Therapeutic implications of gender differences in supraventricular cardiac arrhythmias: lessons of life cannot be learned in a day

A steadily increasing number of catheter ablations to treat atrial arrhythmia are being performed each year. Interestingly, only a minor proportion of these patients are female, as indicated in recent reports. The reasons for this gender difference are difficult to explain and may be related to inter- and intra-gender differences in the occurrence and incidence of supraventricular tachycardias (SVTs), disparities in clinical presentation of male and female patients and gender-specific decisions for optimal therapy or differences in the efficacy of invasive therapy. In this context, it appears crucial that clinical electrophysiologists increase their awareness of potential gender differences and their implications for making the correct diagnosis and selecting the optimal treatment [1–6].

Inter- and intra-gender differences in the incidence of SVTs

Gender differences in cardiac electrophysiology were noticed as early as 1920 based on surface ECG recordings: women display shorter mean sinus node cycle length and longer QT-intervals compared with men. These differences are only marginal but may have clinical implications, such as increased incidence of torsades-de-pointes tachycardia in women. The effects of female gonadal steroid hormones on the expression and function of cardiac ion channels and the differences in autonomic tone between women and men have been discussed previously as potential mechanisms [5–7].

Gender differences play an important role in the most common atrioventricular (AV) re-entrant tachycardias (AVRTs; also known as circus-movement tachycardia). Whereas almost two-thirds (67–70%) of all patients with AV nodal re-entrant tachycardia (AVNRT) are women, a slight male predominance in symptomatic AVRT based on accessory pathways undergoing invasive procedures appears to exist (52–58%). The mechanisms are far from being understood completely, especially when acknowledging that dual AV-nodal pathology – a prerequisite for AVNRT occurrence – is equally distributed among women and men. A shorter refractory period of the slowly conducting AV-nodal pathway may facilitate the occurrence of AVNRT in women. Two periods of highest incidence of AVNRT relate to phases with increased hormonal changes in women (the third decade, when female sex hormone production peaks, and during menopausal age). Sex hormones may directly affect cardiac electrophysiology. Physiologic concentrations of estrogen act like calcium channel antagonists and prolong repolarization. Little is known of the proarrhythmic effects of progesterone, but cardiac repolarization may be regulated by progesterone via a nongenomic pathway. On the other hand, testosterone may shorten the QT-interval, contributing to gender differences [5,6,8–14].

A predominance of male patients (52–58%) with AVRT, based on accessory pathways, has been documented in many reports but this can only be substantiated for patients with symptomatic tachycardia undergoing invasive ablation procedures. In young, asymptomatic patients with pre-excitation indicating overt AV conduction via an accessory pathway, there is an equal gender distribution. In other reports on older patient groups, manifest pre-excitation was more commonly observed in men (69%) but concealed accessory pathways were evenly distributed (48% female). It appears reasonable to assume that a congenital, anatomically distinct structure, such as an accessory pathway, should be equally distributed between the sexes. The reason for the preponderance of male patients in the studied patient populations undergoing catheter ablation is unclear. Differences in AV conduction properties or electrophysiology of accessory pathway conduction between the sexes may account for differences in the frequency of pathway-mediated tachycardia and the incidence of overt pre-excitation. Demascing of pre-excitation in later childhood (after 13 years of age) and increasing prevalence of male subjects may be attributed to prolongation of AV conduction time with growth, especially in boys after puberty. Studies have demonstrated an increase in the percentage of male patients compared with women with pre-excitation from childhood to adolescence [3–6,8,9,15–17].

In addition, a skewed referral pattern known from other cardiological diseases favoring men may accentuate gender differences. Of interest, that tachycardia via accessory pathways appears to occur later in women than men, suggesting a different arrhythmogenic mechanism between the sexes [3–6,8,9,15–17].

Sudden cardiac death occurs rarely in patients with pre-excitation ECGs and is almost exclusively documented in men younger than 30 years. In addition, atrial fibrillation (AF), a common companion of accessory pathways, is more often seen in men than women. No data exist on the incidence of asymptomatic, concealed accessory pathways (not visible on ECGs, only retrograde conduction) in women and men. However, it is noted that overt pre-excitation is more common in men [5,6,12,18].

Inappropriate sinus tachycardia is a rare form of SVT, almost exclusive to middle-aged women. Permanently increased sinus node automaticity may be a pathological variant of the already enhanced sinus node cycle length documented in women. In addition, other forms of atrial tachycardia associated with enhanced automaticity of atrial myocardial structures (e.g., focal atrial tachycardia) appear to be more common in women [5,6].

By contrast, forms of SVT related to structural heart disease (e.g., atrial macro-re-entrant tachycardia and atrial flutter) can be found more frequently in men than women. A potential mechanism may be the predominance of structural heart disease in male patients.

As already indicated, AF has a higher prevalence in men (1.5-times more frequent). This may be a consequence of the higher incidence of risk factors for the occurrence of AF in men, such as myocardial infarction or heart failure. Moreover, female hormones affect potassium channel function and expression in ventricular myocytes. A longer action potential in female atrial cells may therefore be suspected, but has not yet been published. Most cases of AF occur at an age when female hormones are no longer pertinent, indicating a rather functional ion-channel mechanism preventing AF. Estrogen-mediated antifibrotic effects potentiating the action of angiotensin receptor blockage have also been documented. This may lead to less atrial fibrosis at any given age of women compared with men. In addition, estrogen receptors in animal models activate atrial natriuretic peptide in the atria as a potential protective mechanism. However, a fourth factor influencing gender-different prevalences of AF is difference in autonomic tone. A greater parasympathetic influence in women, as suggested by studies on heart rate variability, may not necessarily lead to lower AF incidence [5,6,19–22].

When implementing longer average lifetimes in women, the absolute number of women and men with AF may be equal. AF is associated with a higher risk of thrombembolic complications in women (4.6-fold risk) and cardiovascular mortality (2.5-fold risk) compared with a matched male patient population. Some studies have indicated a greater prevalence of embolic strokes in women with AF; therefore, female gender is considered an additional risk factor for thrombembolic complications during AF [23,24].

In addition to intergender differences in the incidence of SVTs, cyclic phenomena based on changes of female sex hormones during the menstrual cycle have been identified. Even though no molecular basis for pro-arrhythmic effects of progesterone has so far been identified, the incidence of SVTs is greater in phases with high concentrations of progesterone (e.g., the luteal phase of the menstrual cycle or pregnancy). The first onset of SVT during pregnancy was found to be rare, even though symptoms during SVT may be exacerbated. So far, no studies exist correlating the first onset of SVTs to female hormone levels. Practically, this means that inducing a SVT is more likely at phases of the menstrual cycle when estrogen levels are low. Therefore, timing invasive procedures in relation to the individual menstrual cycle (second half) may improve SVT inducibility and efficacy of invasive electrophysiology [25–30].

Differences in clinical presentation of male & female patients

Differences in the timing of the first tachycardia episode in relation to the underlying SVT mechanism are well known. Patients with AVRT have their symptoms at significantly younger ages than AVNRT patients. These differences in time of onset of symptomatic tachycardia are also gender specific. In AVNRT, tachycardia-related symptoms occur at a significantly younger age in women than in men. Whereas in male patients, AVRT is the most common mechanism, with palpitations occuring at an age younger than 30 years (73%); a later onset of first SVT episode implicates AVNRT as the predominant mechanism (85%). In women older than 10 years of age, independent of the time of first symptomatic SVT, AVNRT is the most common mechanism. These observations favor a more gender-specific approach and catheter selection for invasive electrophysiology procedures in SVT based on age at first symptomatic episode [3,31].

In addition, symptoms of SVT differ in women and men. Women have more frequent palpitations than men. Women with AF appear to be more symptomatic and have a higher heart rate during the arrhythmia. The menstrual cycle may affect the general perception of palpitations. In addition, within the perimenstrual period, episodes of SVT occur more frequently, indicating an important influence of hormones on arrhythmogenesis [3,32,33].

The interpretation of symptoms may be different between women and men, which might result in a delay of the appropriate diagnosis. In women, for example, the symptoms of paroxysmal SVT are more frequently mistaken for panic disorders than in men. This may result in a delay of starting an effective antiarrhythmic treatment in women [34].

Differences in invasive therapy

Many studies have documented the high efficacy and low complication rates of catheter ablation for SVTs. All studies performed on catheter ablation strategies have documented comparable efficacy, complication and recurrence rates in women and men. In the treatment of AVNRT or AVRT, no gender differences in success rates, complications or recurrences could be identified. When ablation is indicated in patients with SVT, women have a longer history of tachycardias and have taken a larger number of antiarrhythmic agents than men. The time from first onset of palpitations to invasive treatment was a mean of 5 years longer in women compared with men, reflecting the more conservative approach toward female patients, as well as the differences in clinical presentation as indicated previously. This may, in part, be explained by the (coincidental) timing of onset of symptomatic SVT during the child-bearing years of women, when invasive therapy using radiation may be postponed. However, in the overall group of two studies, 55% of all ablated patients with AVNRT and AVRT were female (618 out of 1124 patients) [3,4].

Whereas later referral of women with AVNRT or AVRT is documented, no differences in time to referral from first onset of symptoms can be found in patients with overt pre-excitation. In these patients, resting ECG documents objective abnormalities that limit the misdiagnosis of palpitations as part of panic disorders in women [4].

The most striking differences between women and men are documented for patients undergoing AF ablation procedures. Within the last few years, a large number of patients have been included in clinical studies on AF ablation. Out of a total of 3477 patients, only 939 (27%) were women. This difference becomes even more pronounced when analyzing recent studies of catheter ablation to treat long-lasting persistent AF. A total of 19% of all patients (n = 415) were female [1,2,35–37].

In AF ablation, controversial findings on gender differences and recurrence rate exist. Whereas Seow et al. reported a sixfold risk for AF recurrence in women [1], Forleo et al. presented data on a larger patient population with comparable results in women (83.1%) and men (82.7%; freedom from AF) [2]. Further studies should evaluate the relevance of female gender on the recurrence of AF after ablation procedures. When women are referred for AF ablation, they have a longer history of AF episodes, more concomitant structural heart disease and are significantly older and more symptomatic (as indicated by quality-of-life measures) than men at the time of ablation. There was a trend towards better symptomatic improvement in women after ablation compared with men, suggesting a higher benefit of the invasive procedure in women. In general, catheter ablation for AF may be a rather attractive alternative to excessive antiarrhythmic drug therapy (with higher adverse effect rates in women). Complication rates were documented to be equally low in women and men in any study on AF ablation.

Overall, there appears to be no gender difference in the need for invasive treatment of SVTs, although this option is significantly less often used in women compared with men. Women have a longer history of tachycardia before initiation of catheter ablation treatment, and undergo more attempts at ‘conservative’ medication therapy, even though catheter ablation has the same efficacy and low complication rates in women and men. Electrophysiologists should be aware of the potential under-referral of women, particularly for AF ablation procedures. To reduce complications of antiarrhythmic drug medication in women and to implement a high benefit of AF-ablation procedures, the number of performed AF ablation procedures in women should increase in the coming years.

In summary, palpitations may be an important indicator for atrial tachycardia. Especially in women, the search for tachycardia should be forced if palpitations occur, and misdiagnosis of panic disorder should be minimized. There appears to be no gender differences in the need for invasive treatment of SVTs, but there is an impressive difference in the implementation of invasive therapy between women and men. Women have a longer history of symptomatic tachycardia before initiation of catheter ablation therapy and undergo more attempts at conservative medication. Knowledge regarding gender-dependent differences in onset and clinical presentation of first symptomatic episodes may be helpful to optimize the technical approach and catheter selection for invasive electrophysiological procedures. In AF ablation, women are under-represented, although invasive treatment appears to be a safe and effective alternative to excessive antiarrhythmic medication (with imminent gender-specific risk in women). Electrophysiologists should raise more awareness regarding these gender-differences, especially because no evidence for delaying invasive catheter ablation strategies in women exists. Even if women are from Venus and men from Mars in regard to objectives of invasive electrophysiological treatment of SVTs, there appear to be no differences. Lessons learned from recent studies on gender differences in electrophysiology from the last few years need to be translated into today’s clinical practice.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.