Arrhythmias in Women

Abstract

There are important gender differences in cardiac electrophysiology that affect the epidemiology, presentation, and prognosis of various arrhythmias. Women have been noted to have higher resting heart rates compared to men. They also have a longer QT interval, which puts them at an increased risk for drug‐induced torsades de pointes. Women with atrial fibrillation are at a higher risk of stroke, and they are less likely to receive anticoagulation and ablation procedures compared to men. Women have a lower risk of sudden cardiac death and are less likely to have known coronary artery disease at the time of an event compared to men. Both men and women have been shown to derive an equal survival benefit from implantable cardioverter defibrillators and cardiac resynchronization therapy, although these devices are significantly underutilized in women. Women also appear to have a better response to cardiac resynchronization therapy in terms of reduced numbers of hospitalizations and more robust reverse ventricular remodeling. Further studies are required to elucidate the underlying pathophysiology of these sex differences in cardiac arrhythmias. © 2012 Wiley Periodicals, Inc.

The authors have no funding, financial relationships, or conflicts of interest to disclose.

Introduction

Sex differences in cardiac electrophysiology affect the epidemiology, presentation, and prognosis of various arrhythmias. These sex differences can have important clinical and therapeutic implications. Although the exact reason for these differences is not known, the potential mechanisms include differences in cardiac size, structure, and the different ways in which hormones, drugs, and electrolytes affect cardiac ion channels in men and women. The purpose of this review is to provide a synopsis of the important gender differences with respect to arrhythmias and to summarize updates from recent studies.

Heart Rate and Electrocardiography

Bazett observed that women have a higher resting heart rate than men.1 In a study of resting heart rate before and after autonomic blockade (administration of propranolol and atropine) as well as after maximal bicycle exercise, women had significantly shorter sinus cycle lengths than men.2 These findings may be explained in part by differences in the intrinsic properties of the sinus node, although covariant analysis revealed maximum exercise capacity to be the only significant predictor of sinus cycle length. It has also been demonstrated that women have lower QRS voltages than men (even after adjustment for differences in left ventricular mass and body weight), as a result of which the use of identical non‐gender specific electrocardiographic (ECG) criteria for left ventricular hypertrophy (LVH) can result in lower sensitivity for detection of LVH in women.3 There are also important gender differences in the QT interval discussed in detail later.

Supraventricular Tachycardia

There are gender differences in the prevalence and presentation of various supraventricular tachycardias (SVTs). Atrioventricular (AV) nodal reentrant tachycardia (AVNRT) is twice as common in women as compared to men, whereas AV reentrant tachycardia as seen in the Wolff‐Parkinson‐White syndrome is more common in men. Atrial and ventricular fibrillation also occur more frequently in men with Wolff‐Parkinson‐White syndrome (Table 1).4 The effects of gender on other less common types of SVTs, such as atrial tachycardia, have not been studied extensively.

Table 1.

Gender of Patients in Relation to Difference Types of Supraventricular Tachycardia

Type of Arrhythmia	Gender		Odds Ratio (M/F)
	Male	Female
Atrial tachycardia
Paroxysmal	12	18	0.66
Incessant	11	8	1.37
AV nodal tachycardia
Common type	51	109	0.47
Uncommon type	0	5	0.00
Accessary pathways
Overt	211	106	1.99
Concealed	61	31	1.96
Slow	12	4	3.00
Fast	49	27	1.81
Circus movement tachycardia	81	49	1.31
Atrial fibrillation	51	15	1.58
Ventricular fibrillation	11	1	5.06
LBBB Mahaim‐type tachycardia	6	2	3.00

Abbreviations: AV, atrioventricular; F, female; LBBB, left bundle branch block; M, male. Reproduced with permission from: Rodriguez LM, de Chillou C, Schlapfer J, Metzger J, Baiyan X, van den Dool A, et al. Age at onset and gender of patients with different types of supraventricular tachycardias. Am J Cardiol. 1992;70:1213–1215.

There is evidence for hormonal effects on the occurrence and timing of SVTs. In a study by Rosano et al, more frequent and longer lasting episodes of SVT were observed in the luteal phase of the menstrual cycle, when there is a fall in estrogen levels and a rise in progesterone levels. The reason for the greater incidence of SVT during the luteal phase is not clear, although it is thought to be linked to body temperature and an increase in sympathetic activity. An increased frequency of ventricular ectopic beats has also been observed in the luteal phase.5

Myerburg et al6 studied the phenomenon of spontaneous premenstrual clustering of SVTs and its implications on the timing of elective electrophysiologic testing. They noted a greater inducibility of SVT during the premenstrual phase. Dagres et al studied 894 patients who underwent catheter ablation either for accessory pathways or AVNRT. Among these, there were 418 men and 476 women. Even though females were more symptomatic and had a faster heart rate, they were referred for ablation much later (average of 28 months) as compared to men.7 There were no differences in the success rates, complications, or rate of recurrence between men and women.

Atrial Fibrillation

The prevalence of atrial fibrillation (AF) at all ages is higher in men than in women. However, because there are more women than men older than 75 years in the general population,8 the absolute number of women with AF is equal to or greater than men in the older age groups. Overall, approximately 50% to 55% of all patients with AF are women, with the number increasing to around 60% in those older than 75 years.9 Women are more likely to experience longer (>24 hours), more symptomatic episodes, frequent recurrences, and significantly higher ventricular rates than men.10 The Canadian Trial of Atrial Fibrillation found that women had a more impaired quality of life as compared to men.11

The risk of death in nonvalvular AF in the original Framingham cohort showed that AF was associated with an odds ratio for death of 1.5 in men and 1.9 in women.12 The Copenhagen City Heart Study, which followed 29310 patients for 4.7 years, found AF to be independently associated with a higher cardiovascular mortality rate in women (hazard ratio [HR]: 4.4) as compared to men (HR: 2.2).13

Female sex has been associated with an additional risk of stroke, especially for those older than 75 years. The SPAF I‐III (Stroke Prevention in Atrial Fibrillation) trials described a particularly high risk of disabling embolic stroke in elderly women with AF.14 The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) study prospectively followed 13559 adults with AF for 2.4 years and found annual rates of thromboembolism in patients not taking warfarin of 3.5% for women compared to 1.8% for men.15 The Canadian Registry of Atrial Fibrillation (CARAF) found that women age 75 years or more were 54% less likely to receive warfarin but twice as likely to receive acetylsalicylic acid as compared to men age 75 years or more. Physicians may be more reluctant to use warfarin anticoagulation due to reports of increased bleeding in women as compared to men, as reported in the CARAF study and SPORTIF (Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation) trials.10, 16 However, the ATRIA study reported similar rates of major hemorrhage in both sexes with no independent major bleeding risk for women. The 3 SPAF trials reported similar annual bleeding risks during anticoagulation therapy regardless of sex.14

The Euro Heart Survey found that treatment for AF was more conservative in women, with significantly less rhythm control than in men.17 In the Canadian Registry, it was found that men were more likely to undergo electrical cardioversion than women. Conversion to normal sinus rhythm was equally successful in both genders (75.9% in women and 79.3% in men).

Radiofrequency catheter ablation is an option for patients who continue to exhibit significant symptoms after attempts at rhythm control. A European study on 221 consecutive patients referred for AF ablation after failing treatment with antiarrhythmic drugs found that women were under‐referred and referred later for ablation. It also found that women were older, and had more hypertension and larger left atrial dimensions than men. Despite these differences, the immediate success rates and complications were similar in both genders. At a mean follow‐up of 2.5 years after the last ablation procedure, 82.7% of men and 83.1% of women were found to be arrhythmia free.18

Ventricular Arrhythmias and Sudden Cardiac Death

More than 300 000 people die suddenly each year in the United States. The Framingham study found that the incidence of sudden cardiac death (SCD) increased with age in both sexes, although the annual rate of SCD in women was around half of that in men at all ages combined. The incidence of SCD in women lagged behind that in men by approximately 20 years. Around 37% of women who had SCD had a history of coronary heart disease, whereas 56% of the men had such a history. Overt coronary artery disease before death markedly elevated the risk of SCD in both genders, although the death rates in women with coronary disease were one‐fourth that in men with coronary artery disease. It was also observed that women were somewhat more likely to have unrecognized myocardial infarction than men. Cardiac failure increased the risk of SCD 5‐fold in both sexes, although the absolute risk of SCD in women was one‐third of that in men (Figure 1).19

Figure 1.

Pie chart illustrating the proportions of various types of underlying structural heart disease in the male and female survivors of cardiac arrest. Abbreviations: CAD, coronary artery disease; DCM, dilated cardiomyopathy; RV, right ventricular; Spasm, coronary vasospasm; VHD, valvular heart disease. Reproduced with permission from Albert et al.21

A prospective population‐based study in Dallas of out‐of‐hospital cardiac arrest found that women more often presented with asystole and pulseless electrical activity, and men usually had ventricular tachycardia and ventricular fibrillation.20 In a retrospective analysis of 355 survivors (271 men, 84 women) of out‐of‐hospital cardiac arrest survivors in Boston, the only independent predictor of cardiac mortality and total mortality in women was the presence of coronary artery disease. A left ventricular ejection fraction (LVEF) <40%, which was the strongest independent predictor of total and cardiac mortality in men, did not have the same prognostic significance in women. This study points out the importance of analyzing women separately from men in studies of heart disease whenever possible, as well as the pitfalls of generalizing findings from a predominantly male population to women.21

Long QT Syndrome

Hereditary long QT syndrome (LQTS) is a familial disorder in which affected members have delayed ventricular repolarization due to mutations in cardiac ion channels. The International LQTS Registry reported that there are major age‐dependent gender differences with respect to lethal cardiac events in patients with congenital LQTS. Male gender is associated with a higher risk of SCD before the age of 15 years, after which there is gender risk reversal, and females are at a 3‐fold higher risk of cardiac events.22 The increased prevalence of QT prolongation and cardiac events in females after puberty may be related to the effects of sex hormones. The decrease in the duration of the QT interval in men after puberty appears to be related to the effects of testosterone. The QTc in men then gradually increases and is almost similar to that in women after the age of 50 years.

Along with gender differences in QT interval with age, differences in QT dispersion have also been noted between men and women. QT dispersion is the difference between the longest and the shortest QT intervals on a 12‐lead ECG. QT dispersion is greater in men than in women and it increases the likelihood of potentially life‐threatening ventricular arrhythmias.

Certain drugs have been associated with QT prolongation (acquired LQTS), which can lead to torsades de pointes (TdP) (polymorphic ventricular tachycardia).23 Women have a greater risk than men of developing TdP when given drugs that prolong cardiac repolarization. Makkar et al examined 332 cases of antiarrhythmic induced TdP, and found that 70% of these patients were women, even though only 44% of the drug prescriptions were registered to women.24 Multiple other studies have shown that women account for the majority of reported cases of drug‐induced TdP.25, 26, 27, 28

Brugada Syndrome

Brugada syndrome is 7 to 8 times more prevalent in men compared to women. Ventricular fibrillation and SCD also tend to occur more frequently in men with Brugada syndrome. Benito et al studied 354 patients with Brugada syndrome (70.8% men). Men had more frequent cardiac events, especially among patients with previous symptoms, type 1 ECGs, and inducible ventricular arrhythmias during electrophysiologic studies. Women showed more conduction disturbances and longer QTc intervals in response to sodium channel blockers. Previous symptoms were the most important predictor of cardiac events in men, and a longer PR interval predicted greater risk in women.29

Sex Differences in Utilization and Response to Implantable Device Therapy

Implantable Cardioverter Defibrillators

Implantable cardioverter defibrillators (ICDs) have been shown to decrease mortality when used for both primary and secondary prevention of SCD. The Antiarrhythmics Versus Implantable Defibrillators (AVID) trial examined the use of ICDs for the secondary prevention of SCD following survival after a life‐threatening ventricular arrhythmia. Mortality was similar in women (14.4%) and men (15.5%) who received an ICD, as compared to 24.4% in the control group, despite gender differences in baseline characteristics and clinical arrhythmia at the time of presentation.30 The Sudden Cardiac Death in Heart Failure trial (SCD‐HeFT) investigated the use of ICDs for primary prevention of SCD in patients with heart failure and ejection fraction ≤35% compared to amiodarone therapy or placebo without further risk stratification, and found that ICD therapy significantly reduced mortality. Of interest, this study found that there was a statistically significant decrease in mortality rates in men but not in women.31 The lower overall SCD risk in women compared to men, and the smaller number of women enrolled in these clinical trials, may explain why treatment differences in women were much smaller and more difficult to detect. In the Multicenter Automatic Defibrillator Implantation Trial (MADIT II), there were no significant differences in the mortality rates between genders in either the control or the ICD group32 (Table 2).

Table 2.

Gender Outcomes in Implantable Cardioverter Defibrillator Clinical Trials

Trial	Enrollment		End Point	Outcome Hazard Ratio (95% CI)
	Total	% Female
AVID	1016	21	Mortality	Men: 14.4% mortality rate; women: 15.5% mortality rate
MADIT I	196	8	Mortality	Not stratified by gender
MADIT II	1232	16	Mortality	Men: 0.66 (P = 0.011; woman: 0.57 (P = 0.132)
MUSTT	704	10	Arrhythmic death or cardiac arrest	EP‐guided therapy; men vs women: 0.88 (.35‐2.23) (P = 0.35)
SCD‐HcFT	2521	23	Mortality	Men: 0.73 (0.57‐0.93); women: 0.96 (0.58‐1.61)
DEFINITE	458	29	Mortality	Men: 0.49 (0.27‐0.90); women: >1.0

Abbreviations: AVID, Antiarrhythmics Versus Implantable Defibrillators; CI, confidence interval; DEFINITE, Defibrillators in Non‐ischemic Cardiomyopathy Treatment Evaluation; EP, electrophysiological; MADIT, Multicenter Automatic Defibrillator Implantation Trial; MUSTT, Multicenter Unsustained Tachycardia Trial; SCD‐HeFT, Sudden Cardiac Death in Heart Failure Trial. Reproduced with permission from: Curtis AB. Are women worldwide under‐treated with regard to cardiac resynchronization and sudden death prevention? J Interv Card Electrophysiol. 2006;17:169–175.

Data from a sample of Medicare beneficiaries who met the criteria for ICD implantation for the primary prevention of SCD revealed that only 8.6/1000 women received an ICD compared with 32.3/1000 men within 1 year of diagnosis.33 An observational study of more than 13 000 patients admitted with systolic heart failure (LVEF <30%) to hospitals participating in the American Heart Association's Get With the Guidelines‐Heart Failure program reported that, among patients eligible for ICD therapy, only 35.4% of them had an ICD or a planned ICD implantation upon discharge. After adjustment for patient characteristics and hospital factors, the adjusted odds of ICD use were 0.73 for African American men, 0.62 for Caucasian women, and 0.56 for African American women, compared with Caucasian men. These differences were not attributable to the proportions of women and African American patients at participating hospitals or to differences in the reporting of LVEF.34

Cardiac Resynchronization Therapy

Cardiac resynchronization therapy (CRT) improves symptoms and outcomes in patients with systolic heart failure and ventricular dyssynchrony. Results from multiple clinical trials have found CRT to be as effective, if not more so, in women as compared to men.35 In a subgroup analysis of the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial, women who received CRT therapy experienced statistically significant improvements in time to first heart failure hospitalization and death compared to women not treated with CRT. Men did not exhibit the same degree of benefit (Figure. 2A,B).36 Although 1 potential explanation could be the greater prevalence of ischemic cardiomyopathy in men (scar cannot be responsive to pacing), these gender differences persist even when controlling for etiology of heart failure.

Figure 2.

Kaplan‐Meier survival curves for time to first heart failure hospitalization or death in (A) women and (B) men treated with cardiac resynchronization therapy vs control. Reproduced with permission from Woo et al.36

An observational registry by Lilli et al on gender‐related differences in left ventricular reverse remodeling revealed that overall, female gender was independently associated with a better response to CRT, defined as the degree of left ventricular reverse remodeling as assessed by echocardiographic reduction of left ventricular end‐systolic volume.37

In the Registry to Improve the Use of Evidence‐Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF) trial, only 35% of indicated female patients initially had a CRT device, which improved to 65% with increased physician education at 24 months.38

Arrhythmias in Pregnancy

ECG changes in pregnancy include an increase in the resting heart rate by about 10 beats/minute, and a leftward shift of the electrical axis occurring secondary to enlargement of the gravid uterus.39 Tawam et al found an increased incidence of new onset (34%) SVTs and an exacerbation of preexisting SVTs in pregnancy. The mechanisms responsible for these observations could be hormonal changes, changes in autonomic tone, or hemodynamic changes seen in pregnancy.40 In pregnancy, the effective circulating volume increases, which in turn can increase myocardial irritability. In addition, estrogen may increase the sensitivity of the myocardium to catecholamines by increasing the number of alpha adrenergic receptors.41 Rashba et al studied 111 pregnant women with known LQTS, and found a significant increase of cardiac events in the postpartum period, but not during pregnancy.42 An increased heart rate during pregnancy provides a protective effect on the QT interval.

Conclusion

There are important gender‐specific pathophysiologic differences in cardiac arrhythmias. A longer time to diagnosis, later referral for invasive procedures, and a less‐intensive resource use pattern has been noted for women with cardiovascular disease in general, and this pattern pertains to women with arrhythmias as well. One must be careful when extrapolating results from clinical trials with a predominantly male population to women. More studies exploring the underlying mechanisms of gender differences in arrhythmias, and a greater awareness of these differences among caregivers, will help facilitate diagnosis and an earlier referral for appropriate management in women.