Biatrial volume ratio predicts low voltage areas in atrial fibrillation

Abstract Background Left atrial volume (LAV) and low voltage areas (LVAs) are acknowledged markers for worse rhythm outcome after ablation of atrial fibrillation (AF). Some studies reported the importance of increased right atrial volume (RAV) as a predictor for arrhythmia recurrences in AF patients. Objective To investigate association between the LAV/RAV ratio and LVAs presence. Methods Patients undergoing first AF ablation were included. LVAs were assessed peri‐procedurally using high‐density 3D maps and defined as <0.5 mV. All patients underwent pre‐procedural cardiovascular magnetic resonance imaging. LAV (biplane) and RAV (monoplane 4‐chamber) were assessed prior to ablation, and the LAV/RAV ratio was calculated. Results The study population included 189 patients (age mean 63 ± 10 years, 33% women, 57% persistent AF, 22% LVAs). There were 149 (79%) patients with LAV > RAV. In univariable analysis LAV > RAV was associated with LVAs (OR 6.803, 95%CI 1.395–26.514, p = .016). The association remained robust in multivariable model after adjustment for persistent AF, CHA2DS2‐VASc score, and heart rate (OR 5.981, 95%CI 1.256–28.484, p = .025). Using receiver operator curve analysis, LAV > RAV (AUC 0.668, 95%CI 0.585–0.751, p = .001) was significant predictor for LVAs. In multivariable analysis, after adjustment for age, persistent AF, and renal function, RAV≥LAV was threefold higher in males (OR 3.040, 95%CI 1.050–8.802, p = .04). Conclusions LAV > RAV is useful for the prediction of electro‐anatomical substrate in AF. LAV > RAV was associated with LVAs presence, while male sex remained associated with RAV≥LAV and less LVAs.

Conclusions: LAV > RAV is useful for the prediction of electro-anatomical substrate in AF. LAV > RAV was associated with LVAs presence, while male sex remained associated with RAV≥LAV and less LVAs.
atrial fibrillation, cardiac magnetic resonance, left atrial size, low voltage areas, right atrial volume

| INTRODUCTION
Becoming a cornerstone therapy in many patients with atrial fibrillation (AF), 1 in some patients, catheter ablation with circumferential pulmonary vein isolation alone is not enough for sinus rhythm maintenance during follow-up. The arrhythmia recurrences remain an important clinical challenge and require individualized AF treatment plan already before intervention. One major feature reflecting left atrial (LA) remodeling is peri-procedural evidence of low voltage areas (LVAs). 2 At least 20%-25% of AF patients have significant LVAs in peri-procedural mapping, which are an important characteristic of AF progression and treatment failure if not treated with additional ablation. 2,3 Therefore, assessment of LVAs presence before catheter ablation is an important task for the electrophysiologist allowing individually tailored AF ablation therapy.
The LA size is another important parameter of AF progression. The role of the LA volume (LAV) and LA function as surrogate parameters for higher AF burden 4 and LVAs presence 5,6 are well described. In addition, there is an association between atrial flutter-a right atrial (RA), and AFa left atrial disease. 7,8 Several studies described an importance of RA assessment as a prognosis marker in heart failure, pulmonary hypertension, and chronic obstructive pulmonary disease. [9][10][11] Diastolic functional changes-as a preliminary stage for AF-appeared to occur earlier in the right chambers 12 suggesting that RA dilatation might be an early marker for atrial remodeling associated with AF initiation. Previous studies reported the importance of increased RA volume (RAV) as predictor for arrhythmia recurrences in AF patients. 13,14 It was hypothesized that RA is more prone to hemodynamic changes and is a more responsive marker of structural remodeling. 13 However, association between RAV and LVAs and the prediction capability for LAV/RAV ratio is unknown. Therefore, we aimed to investigate the indexed LAV/RAV ratio assessed in cardiovascular magnetic resonance (CMR) imaging and the association with LVAs in patients undergoing AF catheter ablation. We hypothesize that the biatrial ratio is an independent predictor for LVAs presence.

| METHODS
The study population was described previously. 6 Briefly, patients presenting for catheter ablation due to symptomatic AF from October 2015 to April 2017 were included in the study. According to current guidelines, AF subtypes were defined as paroxysmal and persistent. 15 Patients with pregnancy, age <18 or >75 years, valvular AF (any valvulopathies >second degree), cancer, acute, or systemic inflammatory diseases, and acute hyperthyreotic state were excluded from the study. The study was approved by the local Ethical Committee (Medical Faculty, University of Leipzig), and patients provided written informed consent for participation.

| Cardiovascular magnetic resonance
Prior to AF catheter ablation, all patients underwent 1.5 T CMR (Ingenia, Philips Medical) for LA anatomy assessment as previously described. 5 Briefly, LAV was determined using a biplane model based on cine 4-and 2-chamber views, and RAV using a monoplane model based on the cine 4-chamber view. Both volumes were indexed to body surface areas, and the LAV/RAV ratio was calculated before ablation. We defined two subgroups according to the LAV/RAV ratio: (1) LAV is greater than RAV (LAV > RAV), and (2) RAV is equal or greater than LAV (RAV ≥ LAV).

| Peri-procedural LA mapping and AF ablation
Transseptal access and catheter navigation were performed with a steerable sheath (Agilis, St. Jude Medical, St. Paul, MN). The electroanatomical mapping was performed in sinus rhythm as described previously. 5 In case of AF at the beginning of the procedure, the arrhythmia was terminated by electrical cardioversion and the mapping was performed in sinus rhythm.

| Statistical analysis
Data are presented as mean and standard deviation for normally distributed or median (interquartile range, 25th and 75th percentiles) for skewed continuous variables, and as proportions for categorical variables. The differences between continuous values were assessed using an unpaired t-test or the Mann-Whitney, and a χ 2 test for categorical variables.
Logistic regression analysis was used to identify factors associated with LVAs. We performed three analyses using logistic regression of LVAs presence (Model 1unadjusted analysis; Model 2adjusted for age and sex; and Model 3adjusted for persistent AF, heart rate, and CHA 2 DS 2 -VASc score. Receiver operating characteristic curves (ROC) were generated to analyze performance of the LAV/RAV ratio predicting LVAs, with the area under the curve (AUC) being equivalent to the c-index for determining the predictive value for the parameters. Finally, we compared the c-indices (i.e., areas under the ROC curves) of LAV > RAV and LAV using DeLong's method. 16 A p-value <.05 was considered statistically significant. All analyses were performed with SPSS statistical software version 26 (SPSS Inc., Chicago).

| Clinical characteristics of the study population
The study population included 189 patients (mean 63 ± 10 years, 33% women, 57% persistent AF) undergoing their first AF catheter ablation. Clinical characteristics of the study population are summarized in Table 1

| DISCUSSION
In our study, we investigated the indexed LAV/RAV ratio and its predictive value on the pre-procedural LVAs in patients undergoing AF catheter ablation (Figure 2). We found that LAV > RAV was associated with sixfold risk for LVAs presence. Also, LAV > RAV was less observed in males.

| Biatrial ratio as parameter for AF progression and LVAs prediction
The role of RA size in AF pathogenesis is controversial. It had been reported that RAV and the RAV/LAV ratio were predictive for AF recurrence after PVI in patients with persistent AF, while LAV was not. 14 Another study confirmed these findings in AF patients after cardioversion. 13

| Clinical implications
LA diameter (LAD) is an acknowledged marker of advanced electroanatomical remodeling. 2,20,21 LA remodeling is associated with increased atrial volume, interstitial fibrosis, and increased myocardial stretch favoring AF sustainability. 22 Previously, we reported that besides anteroposterior LAD, the LAV assessed in CMR is a strong predictor for LVAs presence. 6 In current analysis we confirm the role of LA in AF pathogenesis showing that LAV > RAV was associated with sixfold risk for LVAs presence. Although LAV alone showed better predictive value than LAV > RAV (AUC 0.724 vs. 0.668), the difference between ROC curves was not significant. However, the risk of LVAs presence was more obvious using LAV/RAV ratio than LAV alone (OR 5.98 vs. 1.03). Our results indicate that the LA enlargement indexed for the RAV (as self-reference for enlargement) as reflected with the LAV/RAV ratio is a helpful tool for LVAs prediction and for shaping an individualized AF management approach prior to AF catheter ablation.
The present findings add to our knowledge about the importance of side-specific atrial remodeling. As previously described, LA remodeling is associated with later stages of AF progression resulting from risk factors like aging, hypertension, left ventricular (LV) diastolic dysfunction and an altered electromechanical activation. 23-26 LV stiffness results into higher LA pressure with reduced LA emptying and consequent atrial dilatation. 23 Described pathologic changes represent a common pathway associated with interatrial delay seen as biphasic Pwave in ECG and caused by deterioration of the Bachmann bundle conduction, and finally impaired electromechanical LA activation. 25 These pathophysiologic changes contribute to advanced remodeling and wall deformation that has been associated with LVA. 27 Our study supplement these findings of side specific pathophysiological LA changes (especially in relation to RAV) and emphasize the need for accurate pre-procedural LA assessment.
In contrast, pathophysiology of RA remodeling seems to be different. In patients without heart failure, volume and pressure overload in the RA is mainly associated with pulmonary resistance, valvular disease, and RV dysfunction. [28][29][30] Although AF may contribute to RA dilation as well, 31 AF triggers from the RA are rare 32 and RA ablation in AF patients has not shown any benefit for outcomes. 33 In our study, RAV > LAV was higher in males and was not associated with LVAs. An explanation for such sexspecific difference remains unknown, but it is in accordance with large echocardiographic studies and has not been assigned any clinical significance. 34-36

| Future directions
Our findings show a strong association between LVAs and LAV/RAV ratio. Despite previous data reporting a correlation between RAV ≥ LAV and AF recurrences, our results imply that increased RAV is not a suitable parameter for LVAs prediction and therefore not a marker for left atrial myopathy. This is in line with our previous studies that emphasized the importance of LV diastolic dysfunction, electro-anatomical dysfunction for asymmetric LA remodeling, and ablation outcomes. [23][24][25] Future studies should thus focus on the LA size and its proportional enlargement in relation to the RA, when assessing patients prior to an AF ablation procedure.

ACKNOWLEDGMENT
Open access funding enabled and organized by Projekt DEAL.

CONFLICT OF INTEREST
Philipp Sommer is in the advisory board for Abbott, Biosense Webster, Medtronic, und Boston Scientific.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.