Permanent atrial fibrillation in women: the prevalent role of risk factors and specific mechanisms determining outcome and quality of life

This editorial refers to ‘Sex-related differences in risk factors, outcome, and quality of life in patients with permanent atrial fibrillation: results from the RACE II study’ by M. Kloosterman et al., on pages 1619--1627. Female gender has long been recognized to exert a significant impact on outcome and management decision-making in atrial fibrillation (AF), as women tend to have increased rates of certain adverse events, such as ischaemic stroke and heart failure, with no significant difference in other cardiovascular events, whilst being offered rhythm control less commonly and having restricted or delayed access to interventional treatment such as ablation.1 The completeness of guidance remains suboptimal at different levels (Table 1). Atrial fibrillation in women: levels of knowledge and guidance Population studies Epidemiological surveys dedicated to women Subgroup analyses from randomized clinical trials Limited evidence from studies on sex hormones Experimental studies Population studies Epidemiological surveys dedicated to women Subgroup analyses from randomized clinical trials Limited evidence from studies on sex hormones Experimental studies EHRA, European Heart Rhythm Association; ESC, European Society of Cardiology. Atrial fibrillation in women: levels of knowledge and guidance Population studies Epidemiological surveys dedicated to women Subgroup analyses from randomized clinical trials Limited evidence from studies on sex hormones Experimental studies Population studies Epidemiological surveys dedicated to women Subgroup analyses from randomized clinical trials Limited evidence from studies on sex hormones Experimental studies EHRA, European Heart Rhythm Association; ESC, European Society of Cardiology. The significance of sex- and gender-related disparities in healthcare provision is amplified by the increasing proportion of women surviving to old or very old age due to general improvements in medical therapy. Ageing is frequently characterized by the coexistence of multiple comorbidities, often reciprocally interacting to produce a greater than additive negative impact on the health status, with the prevalence of AF raising exponentially with an old age. After age 75 years and older, nearly two-thirds of patients with AF are women. The associated conditions and risk factors in women developing AF are often different from those that have traditionally been linked to the development of AF in men. In women, AF is more likely to occur on the background of diastolic dysfunction or heart failure with preserved systolic function, advanced or poorly treated hypertension, hypothyroidism, valvular heart disease, impaired renal function, and obesity.1 Interactions between sex and the impact of individual risk factors have also been identified. Female sex-specific risk factors include the influence of sex hormones and types of hormone replacement therapy (although evidence of their role in triggering or protecting against AF has yielded conflicted results), and multi-parity which increases risk of AF by 1.5-fold.2 The processes underlying electrical and structural remodelling as well as atrial electrophysiological properties in women may differ from our understanding of the mechanisms largely based on the studies in men. The studies into the electrophysiological effects of sex hormones have identified oestrogen-dependent differences in the atrial effective refractory period and atrioventricular conduction, longer action potential duration and a more negative resting membrane potential in the pulmonary veins, and altered calcium handling, leading to increased calcium influx.3 There is known effects of sex hormones and types of hormone replacement therapy on ventricular repolarization which needs to be taken into consideration when prescribing and monitoring the antiarrhythmic drug therapy. Older women, particularly of low weight, with reduced kidney function, tend to have a low repolarization reserve and therefore, are more predisposed to proarrhythmias. On the other hand, an increased body mass index and obesity may have a significant impact on the specific mechanisms of the arrhythmia, for example due to epicardial fat and associated low-grade inflammation expressed by elevated C-reactive protein levels, fibroblast growth factor 23, and tissue growth factor β.4 A reduced parasympathetic component of the autonomic nervous system in older women may alter atrioventricular conduction and the ventricular rate response. Women with a long-standing history of AF have been found to have more extensive atrial fibrosis and are more likely to exhibit non-pulmonary vein triggers.5 Amyloidosis is another aspect of atrial remodelling in women as oestrogen induces synthesis of atrial natriuretic peptide which is one of the amyloid-related fibrillar proteins. Notwithstanding these observations, left atrial ablation is offered to women later in the course of the disease and in general five-fold less likely at all compared with their male counterparts. Both the shorter (1 year) and long-term (3 years) freedom from recurrent AF is lower and the complication rate is higher in women.6 The reason for the difference in outcome is likely to be multifactorial, including late referral for the procedure, higher morbidity burden, frailty, and possibly a greater risk of physiology-related adverse events, such as vascular complications, particularly in older women. In women, persistent and long-standing persistent AF varieties are more commonly accepted as ‘permanent’. In-depth analysis is required to establish which factors currently serve as a deterrent to offering the ablation procedure early in the course of AF to a wider female population. Although AF is the arrhythmia of older women, there has been an increase in cases of AF in the young population. In younger women, the occurrence of paroxysmal supraventricular tachycardias which may be determined by natural fluctuations in sex hormones has been known to degenerate into AF. However, the differences in the aetiology, mechanisms, and triggers of arrhythmias specific for women of different ages have never been systematically studied. Whether there are sex-determined genetics patterns that are linked to AF remains under investigation. The effect of AF per se on risk of stroke is 2- to 4.5-fold greater in women compared with men, after adjustment for other major risk factors, and AF-related strokes in women are twice as likely to result in disabling or fatal consequences. While younger women (under 65 years of age) have low risk of stroke, the sharp increase in the rates of stroke in women at older age (an arbitrary threshold is 75 years), being at 10–20% higher than in men of similar age, suggests that the role of female gender as a risk factor for stroke is closely linked to age and possibly other major risk factors serving as a modifier of stroke risk.6 Even if appropriately anticoagulated, the residual risk of ischaemic stroke is higher in women than in men by 15% on non-vitamin K antagonist oral anticoagulants (NOACs) and by 28–54% on warfarin.7 However, no difference in rates of bleeding was detected between genders, and the subgroup analyses from the NOAC trials have even suggested a 16% lower risk of major bleeding in women.8 A great number of reports from substudies of randomized clinical trials and large-scale registries have invariably revealed more frequent and severe symptoms and a highly detrimental effect of AF on quality of life in women compared with their male counterparts. In the ORBIT (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation), quality of life in women was reduced by 33% (24% adjusted for AF-related symptoms) compared with men.9 Women with AF reported consistently lower AFEQT domain scores including daily activities and treatment concern, higher anxiety and depression levels and scored lower on functional status. Female gender had a significant impact on patient-reported outcome measures.10 A poorly explained remains an observation that women continue to endure more symptoms despite rhythm control with either antiarrhythmic drugs or ablation. In this issue of Europace, Kloosterman et al.11 present their post hoc analysis on the sex and gender-related differences in 403 men and 211 women with permanent AF enrolled in the RACE (Rate Control Efficacy) II trial which was a prospective randomized trial that tested the effectiveness of ‘strict’ and ‘lenient’ rate control. During 3-year follow-up, risk factors, cardiovascular events (cardiovascular death, hospitalization for heart failure, stroke and systemic embolism, bleeding, and life-threatening arrhythmic events), and quality of life were compared in men and women. Women exhibited a 1.5-fold higher likelihood of yearly cardiovascular adverse events. In the propensity-score matched cohort to correct for significant differences in raw baseline characteristics, outcome rates were similar between sexes. Women with permanent AF were exposed to a greater number of risk factors (3.7 ± 1.3 vs. 2.9 ± 1.4; P < 0.001) compared with men, which had a negative effect on quality of life. The authors did not observe any difference in stroke rates, probably due to the high adherence to the guidelines on stroke prevention (99%), albeit there was a trend towards more extracranial bleeding in women, likely associated with prevalent bleeding risk factors. Left atrial volume index and duration of AF were predictive of cardiovascular events in women, but not in men. This is post hoc analysis; the study was not designed to assess the sex-and gender-related differences and establish causality of the findings. Nevertheless, the authors have identified a variety of issues concerning permanent (and possibly long-standing) AF in men and women that clearly are different and necessitate both detailed studies and reconsideration of the management and treatment approaches. The occurrence of AF in women generally at older age than in men means that by the time of AF diagnosis, women would have accumulated a higher comorbidity and risk factor burden which may drive their symptoms and the decrease in quality of life rather than permanent AF itself which may be to the contrary to some previous reports. The larger proportion of women present with atrial remodelling, and as demonstrated in the RACE II, left atrial volume index and left atrial enlargement, likely to the longer AF duration and comorbidities, was associated with outcome. Despite a worse symptomatic status and often higher disease burden, which may, in part, be attributed to faster and less effectively controlled ventricular rates due to an increased sympathetic tone and a higher incidence of drug adverse effects or inability to tolerate higher doses, rate control is used as a primary management strategy in the majority of female patients, not in the least because of their presentation at an older age and with more atypical symptoms compared with men. Likewise, with the ablation procedures, it has been suggested that rhythm control strategies involving antiarrhythmic drugs have been associated with higher rates of adverse cardiovascular outcomes compared with rate control, but the studies were not powered to detect such differences and the likelihood of a random error remains a possibility. Multi-factorial changes, such as altered drug efficacy and safety due to age-related impaired drug metabolism, kidney and liver incompetence, low weight, complex drug interaction due to polypharmacy may lead to increased risk of adverse events. Thus, in one of the first registry-based insights into the gender differences with regard to access to therapies, reported in the EuroHeart Survey in 2007, women presenting with moderate symptoms identical to that of men, were offered pharmacological rhythm control in 45% compared with 59% in men.12 Unfortunately, similar trends have been observed in modern era registries.9,13 In the RACE II post hoc analysis, women also used rate control drugs more frequently, especially digitalis preparations. The inequality in access to interventional therapies has been addressed in the 2020 European Society of Cardiology (ESC) Guideline document on the management of AF which has issued the recommendation that women with symptomatic paroxysmal or persistent AF should be offered timely access to rhythm control therapies, including AF catheter ablation, when appropriate for medical reasons (class of recommendation IIA, level of evidence B).14 Women have been often under-represented in the randomized clinical trials of pharmacological therapies for AF and its aspects (e.g. the participation rates of women in earlier trial of warfarin were 20% which increased to 40% in the modern era NOAC trials), but particularly in the studies of interventional and device therapies (ranging from about one quarter to one third of all the participants). There are numerous societal reasons limiting the women’s access to adequate care. Interventions should be implemented at different levels in order to improve AF care in women (Box 1). At the medical societies level, structured research in sex differences in women of child-bearing potential and peri-menopausal, development relevant sex-specific atrial fibrillation models. At the regulator and industry level, mandatory inclusion of older frail women in randomized clinical trials and sponsored registries. At the epidemiological and nationwide registries level, collection of age- and sex-disaggregated data. At the society and government level, establishing national and global programmes policies addressing the socio-economical factors. Gender-responsive guidelines based on adequate evidence base. At the patient level, patient associations and lobbies. Conflict of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of Europace or of the European Society of Cardiology.