Gender issues in arrhythmias: from atrial fibrillation to CRT and arrhythmogenic ventricular cardiomyopathy

Gender is increasingly recognized as an important modulator of disease presentation and outcome1 as well as for the perception of symptoms and the disease process by the treating physician. Sex hormones importantly affect body function, the risk of developing cardiac disease and natural outcome, as well as that of interventions. For instance, in atrial fibrillation, women have a higher risk of stroke. Indeed, out of a maximum of 9 points on the CHA2DS2-VASc score,2,3 female gender is 1 point. Furthermore, due to their smaller body size and hence distribution volume, among other factors, drugs may act differently in women,4 and with anticoagulants their bleeding risk is also increased. The risk of bleeding is particularly high in patients with coronary artery disease and atrial fibrillation undergoing stenting.5–7 This Focus Issue on gender issues in cardiac patients therefore begins with a Current Opinion on the ‘Management of antithrombotic therapy after bleeding in patients with coronary artery disease and/or atrial fibrillation:expertconsensus paper of the European Society of Cardiology Working Group on Thrombosis’, by Sigrun Halvorsen and colleagues from the ESC Working Group on Thrombosis.8 The authors note that although several recommendations have been published dealing with the acute management of bleeding in patients treated with antithrombotic drugs,9,10 there is an unmet need for guidance on how to manage antithrombotic therapy after bleeding has occurred, particularly now that with idarucizumab, a blocking antibody against dabigatran has become available11 and antagonists for other NOACs (non-vitamin K antagonist oral anticoagulants) are in development. Patients with recent bleeding have been excluded from most randomized trials of antithrombotic therapy, and rigorous evidence to inform decisions is scarce. While waiting for observational and randomized data to accrue, this consensus paper offers a European perspective on managing antithrombotic therapy after bleeding in patients with coronary artery disease and/or atrial fibrillation, including which drugs to stop, which to restart, and when. Over two decades after the introduction of cardiac resynchronization therapy into clinical practice, ∼30% of candidates continue to fail to respond to this highly effective treatment of drug-refractory heart failure.12 In a clinical review article entitled ‘Avoiding non-responders to cardiac resynchronization therapy:a practical guide’, Jean-Claude Daubert and colleagues from CHRU/Centre Cardio-Pneumologique in Rennes, France note that since the causes of this non-response are multifactorial, it will require multidisciplinary efforts to overcome the problem.13 Progress has, thus far, been slowed by several factors, ranging from a lack of consensus regarding the definition of non-response, to technological limitations to the delivery of therapy. The authors critically review the various endpoints that have been used in landmark clinical trials of cardiac resynchronization therapy, and the variability in response rates that has been observed because of these different investigational designs, different sample populations enrolled, and different means of delivery of therapy, including new means of multisite and left ventricular endocardial simulation. Precise recommendations are offered regarding the optimal device programming, use of telemonitoring, and optimization of management of heart failure. Potentially reversible causes of non-response to cardiac resynchronization therapy are reviewed, with emphasis on loss of biventricular stimulation due to competing arrhythmias. The prevention of non-response to cardiac resynchronization therapy is essential to improve the overall performance of this treatment and lower its risk/benefit ratio. These objectives require collaborative efforts by the heart failure team, the electrophysiologists, and the cardiac imaging experts. Secular trend in the percentage of CRT devices implanted with an ICD in men vs. women between 2006 and 2012. (A) Panel A shows the percentage of CRT-D implant for the total CRT cohort over the study period, stratified by sex. The p-value shown is for the comparison of time trend in women vs. men. (B) Panel B shows % CRT-D implant in men and women, further stratified by likelihood left ventricular reverse remodelling following CRT as defined by the presence of the following predictors: non-ischaemic cardiomyopathy, left bundle branch block, absence of atrial fibrillation, absence of chronic kidney disease (CRT response score, rage: 0–4). Sex differences are shown within strata of CRT response score (≥ vs. < 3). Within each subgroup of CRT response score (≥ vs. < 3), the p-value shown is for the comparison of time trend in women vs. men. Of recipients undergoing ICD-only during the same time period, Panels C and D show the % women in the total ICD-only cohort (C) and stratified by CRT response score (D) (from Chatterjee NA, Borgquist R, Chang Y, Lewey J, Jackson VA, Singh JP, Metlay JP, Lindvall C. Increasing sex differences in the use of cardiac resynchronization therapy with or without implantable cardioverter-defibrillator. See Pages 1485–1494). In patients with non-valvular atrial fibrillation, it is uncertain whether the higher risk of ischaemic stroke in women reported in some,16 but not all, studies17,18 is due to residual confounding or a true phenomenon. In their manuscript ‘Revisiting sex differences in outcomes in non-valvular atrial fibrillation:apopulation-based cohort study’, Christel Renoux and colleagues from the McGill University in Montreal, Canada assessed this association using standard time-fixed and more accurate time-dependent adjustment for confounders.19 Using the computerized databases of the Régie de l’Assurance Maladie du Québec, the authors identified a cohort of 147 622 patients with non-valvular atrial fibrillation during 2000–2009. During a mean follow-up of 2.9 years, 11 326 patients had a stroke, giving an incidence rate of 2.6 per 100 per year. Using time-fixed adjustment for confounders, women had a moderately higher risk of ischaemic stroke than men, with a hazard ratio of 1.16. However, matching age and using time-dependent adjustment for confounders, women were not at higher risk of stroke than men. Indeed, surprisingly, mortality and bleeding rates were lower in women compared with men. Thus, in non-valvular atrial fibrillation, contrary to the currently used CHA2DS2-VASs score, women do not appear to be at higher risk of thrombo-embolic events compared with men. The small increased risk reported in previous studies may be related to residual confounding, from insufficient adjustment for difference in age in both genders. These provocative findings are discussed in an Editorial by A. John Camm from St George’s University of London.20 Arrhythmogenic ventricular cardiomyopathy is characterized by a preferential, but not exclusive, fibrofatty infiltration of the right ventricular myocardium leading to arrhythmias and potentially sudden cardiac death. In the European Cardiomyopathy Pilot Registry of the EURObservational Research Programme of the European Society of Cardiology, hypertrophic cardiomyopathy was the most common cardiomyopathy, followed by dilated cardiomyopathy and arrhythmogenic ventricular cardiomyopathy, with restrictive cardiomyopathy being the rarest form.21 A lot of progress has been made in family screening,22 diagnosis,23 and management of arrhythmogenic ventricular cardiomyopathy.24 The most important risk factors to develop the disease in genetically prone subjects are male gender and competitive sports.25 From the beginning, it was noted that male patients develop the disease earlier and present with more severe phenotypes as compared with females. In their research article entitled ‘Sex hormones affect the outcome in arrhythmogenic right ventricular cardiomyopathy/dysplasia:froma stemcell-derived cardiomyocyte-based model to clinical biomarkers of disease outcome’, Firat Duru and colleagues from the University of Zurich in Switzerland, with myself as co-author, hypothesized that serum levels of sex hormones may contribute to major arrhythmic cardiovascular events in such patients.26 The serum levels of five sex hormones, and their binding globulins, high sensitivity troponin T, pro brain natriuretic peptide, cholesterol, triglycerides, insulin, and glucose were measured in 54 patients of whom 72% were male. About half of the patients experienced major arrhythmic events. Interestingly, total and free testosterone levels were significantly increased in males with major arrhythmias as compared with those with a favourable outcome, whereas oestradiol was significantly lower in females with arrhythmic events as compared with those no major arrhythmias. Increased testosterone levels remained independently associated with major arrhythmic events in males even after adjusting for age, body mass index, Task Force criteria, ventricular function, and desmosomal mutation status. Furthermore, in induced pluripotent stem cell-derived cardiomyocytes obtained from patients with arrhythmogenic ventricular cardiomyopathy, testosterone worsened and oestradiol improved cellular events associated with the disease process such as cardiomyocyte apoptosis and lipogenesis. Thus, elevated serum testosterone levels in males and decreased oestradiol levels in females are independently associated with major arrhythmic events in arrhythmogenic ventricular cardiomyopathy and cellular mechanisms of the disease process. Therefore, determining the levels of sex hormones may be useful for risk stratification and may open a new window for preventive interventions. Pregnancy is a gender-specific condition that is associated with marked changes in the cardiovascular system that may be particularly relevant in women with valvular27 or congenital heart disease.28 Often anticoagulation is required under these conditions, a prophylactic intervention that may interfere with the growth of the foetus. In their meta-analysis ‘Anticoagulation for pregnant women with mechanical heart valves:asystematic review and meta-analysis’ Rohan D’Souza and colleagues from the Mount Sinai Hospital in Toronto, Canada investigated maternal and foetal outcomes in women with mechanical heart valves treated with vitamin K antagonists, in those with first-trimester heparin followed by vitamin K antagonists as a sequential treatment, or those treated with low molecular weight heparin or unfractionated heparin during pregnancy.29 With vitamin K antagonists, sequential treatment, and low molecular weight heparin, maternal mortality occurred in 0.9, 2.0, and 2.9%, thrombo-embolic complications in 2.7, 5.8, and 8.7%, livebirths in 64.5, 79.9, and 92.0%, and anticoagulant-related embryopathy or foetopathy in 2.0, 1.4, and 0%, respectively. With unfractionated heparin use throughout pregnancy, 11.2% suffered thrombo-embolic complications. Foetal loss and adverse events occurred with first-trimester warfarin doses ≤5 mg/day, although there were more livebirths (i.e. 83.6% vs. 43.9%) and fewer foetal anomalies (i.e. 2.3% vs. 12.4%) with lower doses than with warfarin >5 mg/day. D’Souza et al. conclude that vitamin K antagonists are associated with the fewest maternal complications, but also with the fewest livebirths. Thus, sequential treatment does not eliminate anticoagulant-related foetal or neonatal adverse events. Low molecular weight heparin is associated with the highest number of livebirths. The safety of unfractionated heparin throughout pregnancy and first-trimester warfarin ≤5 mg/day therefore remains unconfirmed. The editors hope that this issue of the European Heart Journal will be of interest to its readers.