Introduction

In recent years, there has been increasing awareness regarding sex and gender differences influencing pathophysiology, diagnosis, and management of cardiovascular diseases, including sustained cardiac tachyarrhythmias, such as atrial fibrillation (AF), atrial flutter (AFL), and other supraventricular tachycardias (SVT). Recent studies have shown that women are significantly undertreated (1, 2). Our study aimed to gather further information from a tertiary referral center in Switzerland to investigate sex and gender differences as well as bias regarding the management of arrhythmias, referral patterns, and electrophysiological properties indicating pathways to improve equality of medical care.

AF is the most common sustained arrhythmia in adults in the Western adult population (3). The age-adjusted incidence of AF is lower in women than in men, indicating that women with AF are older. AFL is generally less common in women than in men, and women with AFL may have a higher burden of comorbid conditions (1).

The most common classical SVTs are atrioventricular nodal reentry tachycardia (AVNRT), atrioventricular reentrant tachycardia (AVRT), and atrial tachycardia (AT). In AVNRT and AT, there is a higher incidence in females, whereas there is a higher incidence of AVRT in males (4, 5). The objective of our study was to investigate sex and gender differences in a mixed population undergoing catheter ablation at a tertiary referral center, including symptoms and manifestation, management, ECG parameters, and EPS findings.

Methods

Patient Population and Data Collection

Four hundred adult patients (145 females, 36.3 %) who were referred for catheter ablation at the University Hospital Zurich for AF, AFL, and SVT were included in our study between January 2019 and January 2021. Retrospective informed consent was obtained from all study patients, allowing their data to be used in research and studies. The population was divided into three groups: Group A included all patients with AF, Group B AFL, and Group C classical SVTs, as described above. The term “sex” refers to biological attributes distinguishing male, female, and/or intersex individuals based on physiological differences, while “gender” encompasses sociocultural norms and identities. For each patient, data was collected, including baseline characteristics, symptoms, medication taken, and EPS findings, and analyzed for sex differences. All data were obtained for medical purposes with informed consent for the electrophysiological procedure. The study design fulfilled the guidelines of the Declaration of Helsinki regarding ethical principles for medical research involving human subjects. The study was approved by the institutional ethical board (Kantonale Ethikkomission Zürich, BASEC 2022–01517).

Statistical Analysis

The statistical analyses were done retrospectively after being collected in the clinical database of the University Hospital Zurich. Categorical data were expressed as counts and percentages. Continuous data were expressed as mean ± standard deviation or median and interquartile range. Normally distributed data between the sexes were compared using an independent t-test. Non-normally distributed data were analyzed using the Mann-Whitney U test. For categorical data, Fisher’s exact test was used. Significance testing was 2-sided with the significance level set at p < 0.05. Data analyses were performed using SPSS (Version 28.0.1.1).

Results

Baseline patient characteristics

All 400 patients underwent catheter ablation of AF, AFL, or SVT. The median age of all patients was 62 (53–70) years. The patient cohort included both men and women, with varying distributions of arrhythmia types across sexes. In the SVT group, AV nodal reentrant tachycardia (AVNRT) was the most common diagnosis in both men and women, with no significant sex difference in its occurrence. A small subset of patients had combined arrhythmic disorders, for which the primary ablation target was used for classification. The differences between the groups are highlighted in Tab. 1.

In group A (AF), women were diagnosed and underwent ablation at an older age compared to men. Among comorbidities, hypertension and chronic kidney disease were more prevalent in women, whereas other conditions were similar between the sexes. Hospitalization and prescription of cardiovascular medication were comparable in women and men. In the AFL and SVT groups, no significant sex differences were observed in age at diagnosis or ablation.

Symptoms

Fig. 2 shows the differences in symptoms for all patients. Women with AF were more likely to report dizziness, while those with AFL experienced a higher incidence of syncope. In SVT, dyspnea was more commonly reported in women than in men.

Arrhythmia management

The time from symptoms or diagnosis to ablation was not significantly different in any group (Tab. 2). Diagnoses were typically made by private cardiologists or general practitioners or in some cases in emergency departments and consecutively referred for catheter ablation. In the AF and AFL groups, more men were referred for EPS.

Electrophysiological study and ablation

In group A (AF), for the treatment of AF, pulmonary vein isolation (PVI) was consistently applied. In group B (AFL), for the treatment of typical AFL, cavotricuspid isthmus (CTI) ablation was performed in almost all patients. In group C (SVT), in the case of AVNRT, slow pathway ablation was performed, and in the case of AVRT, the accessory pathway was ablated. In AT, the aim was to interrupt the reentry circuit or extinguish the focus.

It is important to note that the duration of the EPS refers exclusively to the measurement of conduction intervals, as recorded in the procedural protocol, rather than the total duration of the electrophysiological study and ablation. The dose area product was significantly greater in men with SVT than in women with SVT. Besides that, no difference was found. Overall, we found very high procedural success rates in all the groups, showing equal results between sexes in groups A, B, and C. The success rate in our study was defined in AF (group A) by the proof of exit block around the whole circumference of all pulmonary veins and in AFL (group B) by bidirectional block and in SVTs (group C) by the absence of inducibility and in WPW by the disappearance of the accessory pathway (Tab. 3).

Discussion

This study aimed to provide an analysis of sex- and gender-related differences regarding arrhythmia management in patients being referred for catheter ablation to a tertiary care center in Switzerland, including symptoms at presentation, medication and comorbidities, management, ECG parameters, EPS findings and ablation success.

Our study showed that female subjects in the AF group were diagnosed and ablated 10 years later than men. This data is in line with other studies, where women were older on average when first diagnosed with AF (6, 7). However, we found no difference in the cohorts with AFL or SVT. In contrast to other studies, where generally AVNRT was more common in women (8), we found no differences. This could be explained by the referral bias of the study and the rather small study sample. Referral bias may arise because referring clinicians are less likely to recognize or act upon a wider range of presenting symptoms other than the classical palpitations in women or due to a speculated reluctance to recommend invasive procedures, potentially leading to underrepresentation of women (1). Similarly to other data, AVRT was more common in men (9) because of the more common congenital formation of accessory pathways in male embryos.

Regarding comorbidities, female AF patients had a significantly higher occurrence of hypertension and CKD. Women with AF are more prone to microvascular disease since they are older (10), and the prevalence of CKD is higher (11). Dagres et al. have demonstrated that female patients with AF had more comorbidities such as HF with preserved EF, hypertension, hyperthyroidism, diabetes mellitus, and stroke or transient ischemic attack (12).

Our study elucidated a tendency toward a heightened symptom burden in female patients, aligning with findings from multiple studies (7, 12, 13). Specifically, our investigation indicated that female patients with AF exhibit a greater prevalence of dizziness. However, no statistically significant differences were observed in other symptoms among patients with AF (6). Female patients with AFL experienced syncope more often than males, possibly because of shorter refractory periods of the AVN, leading to faster ventricular rates. Regarding SVT, women reported dyspnea more often than male patients. Schnabel RB et al. demonstrated significant sex differences in reported anxiety, chest pain, dizziness, dyspnea, fatigue, and palpitations (13). Other studies confirmed that women suffer from more unspecific symptoms like anxiety, which are often referred to as “atypical”, leading to misdiagnosis or delayed referral (14). This mislabeling of symptoms persists despite them being common, reinforcing a bias that may contribute to underrecognition and delayed treatment in female patients. Polyuria and frog sign, known as specific signs (15) in AVNRT, were reported rarely and failed to reveal a sex difference, however, it has been shown that polyuria is generally more pronounced in women with AVNRT (16). There may be bias since patients rarely report this symptom unless asked specifically.

Hormones are thought to play a significant role in arrhythmia occurrence. Specifically, there is a greater incidence of SVT manifestation during the luteal phase in women with regular menses (17). Even though the presence of two pathways is similar in women and men from birth, women develop AVNRT more often. Women have a baseline shorter repolarization time. Due to hormonal changes in the estrogen level, the refractory period in female AV-node pathways becomes even shorter, and there are more triggers in terms of SVT (14). During the perimenstrual period and after menopause, the occurrence of AVNRT episodes is more frequent due to lower estrogen levels, leading to differences in refractory periods and conduction velocities (14). Catheter ablation is the standard technique for rhythm control management. In previous studies, the incidence of dual pathways did not differ between men and women (18), but women are more likely to develop AVNRT for the above-
mentioned reasons (Fig. 3).

Several studies have shown no sex or gender differences in either short- or long-term outcome of SVT catheter ablation as well as procedural complications (16, 19). Low estrogen levels influence the probability of a successful procedure in SVT patients because it is dependent on inducibility. Rosano et al. have observed that increased incidence of SVT is a direct effect of sex hormones. More specifically, the luteal phase of the menstrual cycle increased the incidence of paroxysmal SVT (17, 20). Subsequently, it could be taken into consideration that SVT ablation is planned (especially when a re-do procedure is deemed necessary) during the first days of the menstrual cycle, when the inducibility of SVT is highest.

For AF, PVI was consistently applied. In the AFL cohort, CTI ablation was performed, and in cases of SVT, slow pathway ablation was performed for AVNRT, accessory pathway ablation for AVRT, and reentry circuit interruption resp focus extinction for AT. Walters et al. have observed no sex-based difference in left atrial refractoriness and pulmonary vein physiology (21). Other studies have shown that women have more atrial fibrosis (22). Concerning technical ablation parameters specifically in AF ablation, our data, similar to Forleo et al., does not suggest any significant difference in mean fluoroscopy time, total procedure duration, or radiofrequency delivery time (23). In contrast, the MAGIC-AF trial has shown shorter ablation times for women and attributed it to the fact that women lack advanced electrical remodeling or have thinner atrial walls (24). More often than men, women reveal extra-PV triggers (e.g. vena cava, Ligament of Marshall), and there is evidence that women have a greater extent of left atrial fibrosis (1, 6, 25), potentially rendering PVI more complex. In terms of ablation success, our data shows no sex difference across all groups.

Numerous studies have shown sex- and gender-related disparities in the management of AF, AFL, and SVT (8, 23, 26). It has been shown that women with AF and AVNRT are formally diagnosed and referred later than men to their first electrophysiology consultation (8). Our analysis revealed that women in either of the groups were not referred or treated later than men. However, the noted minority of female participants in our study suggests the potential presence of a selection bias since women may not have been referred for invasive procedures and rather being treated conservatively or not being diagnosed at all. In accordance, Dagres et al. have observed that women generally were treated more conservatively (12). The reason for that may be due to physician preference for non-invasive treatments in female patients or even underdiagnosis; or female patients may be less willing to participate in studies or give retrospective consent; however, these are speculative explanations and require further investigation to determine their validity.

However, our data revealed no significant sex differences between referral latencies for ablation, which is likely due to an advanced know-how about arrhythmias and about different manifestations between sexes as well as well-functioning referral ways due to a dense network and strong connections between referring physicians and tertiary ablation centers in Switzerland (16).

Limitations

The study is limited due to its retrospective nature. Dividing the cohort into three groups depending on the type of atrial tachyarrhythmia sheds light on sex and gender differences in those specific diagnoses; however, it resulted in lower patient numbers per group. The observed underrepresentation of female patients in the AF and AFL group raises the possibility of referral bias. This discrepancy may be due to a selection bias by the referring clinicians, fewer women providing consent, or a lower rate of retrospective consent for participation in the study. Additionally, the data is not continuous, and the low number of patients mainly in the AFL and SVT group may be attributed to missing consent or consent not being provided retrospectively.

Conclusion

Our results show important sex and gender differences in the clinical presentation and management of AF, AFL, and SVTs. We demonstrated that in the case of AF, women were significantly older at the time of diagnosis and catheter ablation. Female patients revealed significantly more other symptoms than the classical palpitations in AF, AFL, and SVT, potentially leading to misdiagnosis. In the AF and AFL groups, fewer women were referred, suggesting a selection bias. However, once referred, there were no significant sex differences in referral latencies for ablation, indicating a well-functioning medical network.

Ablation success was high and equal for both sexes. The results of this study and the findings of other investigations highlight the need for awareness of sex and gender differences and a dense network between physicians to ensure equal management for both genders.

Vera Quiriconi 1, Firat Duru 2, Corinna Brunckhorst 2
1 Department of Internal Medicine, Kantonsspital Winterthur, Winterthur, Switzerland
2 Department of Cardiology, University Hospital Zurich, Zurich, Switzerland

Abbreviations
AF Atrial fibrillation
AFL Atrial flutter
ANP Atrial natriuretic peptide
AT Atrial tachycardia
AVNRT Atrioventricular nodal reentry tachycardia
AVRT Atrioventricular reentrant tachycardia
CKD Chronic kidney disease
CTI Cavotricuspid isthmus ablation
EF Ejection fraction
EPS Electrophysiologic study
HF Heart failure
PVI Pulmonary vein isolation
SVT Supraventricular tachycardia

History
Manuscript recieved: 12.12.2024
Accepted after revision: 16.04.2025