–2.8)1.1 (0.8–1.8)<0.001
IW16.8 (13.4–21.4)19.9 (15.7–24.0)<0.0012.6 (2.0–3.7)1.9 (1.5–2.6)<0.001
LW10.0 (8.0–12.7)11.1 (8.5–14.5)<0.0012.8 (2.1–3.5)2.1 (1.4–2.7)<0.001
PW17.1 (13.4–20.8)18.5 (14.6–22.4)<0.0012.8 (1.7–3.8)1.5 (0.9–3.3)<0.001
LAA19.0 (14.3–25.3)20.6 (16.2–27.6)0.0303.9 (0.9–9.6)2.2 (0.5–6.5)<0.001

All data are presented as median and IQR.

AF, atrial fibrillation; LA, left atria; AW, anterior wall; IW, inferior wall; LW, lateral wall; PW, posterior wall; LAA, left atrial appendage; LVZ, low voltage zone.

LVZ in patients with persistent and paroxysmal AF

The median surface area was larger and the median bipolar amplitude smaller in patients with persistent as compared with paroxysmal AF in the entire LA and in each of the predefined regions. The presence of LVZ was found in 55 out of 292 (18.8%) patients with paroxysmal AF, and in 134 out of 247 (54.3%) patients with persistent AF (P < 0.001). In patients with LVZ present the size of the LVZ was significant larger in patients with persistent as compared with paroxysmal AF, however, there was no difference in the size of the LVZ within each of the regions. All data are presented in Table 4.

Table 4
Open in new tab

Characteristics of LA bipolar voltage maps in patients with paroxysmal (n = 292) and persistent (n = 247) AF

Incidence of LVZ n (%)
LVZ area (IQR)
ParoxysmalPersistentP-valueParoxysmalPersistentP-value
LA55 (18.8)134 (54.3)<0.0015.0 (3.0–18.6)12.1 (3.6–28.5)0.026
AW35 (12.0)93 (37.7)<0.0015.3 (3.0–10.3)9.0 (3.0–13.1)0.102
Septum36 (12.3)91 (36.8)<0.0014.3 (1.1–10.3)2.0 (6.8–13.0)0.166
IW15 (5.1)42 (17.0)<0.0012.1 (1.0–4.8)3.0 (2.0–7.7)0.220
LW6 (0.7)29 (11.7)<0.0012.0 (1.8–12.4)3.4 (2.0–9.0)0.623
PW17 (5.8)73 (30.0)<0.0016.0 (2.0–9.1)5.1 (2.0–12.0)0.996
LAA0 (0.0)3 (1.2)0.059–2.2 (1.5–)–
Surface area (cm2)
Amplitude (mV)
ParoxysmalPersistentP-valueParoxysmalPersistentP-value
LA96.0 (83.0–112.0)113.4 (96.3–130.3)<0.0012.7 (1.3–4.3)1.8 (0.8–3.8)<0.001
AW15.0 (12.3–18.7)17.1 (10.5–31.1)<0.0012.1 (0.6–4.1)1.2 (0.2–3.0)<0.001
Septum18.0 (13.2–22.2)21.4 (17.6–27.8)<0.0012.0 (0.8–5.2)1.3 (0.2–3.1)<0.001
IW16.3 (12.8–20.8)20.1 (15.7–24.5)<0.0012.6 (1.3–5.7)2.2 (0.9–5.3)<0.001
LW9.6 (7.6–12.3)11.4 (9.1–15.0)<0.0012.7 (1.1–5.8)2.3 (1.0–4.7)<0.001
PW16.8 (12.9–20.5)18.7 (15.1–22.4)<0.0012.9 (0.9–5.7)1.7 (0.5–4.8)<0.001
LAA18.7 (14.2–24.5)20.6 (16.0–27.9)0.0064.3 (1.1–10.3)2.5 (0.7–6.3)<0.001
Incidence of LVZ n (%)
LVZ area (IQR)
ParoxysmalPersistentP-valueParoxysmalPersistentP-value
LA55 (18.8)134 (54.3)<0.0015.0 (3.0–18.6)12.1 (3.6–28.5)0.026
AW35 (12.0)93 (37.7)<0.0015.3 (3.0–10.3)9.0 (3.0–13.1)0.102
Septum36 (12.3)91 (36.8)<0.0014.3 (1.1–10.3)2.0 (6.8–13.0)0.166
IW15 (5.1)42 (17.0)<0.0012.1 (1.0–4.8)3.0 (2.0–7.7)0.220
LW6 (0.7)29 (11.7)<0.0012.0 (1.8–12.4)3.4 (2.0–9.0)0.623
PW17 (5.8)73 (30.0)<0.0016.0 (2.0–9.1)5.1 (2.0–12.0)0.996
LAA0 (0.0)3 (1.2)0.059–2.2 (1.5–)–
Surface area (cm2)
Amplitude (mV)
ParoxysmalPersistentP-valueParoxysmalPersistentP-value
LA96.0 (83.0–112.0)113.4 (96.3–130.3)<0.0012.7 (1.3–4.3)1.8 (0.8–3.8)<0.001
AW15.0 (12.3–18.7)17.1 (10.5–31.1)<0.0012.1 (0.6–4.1)1.2 (0.2–3.0)<0.001
Septum18.0 (13.2–22.2)21.4 (17.6–27.8)<0.0012.0 (0.8–5.2)1.3 (0.2–3.1)<0.001
IW16.3 (12.8–20.8)20.1 (15.7–24.5)<0.0012.6 (1.3–5.7)2.2 (0.9–5.3)<0.001
LW9.6 (7.6–12.3)11.4 (9.1–15.0)<0.0012.7 (1.1–5.8)2.3 (1.0–4.7)<0.001
PW16.8 (12.9–20.5)18.7 (15.1–22.4)<0.0012.9 (0.9–5.7)1.7 (0.5–4.8)<0.001
LAA18.7 (14.2–24.5)20.6 (16.0–27.9)0.0064.3 (1.1–10.3)2.5 (0.7–6.3)<0.001

All data are presented as median and IQR.

AF, atrial fibrillation; LA, left atria; AW, anterior wall; IW, inferior wall; LW, lateral wall; PW, posterior wall; LAA, left atrial appendage; LVZ, low voltage zone.

Table 4
Open in new tab

Characteristics of LA bipolar voltage maps in patients with paroxysmal (n = 292) and persistent (n = 247) AF

Incidence of LVZ n (%)
LVZ area (IQR)
ParoxysmalPersistentP-valueParoxysmalPersistentP-value
LA55 (18.8)134 (54.3)<0.0015.0 (3.0–18.6)12.1 (3.6–28.5)0.026
AW35 (12.0)93 (37.7)<0.0015.3 (3.0–10.3)9.0 (3.0–13.1)0.102
Septum36 (12.3)91 (36.8)<0.0014.3 (1.1–10.3)2.0 (6.8–13.0)0.166
IW15 (5.1)42 (17.0)<0.0012.1 (1.0–4.8)3.0 (2.0–7.7)0.220
LW6 (0.7)29 (11.7)<0.0012.0 (1.8–12.4)3.4 (2.0–9.0)0.623
PW17 (5.8)73 (30.0)<0.0016.0 (2.0–9.1)5.1 (2.0–12.0)0.996
LAA0 (0.0)3 (1.2)0.059–2.2 (1.5–)–
Surface area (cm2)
Amplitude (mV)
ParoxysmalPersistentP-valueParoxysmalPersistentP-value
LA96.0 (83.0–112.0)113.4 (96.3–130.3)<0.0012.7 (1.3–4.3)1.8 (0.8–3.8)<0.001
AW15.0 (12.3–18.7)17.1 (10.5–31.1)<0.0012.1 (0.6–4.1)1.2 (0.2–3.0)<0.001
Septum18.0 (13.2–22.2)21.4 (17.6–27.8)<0.0012.0 (0.8–5.2)1.3 (0.2–3.1)<0.001
IW16.3 (12.8–20.8)20.1 (15.7–24.5)<0.0012.6 (1.3–5.7)2.2 (0.9–5.3)<0.001
LW9.6 (7.6–12.3)11.4 (9.1–15.0)<0.0012.7 (1.1–5.8)2.3 (1.0–4.7)<0.001
PW16.8 (12.9–20.5)18.7 (15.1–22.4)<0.0012.9 (0.9–5.7)1.7 (0.5–4.8)<0.001
LAA18.7 (14.2–24.5)20.6 (16.0–27.9)0.0064.3 (1.1–10.3)2.5 (0.7–6.3)<0.001
Incidence of LVZ n (%)
LVZ area (IQR)
ParoxysmalPersistentP-valueParoxysmalPersistentP-value
LA55 (18.8)134 (54.3)<0.0015.0 (3.0–18.6)12.1 (3.6–28.5)0.026
AW35 (12.0)93 (37.7)<0.0015.3 (3.0–10.3)9.0 (3.0–13.1)0.102
Septum36 (12.3)91 (36.8)<0.0014.3 (1.1–10.3)2.0 (6.8–13.0)0.166
IW15 (5.1)42 (17.0)<0.0012.1 (1.0–4.8)3.0 (2.0–7.7)0.220
LW6 (0.7)29 (11.7)<0.0012.0 (1.8–12.4)3.4 (2.0–9.0)0.623
PW17 (5.8)73 (30.0)<0.0016.0 (2.0–9.1)5.1 (2.0–12.0)0.996
LAA0 (0.0)3 (1.2)0.059–2.2 (1.5–)–
Surface area (cm2)
Amplitude (mV)
ParoxysmalPersistentP-valueParoxysmalPersistentP-value
LA96.0 (83.0–112.0)113.4 (96.3–130.3)<0.0012.7 (1.3–4.3)1.8 (0.8–3.8)<0.001
AW15.0 (12.3–18.7)17.1 (10.5–31.1)<0.0012.1 (0.6–4.1)1.2 (0.2–3.0)<0.001
Septum18.0 (13.2–22.2)21.4 (17.6–27.8)<0.0012.0 (0.8–5.2)1.3 (0.2–3.1)<0.001
IW16.3 (12.8–20.8)20.1 (15.7–24.5)<0.0012.6 (1.3–5.7)2.2 (0.9–5.3)<0.001
LW9.6 (7.6–12.3)11.4 (9.1–15.0)<0.0012.7 (1.1–5.8)2.3 (1.0–4.7)<0.001
PW16.8 (12.9–20.5)18.7 (15.1–22.4)<0.0012.9 (0.9–5.7)1.7 (0.5–4.8)<0.001
LAA18.7 (14.2–24.5)20.6 (16.0–27.9)0.0064.3 (1.1–10.3)2.5 (0.7–6.3)<0.001

All data are presented as median and IQR.

AF, atrial fibrillation; LA, left atria; AW, anterior wall; IW, inferior wall; LW, lateral wall; PW, posterior wall; LAA, left atrial appendage; LVZ, low voltage zone.

LVZ in patients with conduction disorder

The prevalence of LVZ in patients with SND [15 out of 22 (68%)] was significantly higher than in those without SND [177 out of 517 (34%)], P = 0.002. There was no significant difference in the LVZ area of the entire LA between +LVZ patients with and without SND, 20.8 (3.6–29.3) vs. 9.8 (3.0–26.1) cm2, P = 0.331, respectively.

Furthermore, in 12 out of 22 (54.5%) patients with SND, LVZ was more frequently localized in the anterior wall as compared with 116 out of 517 (22.5%) patients without SND (P = 0.001). Moreover, the area of LVZ at the anterior wall in patients with SND was significantly larger than those without SND [12.3 (5.3–15.0) vs. 7.3 (3.0–11.9), P = 0.036]. The prevalence or size of LVZ in other regions did not reach statistical significance.

A LVZ was present in 16 out of 26 (62%) patients with AVB as compared with 173 out of 513 (33.7%) without AVB, (P = 0.005). However, there were no differences neither on the area of LVZ between patients with and without AVB [11.2 (2.2–32.7) vs. 10.0 (3.1–26.1) cm2, P = 0.802] nor the localization of LVZ regards of predefined regions.

Predictors of LVZ

The median age in patients with LVZ was significantly higher than in patients without LVZ [69.1 (67.6–70.0) vs. 63.0 (61.8–64.0), P < 0.001]. The prevalence of LVZ in female patients (101 out of 230, 43.9%) was significantly higher than in male patients (91 out of 309, 29.4%), P = 0.001. There was no significant difference (P = 0.704) in stroke history between patients with LVZ (7 out of 192, 3.6%) and those without LVZ (15 out of 347, 4.3%).

In the univariate analysis the following variables predicted the presence of LVZ; age, gender, hypertension, diabetes mellitus, ischaemic cardiomyopathy, dilative cardiomyopathy (DCM), SND, AVB, surface area of LA, and CHA2DS2-VASc score. In the multivariate analysis age (OR 1.07, 95% CI 1.05–1.10, P < 0.001), female gender (OR 2.18, 95% CI 1.38–3.43, P = 0.001), SND (OR 3.90, 95% CI 1.24–12.21, P = 0.020), larger surface area of LA per cm2 (OR 1.01, 95% CI 1.00–1.02, P = 0.016), and persistent AF (OR 5.03, 95% CI 3.20–7.90, P < 0.001) remained statistically significant.

Discussion

Main findings

In the present study we report baseline bipolar voltage maps of the LA in a large cohort of patients undergoing RF catheter ablation for paroxysmal and persistent AF. Areas of LVZ in patients with persistent AF were larger than in patients with paroxysmal AF and the most frequent localization was anterior wall, septum, and posterior wall. Furthermore, the presence of LVZ was associated with age, female gender, larger LA surface area, and SND.

Presence and distribution of LVZ in AF patients

The understanding of AF pathophysiology has advanced over the years through increased awareness of persistent change in atrial structure and function. Structural remodelling that is consistently seen in models of AF and in patients with AF includes atrial enlargement, cellular hypertrophy, dedifferentiation, fibrosis, apoptosis, and myolysis.8 Moreover, fibrotic atrial infiltration has been described in AF patients in histological and autopsy studies.2 The presence of (micro) fibrosis leading to changes in cellular coupling results in spatial ‘non-uniform anisotropic’ impulse propagation, which is a potential cause of atrial activation abnormalities underlying the initiation and perpetuation of re-entrant arrhythmias like AF.9 Due to the limitations of fibrosis assessment from histological specimens of larger areas of the human heart, cardiac imaging and electroanatomically bipolar voltage mapping have been used as a surrogate marker in the ventricles. In contrast to the ventricles, no studies have described the correlation between local electrograms or imaging findings and the histology of the corresponding myocardium in the atria. Therefore, there are no clear cut-off values for significant fibrosis in the atria, although in most studies a 0.5 mV cut-off has been used.6,10 Recent clinical research has highlighted the presence of delayed-enhancement on magnetic resonance images and LVZ in electroanatomical voltage maps of the LA, which might represent areas of atrial tissue fibrosis.6 But there are still inherent limitations of image quality in cardiac MRI, especially when scanning the thin LA wall compared with the left ventricular wall.

In the present study, the area of LVZ in patients with persistent AF was larger as compared with paroxysmal, which is in line with previous findings from autopsies demonstrating more fibro-fatty infiltration in patients with persistent AF, but variability in the extent of fibrosis among patients with AF is very high.2,11 The most frequent localization of LVZ was anterior wall, septum, and posterior wall, which might be related to higher stretch load in these areas.12

Even though there is no direct evidence that LVZ represents fibrosis of the atrial muscle, loss of amplitude in the electrocardiogram are related to loss of muscle which most often are replaced by fibro-fatty infiltration.2 Thus, the distribution pattern of LVZ in the present study indicates that LVZ might be related to fibro-fatty infiltration.

Conduction disorders and presence of LVZ in patients with AF

SND is mainly a disease of the elderly and its incidence increases with age in an exponential manner. In 1977, Thery et al. demonstrated a direct correlation between sinoatrial node (SAN) fibrosis and the occurrence of tachy-brady syndrome.13 However, it is still unclear whether fibrosis upregulation always precedes SND, or if fibrosis is a response to SND in humans. Nevertheless, in SND animal models and recent clinical late-gadolinium MRI studies where structural remodelling in the SAN was studied, up-regulated fibrosis in the SAN pacemaker complex was found.14 In our current study, there was an association between LVZ in the LA and SND in the multivariate analysis, suggesting a more progressive conduction disorder in patients with both AF and SND. Other studies using electroanatomical mapping of the right atrium in patients with clinical evidence of SND also showed reduced right atrial voltage and conduction velocities indicating that tissue remodelling and fibrosis are involved in manifestation of clinical arrhythmias.15

Degenerative aetiology has also been considered as the most common cause of AVB in elder patients. Similarly, the prevalence of AF increases along with the age of the population. However, scientific literature is surprisingly scarce regarding the pathology of AVB in the AF population. In the current study, the association between LVZ and AVB was only significant in the univariate analysis. These finding supports the clinical findings that the association between atrial fibrillation and AVB is not as clear as compared with SND, where degeneration in the atria are more prominent. However, results from the present study should be interpreted with caution due to the relative low number of patients with conduction disorders and the lack of right atrium voltage maps and voltage maps in patients with conduction disorders and no history of AF serving as controls.

Other patient characteristics and association with LVZ

Several epidemiological studies imply that occurrence of AF is age-related.16 On the level of pathology an association between age and atrial fibrosis has been listed as one of the etiological factors underlying AF development in management guidelines.17 However, a recent pathological study could not identify such correlation in a similar age span population, suggesting that age-related increase in fibrosis extent does not reach the magnitude of changes observed in AF patients.2 Although our data shows that the presence of LVZ was correlated with age, the authors propose that age contribution to fibrosis development is limited and unlikely to be the sole explanation of the advanced fibrosis observed in AF patients. We speculate that the time course of the progression of AF and their individual clinical manifestations vary depending on the underlying pathology. Furthermore, as previously described from autopsies the content of fibrosis were higher in persons with large atria.18 This is in line with the results from the present study demonstration an association between LVZ and surface size of the LA. Epidemiological studies have also showed that larger height increases the risk of AF.19 Since females in general are smaller and have smaller atria, we think that they might present with clinical AF in a later state of fibro-fatty infiltration as compared with men with larger atria, which could explain why female gender were associated with LVZ in our cohort.

In our current study, we could not correlate a previous history of stroke to the incidence or area of LVZ. The link between prior stroke and LVZ might be more difficult to identify in patients under effective OAC. Furthermore, other etiologies than emboli from the heart might have caused the ischaemic stroke, since the majority of patients included in the present study have one or more risk factor for cerebrovascular disease.

Limitations

We did not obtain voltage maps from the LA in age-matched patients without AF to serve as controls, which might have strengthened the association between LVZ and atrial conduction disturbances. Previous studies in younger patients comparing patients with AF and left-sided accessory pathways or focal atrial tachycardias showed a higher incidence of LVZ in patients with AF. It would be challenging to obtain left-sided voltage maps in patients undergoing other left-sided procedures with similar age and comorbidities as the patients in the present study. Because of the nature of catheter ablation for atrial fibrillation, we only systematically obtained voltage maps from the LA and only in a few patients from the RA. Obtaining systematically voltage map data from the RA would have been interesting and might have changed the results, since fibro-fatty infiltration responsible for SAN dysfunction and AVB might be more prominent and sometimes only present in the RA.

Moreover, we were not able to obtain tissue for histological analysis from patients to confirm that the LVZ detected by EAM could reflect fibro-fatty infiltration in human atria. In the present study we only evaluated voltage values, and specific characteristics of the electrograms, like fragmented potentials were not registered but might be important for initiation and persistence of AF. Another concern is whether in current technique settings the resolution of employed bipolar voltage map could identify the entire LVZs with appropriate clinical meanings. These questions warrant further studies.

Conclusions

This study presents detailed characteristics of bipolar voltage maps from the left atrium in a large cohort of AF patients where area of LVZ in patients with persistent AF was predominantly larger than in patients with paroxysmal AF. The most frequent localization of LVZ was anterior wall, septum, and posterior wall. Furthermore, the prevalence of LVZ was associated with higher age, female gender, larger LA surface area, and sick sinus node disease.

Conflict of interest: C.P. has received modest lecture honoraria from St. Jude Medical, Biotronik, Boehringer Ingelheim and Biosense Webster. C.P. is a member of the St. Jude Medical, Siemens and Biosense Webster advisory boards, and has received research support from St. Jude Medical, Biotronik, Imricor, and Philips. Y.H. has received modest lecture honoraria from St. Jude Medical. TG has received modest lecture honoraria from Biosense Webster. M.P. has received modest educational sponsoring from St. Jude Medical. The other authors have no conflicts of interest to disclose.

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Clinical Research > Ablation for atrial fibrillation
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