How gender impacts pathophysiology treatment of cardiac arrhythmia

Cecilia Linde

Differences between men and women mean that outcomes after cardiac events can differ between the sexes. Cecilia Linde writes in Cardiac Rhythm News about a new consensus document that looks to address these issues.

There is an increasing awareness that sex is a major determinant of the incidence, aetiology and clinical presentation of arrhythmias and that there are sex differences in access and response to arrhythmia therapies. Women traditionally were under-represented in the clinical trials but trial results have been extrapolated to the female population assuming identical results in men and women. Insufficient knowledge of physiology, epidemiology, and treatment outcome in women have led to lack of sex specific recommendations and underutilisation of existing guideline-based therapies, in women1. In our document we emphasise when evidence indicates equal management and when the evidence is insufficient which in turn calls for further studies. The women in electrophysiology of the European Heart Rhythm Association (EHRA) chaired by Andrea Sarkosy and committee member Cecilia Linde initiated this consensus document which encompasses a wider range of arrhythmias and which was elaborated by key opinion leaders in the field from Europe, United States and Canada and Japan. We provide an overview of sex differences in the pathophysiology, epidemiology and management of cardiac arrhythmias, to highlight the factors limiting the access to contemporary therapies, and to develop the pathways that may improve quality of medical care in women with cardiac arrhythmias. Each arrhythmia chapter is ended by key messages, consensus recommendations, gaps of knowledge and ideas for future clinical trials.

The best known sex differences regard the longer QT duration in women compared to men. Even though this difference primarily sets off at puberty and becomes less prominent after menopause, it leads to a higher risk in women for torsade de pointes (Tde) ventricular tachyarrhythmia in the acquired LQT syndrome and in the congenital LQT syndrome. The document stresses the increased risk for Tde during the peripartum period due to stress and sleep deprivation and that beta-blockers should not be discharged during pregnancy or in the 9–12 months peripartum period for this reason. In particularly vulnerable patients with QTc>500 ms, a wearable implantable cardiac defibrillators (ICD) could be considered in the absence of guidelines recommendations to prevent sudden cardiac death.

Regarding supraventricular tachyarrhythmia the risk of developing AV-nodal reentry tachycardia (AVNRT) is almost twice as high in women than in men which probably is linked to the shorter slow pathway refractoriness with a wider vulnerability in women. Orthodromic reentrant tachycardia (ORT) is twice as common in men than in women. This correlates to the doubled incidence of accessory pathways in men as compared to women, and consequently, ventricular fibrillation (VF) due to an antegradely conducting accessory pathway occurs less often in women than men. Quality of life is impaired in all paroxysmal supraventricular tachycardia (PSVT) patients, but women have worse quality of life and suffer more often from tachycardia related anxiety which in turn increases the risk of being misdiagnosed as panic disorders in women. There is evidence that referral or ablation is therefore delayed in women even though results are equally positive.

Regarding atrial fibrillation (AF) the age-adjusted incidence and prevalence is lower in women. Women with AF are older, have a higher prevalence of hypertension, valvular heart disease, and heart failure with a preserved ejection fraction and a lower prevalence of coronary heart disease in comparison with men. Women are less likely to undergo rhythm control therapy than men (cardioversion, pulmonary vein (PV) ablation) and more likely to undergo AV-nodal ablation. When treated with antiarrhythmic drugs women are more likely to have life-threatening adverse events and to develop bradycardia and need a pacemaker. Regarding risk for thrombo-embolic disease, female sex is a stroke risk modifier that increases the risk of AF-related stroke in the presence of other conventional stroke risk factors. Female AF patients with acute stroke have a greater stroke severity and worse long-term outcome in terms of permanent disability, compared to males with AF. Anticoagulation with warfarin may be less well controlled in female AF patients, thus affecting the effectiveness of warfarin; moreover, females with AF have a greater residual stroke risk even with well-controlled vitamin-K anticoagulants (VKAs). The efficacy and safety of non-vitamin-K oral anticoagulants (NOACs) relative to warfarin in the respective pivotal randomised control trails (RCTs) were consistent in both sexes, but females were largely underrepresented in those trials constituting about 20% of enrolled patients. Women with AF are referred for catheter ablation later than men which may reflect that AF occurs later in life in women. Women presenting with AF suffer worse symptoms than men and tend to have a less favourable result by pulmonary vein isolation (PVI). Importantly, women suffer significantly more procedural complications from AF ablation including perforation/tamponade which was recently shownin the EurObservational Research Programme (EORP) registry in Europe. There is also evidence to suggest that the substrate for AF may differ between sexes and be outside of pulmonary vein (PV) in women which needs further exploration.

Regarding sudden cardiac death (SCD) women have a lower incidence than men, even when accounting for predisposing risk factors such as coronary artery disease (CAD), myocardial infarction (MI) and heart failure (HF). Women are also less likely to have underlying coronary CAD as a risk factor for SCD and more likely than men to have a structurally normal heart, suggesting a sex difference in arrhythmic substrate.

In randomised studies of cardiac resynchronisation therapy (CRT) and implantable cardioverter defibrillators (ICD) women have constituted 20% making it difficult to draw firm conclusions. A common perception is that women benefit less from ICDs and more from CRT. Although women have a lower rate of appropriate shocks than men there is no interaction between treatment effect and sex. For CRT women with wide QRS and left bundle branch block (LBBB) have excellent results of CRT therapy and may derive a benefit at shorter QRS widths than men. Recently, height irrespective of sex has emerged as an important predictive factor of CRT benefit, with shorter persons with wide QRS having the greatest benefit. For antibrady-cardiapacing the most important knowledge gap is the risks of complications with leadless pacing which have been reported to be higher in women.

Finally, we conclude with suggestions for actions which could help in overcoming the low enrolment of women in trials. A balanced proportion of men and women corresponding to the prevalence of the studied disease should be included in RCTs. Regular statistical updates of therapy access and implementation should always be analysed by sex. Female cardiologists

should be adequately represented in associations, steering committees of RCTs, in guideline task forces and scientific documents to ensure gender equality. Female patients should be equally included as patient representatives in such committee and guidelines elaboration.

Cecilia Linde is professor of Cardiology at Theme of Heart and Vessels at the Karolinska University Hospital in Stockholm, Sweden.

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