Academic Editors: Bernard Belhassen and Petr Ostadal
Evidence on sex differences in the pathophysiology and interventional treatment of ventricular arrhythmia in ischemic (ICM) or non-ischemic cardiomyopathies (NICM) is limited. However, women have different etiologies and types of structural heart disease due to sex differences in genetics, proteomics and sex hormones. These differences may influence ventricular electrophysiological parameters and may require different treatment strategies. Considering that women were consistently under-represented in all randomized-controlled trials on VT ablation, the applicability of the study results to female patients is not known. In this article, we review the current knowledge and gaps in evidence about sex differences in the epidemiology, pathophysiology and catheter ablation in patients with ventricular arrhythmias.
Sex differences in ventricular arrhythmia (VA) are well established for inherited channelopathies including the Long-QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. Considerable less is known about sex differences in the pathophysiology and interventional treatment of (VA) in ischemic (ICM) or non-ischemic cardiomyopathies (NICM). In this article, we review the current knowledge and gaps in evidence about sex differences in the epidemiology, pathophysiology and catheter ablation in these patients.
Epidemiological sex differences in ICM and NICM are well recognized. In the United States, men have a higher prevalence of ICM compared to women with a ratio of about 1.34 to 1.00 [1, 2]. Women generally have a lower extent of obstructive coronary artery disease, despite a higher burden of comorbidities and a higher age at presentation [3, 4, 5, 6]. In women, microvascular coronary dysfunction is a more frequent cause of ICM, compared to a higher prevalence of epicardial obstructive coronary artery disease in men [7, 8, 9]. In NICM, sex differences depend strongly on the underlying etiology . Overall, men also prevail with a ratio of 1.27 to 1.00 over women . More specifically, dilated cardiomyopathy has a male to female ratio of 1.44–3.41 to 1.00 [11, 12, 13, 14], and hypertrophic cardiomyopathy of 1.70 to 1.00 .
Fewer studies have investigated sex differences in patients with VA and structural heart disease that undergo catheter ablation. Baldinger et al.  analyzed 948 consecutive patients undergoing 1314 catheter ablations for sustained monomorphic ventricular tachycardia (VT) over a span of 10 years. Of those 948 patients, 486 patients had ICM with only 9% of them being female and 301 patients had NICM with 22% of them being female. Compared to men, women were younger at the time of ablation both with ICM (63 vs 68 years, p = 0.05) and NICM (53 vs 59 years, p = 0.026). Despite their younger age, they had similar disease severity and outcomes compared to men . Nakagawa et al.  analyzed patients undergoing catheter ablation according to their VT location. They found that more women than men presented with right ventricular outflow tract (RVOT) – VT, with a male to female ratio of 0.49 to 1.00 (153 vs 311 patients). In contrast, more male than female patients presented with left ventricular–VT with a male to female ratio of 3.37 to 1.00 (175 vs 52 patients). The authors found a more equal sex distribution for left ventricular outflow tract (LVOT)-VT with a ratio of 1.38 to 1.00 (33 vs 24 patients) . Tanaka et al.  investigated 625 consecutive patients with symptomatic, drug resistant idiopathic VA undergoing catheter ablation, of whom 310 (49.6%) were women. While women and men were distributed equally overall, they again showed that RVOT-VA were more frequent in women compared to men with a male to female ratio of 0.68 to 1.00. LVOT-VA were more frequent in men with a male to female ratio of 1.37 to 1.00. Overall, catheter ablation outcomes were similar and sex was not a predictor for ablation success in multivariate analyses .
The female underrepresentation in catheter ablation for VT in ICM might be due to different referral rates between sexes for invasive cardiac procedures . However, women may also have a lower incidence of monomorphic VT in the setting of ICM, though prior data on this are scarce and would not be expected to fully explain the large difference in the number of catheter ablations performed between male and female patients.
The investigation of pathophysiological sex differences on a genetic or
cellular level in ICM and NICM in humans is mainly limited by the number of
available tissue samples. In healthy individuals, differences in gene expression
are usually due to X- and Y-linked genes. Mechanisms that regulate sexual
dimorphisms seem to be tissue-specific in the heart . For example, genes
encoding ion-channels and transporter subunits show reduced expressions of
several potassium channel subunits, connexin43 and phospholamban in non-diseased
female heart explants and an isoform switch in Na
In a study of 70 men and 32 women with dilated cardiomyopathy and end-stage
Sex hormones are thought to account for a large portion of sex differences in arrhythmia incidence and outcome. While the presence of estradiol receptors in cardiac tissue is known since over 40 years , their specific effects-especially in cardiomyopathies-are not yet fully understood.
Several experimental animal studies investigated the effects of estradiol on ventricular electrophysiology. Hara et al.  studied the effects of gonadal steroids on the cardiac action potential in rabbits. Estradiol-treated study animals had a significantly longer action potential duration and significantly more early afterdepolarizations, both of which are known to increase the likelihood of VA . In dogs, cisapride in the presence of 17 beta-estradiol led to a greater increase of ventricular repolarization, a higher incidence of early afterdepolarizations and a subsequently higher rate of Torsades de Pointes . In guinea pigs, James et al.  showed varying L-type Calcium currents at different time points of the estrus cycle. These findings might have translational implications to humans, as guinea pigs have a conventional estrus cycle similar to humans. These experimental findings support the role of estradiol in different VA risks between men and women and suggest a dynamic VA risk at different time points in the menstrual cycle.
Data on the influence of sex hormones on VA in humans consists mainly of
observational cohort studies. In a cohort of 20 women with premature ventricular
complexes (PVCs) and a control group of 18 healthy women, the number of PVCs in
the menstruation period was 210 beats/day and decreased to 86 beats/day in the
ovulation period (p
Studies to investigate scar patterns, electrograms and VT circuits usually
underrepresent women by a ratio of 1:4 to men. Thus, sex specific analyses are
often precluded [43, 44]. Moreover, only few studies investigated
electrophysiological sex differences in patients with ICM or NICM. In an
observational cohort study, Buxton et al.  reported a lower rate of
inducible VT in female ICM patients compared to male. However, in their overall
cohort of 1721 patients, only 14 (0.8%) were female and in the 549 inducible
patients, only 9 (1.6%) were female . Kuo et al.  analyzed 160
patients with NICM of whom 26 (16.3%) were female. The investigators compared
endocardial uni- and bipolar and epicardial bipolar voltages, but did not find
any significant differences. Similarly, they did not find sex differences in scar
extent, distribution or transmurality based on cardiac MRI studies . However,
their analyses might have been limited by the small group of female patients.
Yang et al.  analyzed 93 patients with idiopathic RVOT-VT of whom 63
(67.7%) were female: women had a lower RV voltage (3.0
Based on the paucity of data for sex differences in electrophysiological properties in structural heart disease, it is difficult to draw conclusions that can be generalized to larger patient populations. Regarding the definition of low-voltage zones, more research is needed to assess if current voltage cut-offs are similarly applicable to men and women, considering that women accounted only for 8–25% in the original studies defining the cut-offs [50, 51, 52].
Women were underrepresented in most of the major randomized controlled trials that investigated the outcome of catheter ablation for VA and subsequently influenced guideline recommendations (Fig. 1). The SMASH-VT (Substrate Mapping and Ablation in Sinus Rhythm to Halt Ventricular Tachycardia) trial enrolled 128 patients with ICM and investigated whether prophylactic radiofrequency catheter ablation of ventricular substrate would reduce the incidence of ICD therapy. Of those, only 17 (13.3%) were women . The VTACH (Ventricular Tachycardia Ablation in Coronary Heart Disease) trial enrolled in total 107 patients with stable VT in the setting of ICM, of whom only 7 (6.5%) were female, and tested if catheter ablation for VT before implantation of an ICD conveys a potential benefit . Of the 111 ICM patients enrolled in the SMS (Substrate Modification Study) trial investigating the effect of prophylactic catheter ablation of arrhythmogenic ventricular substrate on VA recurrence, 18 (16.2%) were female . In the VANISH (Ventricular Tachycardia Ablation versus Escalation of Antiarrhythmic Drugs) trial, that compared VT catheter ablation versus escalated antiarrhythmic drugs in ICM patients, 18 (6.9%) out of 259 patients were women . Similarly, the prematurely terminated BERLIN-VT (Preventive Ablation of Ventricular Tachycardia in Patients With Myocardial Infarction) study enrolled only 24 (14.7%) female patients out of 163 patients with ICM . These small numbers of enrolled women preclude any meaningful subgroup analyses to investigate the efficacy and safety in female patients with ischemic cardiomyopathy. Moreover, they question the broad applicability of the trial findings to female patients. The recently presented, but not yet published, PAUSE-SCD (Pan-Asia United States PrEvention of Sudden Cardiac Death Catheter Ablation) trial (NCT02848781) investigated catheter ablation versus conventional medical therapy in patients with either ICM or NICM, monomorphic VT and an indication for ICD. The trial randomized 121 patients, of whom 23 (19.0%) were female, and met its primary composite endpoint of VT recurrence, cardiovascular rehospitalization and death. Importantly the investigators performed subgroup analyses and showed a significant interaction for sex, with less benefit in female compared to male patients.
Sex distribution in randomized-controlled trial investigating catheter ablation for ventricular tachycardia.
Based on the female under-representation in randomized VT ablation trials, their results may not be fully applicable to women [58, 59]. As shown in the subgroup analysis of the PAUSE-SCD trial, women may confer no or less benefit from ablation compared to men, though these results should not be over-interpreted as they are based on small sample sizes.
VT ablation approaches based on activation and entrainment mapping should be equally effective in female and male patients as each individual VT is delineated. This may, however, not hold true for purely substrate based ablation approaches during sinus rhythm due to sex differences in scar and isthmus distribution. We therefore reviewed sex distribution in the pivotal studies that tested these ablation strategies. Unfortunately, similarly to the randomized controlled trials on VT ablation and cardiovascular outcomes, women were markedly underrepresented in studies on substrate based ablation strategies. A linear ablation approach within the scar, guided by pacemapping, was investigated in a ICM and NICM population with 1 out of 4 patients being female . Similarly, scar dechanneling in NICM was tested in a population including 18% women . Endo-epicardial scar homogenization approaches in ICM included 19% women in the initial study . Scar core isolation was tested in the initial study in ICM and NICM with only 5% being female . The elimination of local abnormal ventricular activities in ICM and NICM was tested in a population with a female proportion of 10% . Studies investigating the ablation of late potentials included 8, 6 and 13% of female patients [65, 66, 67]. Ablation based on isochronal late activation maps ICM and NICM was tested in a population with 15% female patients .
Similarly to the randomized trials mentioned above, these small proportions of female participants do not allow sex specific analyses of these ablation approaches and can not ascertain similar outcomes inbetween sexes.
As women were generally underrepresented in the above mentioned trials and studies, registry data may be more informative on outcomes and complications of VT ablation in females compared to males.
In a report from the International Ventricular Tachycardia Ablation Center
Collaborative Group Study, women had significantly higher rates of VT recurrence
in the year following ablation than men (30.5% vs 25.3%) despite being younger,
having a higher left ventricular ejection fraction and fewer medical
comorbidities (Fig. 2, Ref. ). Again only 262 (12.7%) out of 2062 patients with
structural cardiomyopathy were women . Hosseini et al.  analyzed
Ventricular tachycardia–free and transplant-free survivals by sex. (A) Women had worse 1-year ventricular tachycardia–free survival than men following ablation (log-rank p = 0.03). (B) Women with ischemic cardiomyopathy had worse 1-year ventricular tachycardia–free survival than men with ischemic cardiomyopathy following ablation (log-rank p = 0.03). (C) Women and men with nonischemic cardiomyopathy had similar 1-year ventricular tachycardia–free survival following ablation (log-rank p = 0.55). (D) Women and men had similar long-term survival free of death and heart transplant (log-rank p = 0.24). Adapted from Frankel et al.  with permission.
Comparison of women and men undergoing catheter ablation for
sustained monomorphic ventricular tachycardia in different subgroups. Estimated
recurrence free survival at 1 year was 87
Taken together, some but not all observational studies point to an inferior outcome and higher complication rate in female patients compared to males. These differences might be related to the investigated study populations.
Women have different etiology and distribution of structural heart disease compared to men. These differences span from genetics, proteomics to sex hormones and may influence ventricular electrophysiological parameters. As women were considerably under-represented in all randomized-controlled trials on VT ablation, the applicability of the study results to female patients is not known. Future studies on catheter ablation need to increase female recruitment in order to address this lack of knowledge that is important to half of the planet’s population.
PK, GC, TT, TK and MH—structured and organized the review; PK, TT and TK—revised the literature; PK—synthesized the study data; PK and MH—wrote the original draft of this paper; PK, ES and CA—updated the review by analyzing prior data; GC, TT, TK, ES, CA, JD, TP, ND, FS, PJ and MH—revised and edited the original draft of this paper; MH—supervised the entire work as senior author. All authors have read and approved the submitted version.
We thank Patrick Badertscher for his assistance in editing the manuscript.
PK is supported by the University of Basel, the Mach-Gaensslen foundation and the Bangerter-Rhyner foundation (Bangerther Rhyner: 8472/HEG-DSV; University of Basel: 3MS1039; Mach Gaensslen: no number).
The authors declare no conflict of interest.