Sex differences in atrial electrophysiology: From a Blind Spot towards an Eye-Opener

The worldwide prevalence of the most common cardiac arrhythmia, atrial fibrillation (AF), is continuously rising, which is caused by the increased life expectancy, lifestyle changes and improved clinical care of other (cardiovascular) co-morbidities such as hypertension, valvular heart disease, COPD and diabetes mellitus. (1) The pathophysiology of AF is complex and influenced by a complex interplay between sex, age, genetics, modifiable- and non-modifiable risk factors. (1) Though both males and females are affected, multiple studies have reported sex differences in epidemiology, pathophysiology, presentation, prognosis and even response to AF treatment. (1-5) For example, females have more and severer symptoms, experience higher ventricular rates during AF episodes and have higher AF recurrence rates after pulmonary vein isolation (PVI). (2,5) Consequently, the quality of life of female AF patients is more affected than male AF patients. (2-4) Insights into sex differences in initiation and perpetuation of AF development are, however, scarce.
In this chapter, a short overview is provided on the current knowledge of sex differences in 1) AF epidemiology, 2) AF pathophysiology and 3) post-operative AF. This chapter is concluded with the aims and the outline of this thesis.
Sex differences in AF epidemiology
The incidence of AF is higher in males compared to females in all age groups. (4,6) Moreover, males have a higher lifetime risk for developing AF episodes compared to females (23.8% versus 22.2%). (4) In contrast, AF-associated mortality is higher in females, who are also generally older when diagnosed with AF. (4) AF in females is more often associated with valvular heart disease whereas AF in males is frequently related to coronary artery disease. (4, 7,8)

Atrial fibrillation pathophysiology
The pathophysiology of AF has a high complexity and is yet not fully understood. In the past decades, multiple mechanisms underlying AF have been proposed, including single or multiple foci, large mother waves giving rise to multiple daughter waves, fixed and shifting rotors, unstable reentrant circuits, multiple independent wandering wavelets, a combination of foci and multiple wavelets and endo- epicardial asynchrony, giving rise to transmural propagation of fibrillation waves. (1,9-11) It is most likely that there is not one mechanism underlying AF, but that mechanisms vary between patients also change over time.
Development of AF requires both triggers and arrhythmogenic substrates. When AF progresses from paroxysmal AF to persistent types of AF, it changes from a trigger-driven to a more substrate mediated arrhythmia. (11)
Triggers of AF consist of ectopic foci, most commonly originating from the pulmonary veins, as demonstrated by Haissaguerre et al. in 1998. (9) However, foci may also originate from other atrial sites such as the superior and inferior caval veins, the coronary sinus, crista terminalis, Eustachian ridge and the ligament of Marshall. (12)
Females more often have non-pulmonary vein foci; these foci are frequently located at the right atrium; coronary sinus and intra-atrial septum. (13) The presence of non-pulmonary vein foci may offer a partial explanation for the higher AF recurrence rates in female patients after undergoing a catheter-based PVI. (14-18) Another possible origin of ectopic foci inducing AF are anatomical structures such as left atrial diverticula (LAD) and left atrial accessory appendages (LAAA) that are commonly detected on computed tomography images obtained from patients with AF referred for a PVI. (19) Prior studies reporting on LAD do not always provide clear definitions resulting in confusion with other anatomical structures such as LAAA and atrial aneurysms. In addition, their role in AF development is still not well understood.
Atrial fibrillation pathophysiology: substrate
In a recent study, electro-anatomical activation and voltage maps were obtained from male and female patients prior to PVI. (20) Left atrial electrical remodeling - consisting of a decrease in mean left atrial bipolar potential voltages, lower intra-atrial conduction velocities and a larger proportion of fractionated potentials- was more pronounced in female patients. (20) The observation of more extensive atrial remodeling in female patients was also supported by the findings of Chochet et al. (21) Gadolinium enhanced cardiac magnetic resonance left atrial images demonstrated that the LA contained significantly more fibrosis (collagen volume fraction) in female patients with AF compared to male AF patients.
Examination of sex differences in biological markers in patients with paroxysmal or persistent AF who underwent radiofrequency PVI revealed that female patients had higher adipokine levels (markers associated with oxidative stress and inflammation) compared to males, although they had a similar amount of visceral fat. (22) Adipokines secreted by epicardial fat cause tissue inflammation which in turn contributes to fibrotic remodeling of the atria. Deposition of fibrotic tissue enhances tissue anisotropy and may aggravate slowing of conduction. These areas of slow conduction may in turn facilitate initiation and perpetuation of AF episodes. (23)
Post-operative AF recurrences
As mentioned above, female patients experience more AF recurrences after catheter based PVI compared to male patients. (14-18) Prior studies reporting on outcomes of ablative therapy mainly focused on the influence of sex on only early or late AF recurrence rates. (14-18) However, data on sex differences in outcome of video assisted thoracoscopic PVI (VATS PVI) surgery is not available. In addition, it is unclear whether characteristics of recurrent AF episodes are different in male and female patients.
The most commonly encountered complication after open chest surgery is the occurrence of post-operative AF (POAF). (24-26) Depending on the type of cardiac surgery performed, POAF incidences range from 20% and even up to 80%. (24-26) Although POAF is considered to be a transient event after cardiac surgery, it is associated with a diversity of adverse events including an increased stroke risk, heart failure, increased mortality, prolonged hospital admission as well as hospital re-admission and even the occurrence of AF episodes during long-term follow up. (24-26) Multiple pre-, intra- and post-operative factors contribute to AF development including age, obesity and aorta-cross clamp time, but also myocardial damage and inflammatory responses due to surgery itself. (25) Nonetheless, studies that reported on sex differences in POAF show conflicting results. (26-28)
Aims of this thesis
The observations on sex differences in relation to AF as discussed above indicate that the atrial arrhythmogenic substrate may be more complex in female patients. When female patients experience AF episodes, the AF burden may be higher in females compared to males.
Although males and females differ in AF susceptibility, the exact mechanism responsible for the reported sex-related differences in AF initiation and maintenance are insufficiently understood. Moreover, there is at present even no data available on sex differences in electrophysiological properties between males and females during sinus rhythm. Investigating sex differences in atrial electrophysiology would therefore be the first step towards understanding sex differences in AF pathophysiology.