Gender Differences in Atrial Fibrosis and Cardiomyopathy Assessed by Left Atrial Low-Voltage Areas During Catheter Ablation of Atrial Fibrillation

Abstract

Atrial myocardial degeneration predisposes to atrial fibrillation (AF), ischemic stroke, and heart failure. Studies suggest the presence of gender differences in atrial myocardial degeneration. This study aimed to delineate gender differences in the prevalence, predictors, and prognostic impact of left atrial low-voltage areas (LVAs). This observational study included 1,488 consecutive patients who underwent initial ablation for AF. Voltage mapping was performed after pulmonary vein isolation during sinus rhythm. LVAs were defined as regions where bipolar peak-to-peak voltage was <0.50 mV. LVA prevalence was higher in women (38.7%) than in men (16.0%). High age, persistent form of AF, diabetes mellitus, and a large left atrium were shown to be common predictors in both gender categories. Heart failure and history of stroke/thromboembolic events were men-specific predictors of LVA existence. Women experienced more AF recurrence than men (31.1% vs 25.7%, p = 0.027). LVA existence was significantly associated with increased AF recurrence in each gender category, with a respective hazard ratio, 95% confidence interval, and p value of 2.45, 1.87 to 3.22, and <0.0001 in men and 1.82, 1.33 to 2.49, and <0.0001 in women. In conclusion, LVA was more frequent in women than men, and predicted frequent AF recurrence irrespective of gender category. Atrial myocardial degeneration predisposes to atrial fibrillation (AF), ischemic stroke, and heart failure. Studies suggest the presence of gender differences in atrial myocardial degeneration. This study aimed to delineate gender differences in the prevalence, predictors, and prognostic impact of left atrial low-voltage areas (LVAs). This observational study included 1,488 consecutive patients who underwent initial ablation for AF. Voltage mapping was performed after pulmonary vein isolation during sinus rhythm. LVAs were defined as regions where bipolar peak-to-peak voltage was <0.50 mV. LVA prevalence was higher in women (38.7%) than in men (16.0%). High age, persistent form of AF, diabetes mellitus, and a large left atrium were shown to be common predictors in both gender categories. Heart failure and history of stroke/thromboembolic events were men-specific predictors of LVA existence. Women experienced more AF recurrence than men (31.1% vs 25.7%, p = 0.027). LVA existence was significantly associated with increased AF recurrence in each gender category, with a respective hazard ratio, 95% confidence interval, and p value of 2.45, 1.87 to 3.22, and <0.0001 in men and 1.82, 1.33 to 2.49, and <0.0001 in women. In conclusion, LVA was more frequent in women than men, and predicted frequent AF recurrence irrespective of gender category. In most patients with atrial fibrillation (AF), the disease is believed to develop from an underlying diseased atrial myocardium.1Guichard JB Nattel S Atrial cardiomyopathy: a useful notion in cardiac disease management or a passing fad?.J Am Coll Cardiol. 2017; 70: 756-765Crossref PubMed Scopus (126) Google Scholar, 2Reddy YNV Obokata M Gersh BJ Borlaug BA High prevalence of occult heart failure with preserved ejection fraction among patients with atrial fibrillation and dyspnea.Circulation. 2018; 137: 534-535Crossref PubMed Scopus (67) Google Scholar, 3Reddy YNV Obokata M Verbrugge FH Lin G Borlaug BA Atrial dysfunction in patients with heart failure with preserved ejection fraction and atrial fibrillation.J Am Coll Cardiol. 2020; 76: 1051-1064Crossref PubMed Scopus (133) Google Scholar Left atrial bipolar voltage decreases with the progression of myocardial degeneration, including fibrosis and other pathophysiological changes.4Yamaguchi T Otsubo T Takahashi Y Nakashima K Fukui A Hirota K Ishii Y Shinzato K Osako R Tahara M Kawano Y Kawaguchi A Aishima S Takahashi N Node K Atrial structural remodeling in patients with atrial fibrillation is a diffuse fibrotic process: evidence from high-density voltage mapping and atrial biopsy.J Am Heart Assoc. 2022; 11e024521Crossref Scopus (5) Google Scholar In the clinical setting, atrial voltage mapping is often performed to predict the probability of AF recurrence after catheter ablation5Rolf S Kircher S Arya A Eitel C Sommer P Richter S Gaspar T Bollmann A Altmann D Piedra C Hindricks G Piorkowski C Tailored atrial substrate modification based on low-voltage areas in catheter ablation of atrial fibrillation.Circ Arrhythm Electrophysiol. 2014; 7: 825-833Crossref PubMed Scopus (370) Google Scholar,6Masuda M Fujita M Iida O Okamoto S Ishihara T Nanto K Kanda T Tsujimura T Matsuda Y Okuno S Ohashi T Tsuji A Mano T Left atrial low-voltage areas predict atrial fibrillation recurrence after catheter ablation in patients with paroxysmal atrial fibrillation.Int J Cardiol. 2018; 257: 97-101Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar and to guide ablation strategies.5Rolf S Kircher S Arya A Eitel C Sommer P Richter S Gaspar T Bollmann A Altmann D Piedra C Hindricks G Piorkowski C Tailored atrial substrate modification based on low-voltage areas in catheter ablation of atrial fibrillation.Circ Arrhythm Electrophysiol. 2014; 7: 825-833Crossref PubMed Scopus (370) Google Scholar,7Yang B Jiang C Lin Y Yang G Chu H Cai H Lu F Zhan X Xu J Wang X Ching CK Singh B Kim YH Chen M STABLE-SR InvestigatorsSTABLE-SR (electrophysiological substrate ablation in the left atrium during sinus rhythm) for the treatment of nonparoxysmal atrial fibrillation: a prospective, multicenter randomized clinical trial.Circ Arrhythm Electrophysiol. 2017; 10e005405Crossref Scopus (91) Google Scholar,8Masuda M Asai M Iida O Okamoto S Ishihara T Nanto K Kanda T Tsujimura T Matsuda Y Okuno S Hata Y Mano T Additional low-voltage-area ablation in patients with paroxysmal atrial fibrillation: results of the randomized controlled VOLCANO trial.J Am Heart Assoc. 2020; 9e015927Crossref Scopus (33) Google Scholar Gender differences in various aspects of cardiovascular disease have been highlighted.9Prajapati C Koivumäki J Pekkanen-Mattila M Aalto-Setälä K Sex differences in heart: from basics to clinics.Eur J Med Res. 2022; 27: 241Crossref PubMed Scopus (2) Google Scholar Some studies have reported that women are more likely to experience left atrial low-voltage areas (LVAs)than men,6Masuda M Fujita M Iida O Okamoto S Ishihara T Nanto K Kanda T Tsujimura T Matsuda Y Okuno S Ohashi T Tsuji A Mano T Left atrial low-voltage areas predict atrial fibrillation recurrence after catheter ablation in patients with paroxysmal atrial fibrillation.Int J Cardiol. 2018; 257: 97-101Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar,8Masuda M Asai M Iida O Okamoto S Ishihara T Nanto K Kanda T Tsujimura T Matsuda Y Okuno S Hata Y Mano T Additional low-voltage-area ablation in patients with paroxysmal atrial fibrillation: results of the randomized controlled VOLCANO trial.J Am Heart Assoc. 2020; 9e015927Crossref Scopus (33) Google Scholar suggesting that AF in women may derive from more advanced atrial myocardial degeneration than AF in men. To date, however, no detailed information regarding gender differences in LVAs has yet appeared. Here, we aimed to delineate the gender differences in LVAs, including their prevalence, predictors, and prognostic impact. This retrospective prospective observational study enrolled 1,488 consecutive patients who underwent the initial ablation of AF at Kansai Rosai Hospital from December 2014 to March 2022. Patients in whom the left atrial voltage map was not completed were excluded. Other exclusion criteria were age <20 years, previous left atrial catheter or ablation, and previous MAZE surgery. The total study population of 1,488 patients was divided into 2 gender categories, with 987 men and 501 women. This study complied with the Declaration of Helsinki. Written informed consent for the ablation and participation in the study was obtained from all patients, and the protocol was approved by our institutional review board. Pulmonary vein isolation (PVI) was performed in all patients using a linear radiofrequency catheter or cryoballoon. Other additional ablations, including LVA homogenization, linear ablation, ablation for induced atrial tachycardias, and ablation for nonpulmonary-vein AF triggers were added at the discretion of the attending physicians. An electroanatomical mapping system (CARTO 3, [Biosense Webster, Inc., Diamond Bar, California]; Ensite NavX, [Abbott, Abbott Park, Illinois], or Rhythmia, [Boston Scientific, Boston, Massachusetts]) was used for ablation guidance and mapping in patients with radiofrequency ablation. After PVI and before other additional ablations, left atrial voltage mapping was performed under sinus rhythm or atrial paced rhythm from the right atrium. The multielectrode mapping catheter used in most cases was a PENTARAY (Biosense Webster), Lasso NaV (Biosense Webster), HD grid (Abbott), or Orion (Boston Scientific, Waltham, Massachusetts). A 3.5-mm or 4.0-mm ablation catheter was used as an auxiliary in some areas with difficulty in catheter-tissue contact. The bandpass filter was set at 30 Hz to 500 Hz. Adequate endocardial contact was confirmed by distance to the geometry surface and stable electrograms. Mapping points were acquired to fill all color gaps on the voltage map. Respective fill and color interpolation thresholds were 15 mm and 23 mm for CARTO 3 and 20 mm and 7 mm for Ensite NavX. The interpolation threshold for Rhythmia was set at 5 mm. The presence of LVAs was determined when the size of total areas with a bipolar peak-to-peak voltage <0.50 mV was ≥5 cm2.10Sunaga A Masuda M Inoue K Tanaka N Watanabe T Furukawa Y Egami Y Hirata A Makino N Minamiguchi H Oka T Minamisaka T Takeda T Yamada T Kitamura T Kida H Oeun B Sato T Sotomi Y Dohi T Okada K Suna S Mizuno H Nakatani D Hikoso S Sakata Y OCVC-SUPPRESS-AF InvestigatorsThe efficacy and safety of left atrial low-voltage area guided ablation for recurrence prevention compared to pulmonary vein isolation alone in patients with persistent atrial fibrillation trial: design and rationale.Clin Cardiol. 2021; 44: 1249-1255Crossref PubMed Scopus (2) Google Scholar Patients were followed every 4 to 8 weeks at the dedicated arrhythmia clinic of our institution for a minimum of 2 years. Routine electrocardiograms (ECGs) were obtained at each outpatient visit, and 24-hour ambulatory Holter monitoring was performed at 6 and 12 months postablation. When patients experienced symptoms suggestive of an arrhythmia, a surface ECG, ambulatory ECG, and/or cardiac event recording were also obtained. Either of the following events after the initial 3 months after ablation (blanking period) was considered to indicate AF recurrence: (1) atrial tachyarrhythmia (AF and regular atrial tachycardia) recorded on a routine or symptom-triggered ECG during an outpatient visit; or (2) atrial tachyarrhythmia of at least 30-second duration on ambulatory ECG monitoring. No antiarrhythmic drugs were prescribed after the ablation procedure unless AF recurrence was observed. Continuous data are expressed as the mean ± SD or median (interquartile range). Categorical data are presented as absolute values and percentages. Tests for significance were conducted using the unpaired t test, or nonparametric test (Mann-Whiney U test) for continuous variables, and the chi-square test or Fisher's exact test for categorical variables. A logistic regression model was used to identify clinical factors associated with LVA existence. Cox proportional hazard models were used to determine the prognostic significance of LVA in the prediction of AF recurrence. Variables with a p ≤0.05 in the univariate models were included in the multivariate analysis. AF recurrence-free survival rates were calculated using the Kaplan–Meier method. Survival curves between groups were compared with a 2-sided Mantel-Haenszel (log-rank) test. All analyses were performed using commercial software (SPSS version 26.0, SPSS, Inc., Chicago, Illinois). Patient characteristics are compared between men and women in Table 1. Women were older, smaller in height, lighter in weight, thinner, more likely to have paroxysmal AF, and had a greater decrease in renal function and a higher CHA2DS2VASc score. Women also had higher clinical scores predicting the presence of LVAs (SPEED and DR-FLASH).11Kosiuk J Dinov B Kornej J Acou WJ Schönbauer R Fiedler L Buchta P Myrda K Gąsior M Poloński L Kircher S Arya A Sommer P Bollmann A Hindricks G Rolf S Prospective, multicenter validation of a clinical risk score for left atrial arrhythmogenic substrate based on voltage analysis: DR-FLASH score.Heart Rhythm. 2015; 12: 2207-2212Abstract Full Text Full Text PDF PubMed Google Scholar,12Matsuda Y Masuda M Asai M Iida O Okamoto S Ishihara T Nanto K Kanda T Tsujimura T Hata Y Uematsu H Mano T A new clinical risk score for predicting the prevalence of low-voltage areas in patients undergoing atrial fibrillation ablation.J Cardiovasc Electrophysiol. 2020; 31: 3150-3158Crossref PubMed Scopus (6) Google Scholar On echocardiography, female patients had smaller atrial and ventricular chamber sizes, a higher left ventricular ejection fraction, and lower left ventricular mass.Table 1Baseline characteristicsMenWomenn = 987n = 501pAge, years66.5 ± 10.671.3 ± 8.2<0.0001Height, cm168.8 ± 6.7153.6 ± 6.4<0.0001Weight, Kg70.0 ± 12.255.4 ± 10.9<0.0001Body mass index, kg/m224.3 ± 3.723.5 ± 4.6<0.0001AF type<0.0001 Paroxysmal, AF AF mellitus, or ± ± ± ± ± ± ± ± Left atrial ± ± Left ventricular ± ± Left ventricular ejection fraction, ± ± Left ventricular mass index, ± ± = atrial = = = of in a new AF = atrial = = = of characteristics are in Table were gender differences in the of mapping and ablation used for of mapping system was between ablation used for CARTO ablation, vs ablation, Ensite vs and Rhythmia vs p The of mapping points was more in men than in women. Women underwent the following ablation more than nonpulmonary-vein ablation, isolation of the and left atrial linear ablation. The of other ablation was in men and characteristicsMenWomenn = 987n = mapping presence 5 20 catheter used for pulmonary vein isolation of pulmonary Left atrial Left atrial of = low-voltage in a new LVA = low-voltage Left atrial LVA prevalence was higher in women than in men Table of LVA was also higher in women than in men In both LVAs were at the and higher LVA prevalence in women was every left atrial by age a higher LVA prevalence in women to No women had 3 LVA prevalence by left atrial A higher LVA prevalence in women than men was when left atrial was LVA prevalence and of women for LVA prevalence and of women for LVA existence are shown by left atrial A higher LVA prevalence in women than men were when left atrial was mm. for between men and LVA prevalence and of women for LVA existence are shown by left atrial A higher LVA prevalence in women than men were when left atrial was mm. for between men and women. The between LVA existence and clinical factors is in 3 and High age, persistent form of AF, diabetes mellitus, and large left atrium were to be common predictors in both gender categories. Heart failure and history of stroke/thromboembolic events were men-specific predictors of LVA associated with LVA existence among = ± ± mass ± ± AF, mellitus, was defined as or AF = atrial = confidence = = hazard LVA = low-voltage ± ± atrial ± ± ventricular ejection fraction, ± ± with p in the univariate were in the multivariate analysis. was defined as or = atrial = confidence = = hazard LVA = low-voltage in a new Table associated with LVA existence among = ± ± mass ± ± AF, mellitus, was defined as or AF = atrial = confidence = = hazard LVA = low-voltage ± ± atrial ± ± ventricular ejection fraction, ± ± with p in the univariate were in the multivariate analysis. was defined as or = atrial = confidence = = hazard LVA = low-voltage in a new with p in the univariate were in the multivariate analysis. with p in the univariate were in the multivariate analysis. a median of to AF recurrence after initial ablation in of 1,488 patients Kaplan–Meier that women experienced more AF recurrence than men LVA existence was significantly associated with increased AF recurrence in both gender categories. LVA existence predicted AF recurrence after ablation with a respective hazard ratio, 95% confidence interval, and p value of 2.45, 1.87 to 3.22, and <0.0001 for men, and 1.82, 1.33 to 2.49, and <0.0001 for women. This retrospective study gender differences in the prevalence, associated and prognostic significance of The were as LVA prevalence was higher in women than in men, irrespective of age and left atrial LVAs were at the in both men and with higher prevalence in women at each left atrial common predictors of LVA existence were age, persistent form of AF, diabetes mellitus, and large left atrium. Heart failure and a history of were men-specific predictors of LVA existence. women AF recurrence more LVA prognostic significance of delineate gender differences in LVAs and left atrial in atrial bipolar voltage is reported to be associated with atrial myocardial degeneration, as by degeneration, and of as on of atrial myocardial obtained from the right atrial during the AF ablation T Otsubo T Takahashi Y Nakashima K Fukui A Hirota K Ishii Y Shinzato K Osako R Tahara M Kawano Y Kawaguchi A Aishima S Takahashi N Node K Atrial structural remodeling in patients with atrial fibrillation is a diffuse fibrotic process: evidence from high-density voltage mapping and atrial biopsy.J Am Heart Assoc. 2022; 11e024521Crossref Scopus (5) Google Scholar In studies using cardiac reported the of LVAs and areas with suggesting that LVA The higher prevalence of LVAs in has been Y Masuda M Asai M Iida O Okamoto S Ishihara T Nanto K Kanda T Tsujimura T Hata Y Uematsu H Mano T A new clinical risk score for predicting the prevalence of low-voltage areas in patients undergoing atrial fibrillation ablation.J Cardiovasc Electrophysiol. 2020; 31: 3150-3158Crossref PubMed Scopus (6) Google T A J D L H H S of atrial fibrillation of left atrial bipolar voltage using and Electrophysiol. 2018; PubMed Scopus Google Scholar was confirmed age and left atrial size pathophysiological be female are reported to have increased G Sex differences in in ventricular are by the Cardiol. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar and increased of B A A N S S remodeling in atrial Cardiovasc PubMed Scopus Google Scholar of B and to cardiac F and cardiac PubMed Scopus Google Scholar In during myocardial remodeling in including a decrease in with Wang H L of in J Heart 2014; PubMed Scopus Google Scholar of the system in to Wang H L of in J Heart 2014; PubMed Scopus Google Scholar increased of J S by and in the heart from of J PubMed Scopus Google Scholar that LVAs in women were at age and significantly increased at age the of also the of a in the underlying of AF Atrial remodeling be into and structural and both of likely to as and and K T Nattel S Atrial fibrillation for PubMed Scopus Google Scholar that AF in women advanced atrial myocardial degeneration, other factors as remodeling and a in AF in men. This by the higher of AF in men than X P C S D in atrial fibrillation prevalence, risk and in the Heart a 2015; Full Text Full Text PDF PubMed Google Scholar female patients with AF more left atrial myocardial degeneration. that age, persistent form of AF, and diabetes were common predictors of LVA irrespective of factors have been reported in previous studies and are to be associated with atrial myocardial Y Masuda M Asai M Iida O Okamoto S Ishihara T Nanto K Kanda T Tsujimura T Hata Y Uematsu H Mano T A new clinical risk score for predicting the prevalence of low-voltage areas in patients undergoing atrial fibrillation ablation.J Cardiovasc Electrophysiol. 2020; 31: 3150-3158Crossref PubMed Scopus (6) Google B Nattel S Atrial and clinical in atrial fibrillation.J Am Coll Cardiol. PubMed Scopus Google Scholar, aspects of in diabetes PubMed Google Scholar, cardiac and Cardiol. Full Text Full Text PDF PubMed Google Scholar, J M structural and remodeling after atrial fibrillation in the PubMed Scopus Google Scholar, Y Gaspar T M J Richter U S J Piorkowski C and predictors of voltage in the left atrium in patients with atrial 2018; PubMed Scopus Google Scholar a history of heart failure and stroke/thromboembolic events has been associated with LVA existence in men. atrial in heart failure patients atrial and to atrial myocardial degeneration and LVA existence. Left atrial is to on diseased atrial and and events are more frequent in patients with atrial JB Nattel S Atrial cardiomyopathy: a useful notion in cardiac disease management or a passing fad?.J Am Coll Cardiol. 2017; 70: 756-765Crossref PubMed Scopus (126) Google Scholar The impact of heart failure and stroke/thromboembolic events be in men men are by to atrial myocardial degeneration. that AF recurrence was higher in women than in men is with previous X L J S D differences in catheter ablation of atrial fibrillation: a review and PubMed Scopus Google N Inoue K A K T T H Y Y K Okada M Tanaka K Y Oka T Y A K K T S Sex differences in atrial fibrillation ablation from a 2020; PubMed Scopus Google Scholar In gender on in patients with and LVAs in that the gender in AF recurrence after ablation is of a in the of atrial myocardial degeneration. Atrial fibrotic degeneration is reported to to an atrial arrhythmogenic substrate that is associated with and of in predisposes to nonpulmonary-vein AF and of AF S G S J of atrial fibrillation in Res. PubMed Scopus Google Scholar, L L of cardiac 2015; PubMed Scopus Google Scholar, between atrial and and Full Text Full Text PDF PubMed Scopus Google Scholar, F R J G into the of remodeling in fibrotic in atrial Full Text Full Text PDF PubMed Scopus Google Scholar we that LVA existence was associated with frequent AF recurrence in both men and women. that most ablation in study population were PVI LVA existence the presence of vein arrhythmogenic In gender differences were in of ablation differences be by more frequent paroxysmal AF and smaller left atrial size in women. The results of study be to mean that AF in women more from myocardial degeneration. This at 2 characteristics of AF in AF ablation and frequent ischemic JB Nattel S Atrial cardiomyopathy: a useful notion in cardiac disease management or a passing fad?.J Am Coll Cardiol. 2017; 70: 756-765Crossref PubMed Scopus (126) Google N Inoue K A K T T H Y Y K Okada M Tanaka K Y Oka T Y A K K T S Sex differences in atrial fibrillation ablation from a 2020; PubMed Scopus Google Scholar patients be considered for additional ablation atrial substrate after after ablation to AF and to ischemic studies to delineate gender differences are to management of patients with AF. of study as we conducted voltage mapping after of LVAs the pulmonary vein not be determined of ablation LVAs were not considered of LVA existence to voltage and LVAs were by mapping and mapping factors the results of a voltage map. of ablation was at the discretion of the based on and and was not This have the AF recurrence of ablation used for and mapping in men and women the results of AF recurrence and LVA AF recurrence after was based on the symptoms of the to the that of AF have been In of information on antiarrhythmic drugs to the results on AF recurrence. In conclusion, LVA prevalence was higher in women than in men, irrespective of age and left atrial suggesting that AF in women is more from myocardial degeneration. LVA existence predicted AF irrespective of gender category, the higher LVA prevalence in women to the more frequent recurrence of AF in women. results suggest the to the management of AF. Masuda a with that and The have no of to

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