Heart Rate and Heart Rate Variability

In 1920, Bazett showed that women have higher resting heart rates than do men.¹ This observation was confirmed in 1989 by the Coronary Artery Risk Development in Young Adults (CARDIA) study, in which the average heart rate in women was 3 to 5 beats/min faster than in men. This gender-related difference in heart rate is present as early as childhood, but the etiology of this disparity is unclear. Potential explanations include differences in exercise tolerance, autonomic modulation, and the intrinsic properties of the sinus node. It has been shown that this difference persists even after sympathetic and parasympathetic blockade with propranolol and atropine, which suggests an intrinsic difference in the sinus node itself as the etiology. Women have also been found to have shorter sinus node recovery times after overdrive pacing.

Gender-related differences are also present in heart rate variability. Several studies of patients who underwent 24-hour Holter monitoring showed that women have a smaller low-frequency component and a smaller low-frequency to high-frequency ratio over the range of heart rate variability, which suggests a greater parasympathetic influence in female hearts.² This finding is probably related to hormonal influences on cardiac autonomic modulation. Postmenopausal women who are not on estrogen replacement therapy have lower baroreflex sensitivity and smaller low-frequency and high-frequency spectral components of heart rate variability compared with age-matched men or with women on estrogen replacement therapy. It is possible that these differences are related to the worse outcomes experienced by women after myocardial infarction (MI), since reduced baroreflex sensitivity and a reduced low-frequency component of heart rate variability are associated with an increased risk of life-threatening arrhythmias after MI.

Atrioventricular Conduction Properties

Gender-related differences in atrioventricular (AV) conduction have been reported in several studies. Women have shorter P-R, atrial-His (AH), and His-ventricular (HV) intervals, as well as shorter AV block cycle lengths than do men. The incidence of dual AV nodal pathways is similar in men and women. Among patients with dual AV nodal pathways and symptomatic AV nodal re-entry tachycardia (AVNRT), women have been found to have shorter slow-pathway effective refractory periods (ERP) and tachycardia cycle lengths but similar fast-pathway ERPs compared with men.

Amplitude and Duration of the QRS Complex

QRS complexes of shorter duration and lower amplitude have been reported in women. These differences remain after correcting for cardiac mass, body weight, and disease states such as ventricular hypertrophy. The accuracy of traditional electrocardiographic criteria for the diagnosis of left ventricular hypertrophy (QRS voltage, QRS duration, and the product of QRS voltage and duration) is significantly lower in women than in men.

Differences in Repolarization

Women have nonspecific repolarization changes more frequently than do men, according to an analysis of the electrocardiographic data from 38,000 postmenopausal women who participated in the Women’s Health Initiative study. This study revealed that these changes were frequent and could be predictors of cardiovascular events in this population. A wide QRS/T angle, prolonged QRS duration, prolonged QTc interval, and reduced heart rate variability may be predictors of cardiovascular mortality in postmenopausal women.

Q-T Interval and QT Dispersion

Bazett also noted that women have longer Q-T intervals than do men on the surface electrocardiogram (ECG).¹ However, in a normal population, boys and girls have similar corrected Q-T intervals.³ At the time of puberty, the average male QTc interval shortens, leaving adult women with longer QTc intervals compared with adult men. As men age, their QTc intervals gradually increase, and by age 65 years, their QTc intervals are again comparable with those in women.

Several studies have implicated androgens (specifically testosterone) rather than estrogens in the etiology of this age-dependent gender-related difference in QTc intervals. For example, castrated men have longer repolarization times (JTc interval) compared with noncastrated men; women with virilization syndrome have shorter QTc intervals compared with castrated men and healthy women; and athletes who take large doses of anabolic steroids have shorter QTc intervals. Another study found no effect of hormone replacement therapy on the QTc intervals of postmenopausal women.

QT dispersion—the difference between the longest and the shortest Q-T intervals on a 12-lead ECG—is greater in men than in women. Increased dispersion of repolarization correlates with re-entrant–type ventricular arrhythmias, which may explain, in part, the increased risk of sudden cardiac death (SCD) in men compared with women. In contrast, absolute Q-T interval prolongation may result in arrhythmias related to early afterdepolarizations (EADs), specifically polymorphic ventricular tachycardia (torsades de pointes), the risk of which is higher in women. The principal gender-related differences in electrocardiography and cardiac electrophysiology are summarized in Table 50-1.

Table 50-1 Principal Gender-Related Differences in Electrocardiography and Cardiac Electrophysiology

Supraventricular Tachycardias

Significant gender-related differences exist in the prevalence and clinical course of various supraventricular tachycardias (SVTs). For example, AVNRT has a 2 : 1 female-to-male predominance, while AV re-entrant tachycardia (AVRT) and the Wolff-Parkinson-White (WPW) syndrome are twice as common in men compared with women. Atrial fibrillation (AF) and ventricular fibrillation (VF) also occur more often in men with WPW syndrome. The gender-related differences in AV conduction properties mentioned above may contribute to the differences in gender distribution observed in patients with AVNRT and those with ventricular pre-excitation. Despite these differences in SVT, radiofrequency (RF) catheter ablation is equally efficacious in men and women.

Evidence of hormonal effects on the triggers and timing of SVTs is also present. In premenopausal women with a history of SVT, the number of SVT episodes and the symptoms vary cyclically, being more pronounced during the luteal phase of the menstrual cycle when progesterone levels are elevated. Another study has reported a perimenstrual clustering of SVT episodes and a cyclical variation in SVT inducibility. Some patients who were not inducible during an electrophysiological study (EPS) performed at mid-cycle have been found to be inducible when the study was repeated during menstruation. On the basis of this study, premenopausal women should be asked about any relationship of their SVT to the menstrual cycle, and EPS should be scheduled accordingly to increase the probability of inducibility.

Inappropriate sinus tachycardia, an uncommon SVT characterized by a high resting heart rate and an exaggerated heart rate response to stress, appears almost exclusively in women. Most patients diagnosed with this disorder are women younger than 40 years. The etiology is not fully understood, but it is thought to involve abnormal autonomic regulation of the sinus node or to be related to an immunologic disorder involving cardiac β-adrenergic receptors.

Atrial Fibrillation

A number of studies have noted differences in the presentations, outcomes, and prognoses between men and women with AF. In the Framingham Heart Study, men were found to have a 1.5-fold higher risk of developing AF compared with women. While the prevalence of AF increases with aging in men, it does not change in women. However, because of the overall greater longevity of women, the absolute number of women with AF is greater than that of men in older age groups. Men are also more prone to developing AF after cardiothoracic surgery and to have lone AF, particularly when it is not familial. A recent study found reduced testosterone levels but similar estrogen levels in men with lone AF compared with controls.

In women, valvular heart disease and heart failure are the predominant cardiac diseases associated with AF, while men more commonly have AF in association with ischemic heart disease.² Women with paroxysmal AF tend to present with longer episodes and faster ventricular rates. They are also more likely to have cardioembolic complications. Most importantly, AF has been shown to diminish the survival advantage in women, increasing the risk of death regardless of gender (odds ratio [OR], 1.5 for males, 1.9 for females) (Figure 50-1).⁴

FIGURE 50-1 A, Kaplan-Meier mortality curves for subjects aged 55 to 74 years. A log-rank test gave chi-square values of 42.90 for men (P < .0001) and 70.93 for women (P < .0001). B, Kaplan-Meier mortality curves for subjects aged 75 to 94 years. A log-rank test gave chi-square values of 51.44 for men (P < .0001) and 101.51 for women (P < .0001).

(From Benjamin EJ, Wolf PA, D’Agonstino RB, et al: Impact of atrial fibrillation on the risk of death: The Framingham Heart Study, Circulation 98:946–952, 1998.)

The Euro Heart Survey on Atrial Fibrillation recently reported similar gender-related differences. In a population of 5333 patients, women with AF were older and had a lower quality of life, more significant comorbidities, and more symptoms compared with men. Overall, women were treated less aggressively, with fewer cardioversions and catheter ablations, although both genders were prescribed anticoagulation at similar rates. At 1 year, women did have a significantly higher rate of stroke (2.2% vs. 1.2%; P = .011) and major bleeding events (2.2% vs. 1.3%; P = .028). No differences in mortality or heart failure exacerbations were observed.

Although the findings above suggested that a more aggressive treatment approach for women with AF may be warranted, the best way to accomplish this is not readily apparent. Management of thromboembolic risk is difficult in older patients because of the competing risks of stroke and bleeding from anticoagulation.⁵ Maintenance of sinus rhythm, an attractive option at first glance, may not be beneficial, as indicated by the results of the AFFIRM trial, in which no difference was shown in survival or quality of life with a rhythm control strategy versus a rate control strategy.⁶ In addition, women’s greater risk of Q-T interval prolongation and torsades de pointes, as well as the more frequent occurrence of bradyarrhythmias associated with amiodarone use for AF requiring pacemaker insertion, must be recognized when choosing to prescribe antiarrhythmic drugs.

Catheter ablation is an increasingly popular treatment option for patients with AF refractory to medical therapy. Despite the older age, longer history of AF, and greater number of comorbidities in women, AF ablation offers similar acute success rates and complication rates in men and women. At an average of 2 years follow-up, both genders experienced similar percentages of freedom from arrhythmia (83.1% in women vs. 82.7% in men) in a recent study.

Congenital Long QT Syndrome

Women present with congenital long QT syndrome (LQTS) more often than do men. According to the International LQTS Registry, 70% of patients are female, and female gender itself is an independent risk factor for the development of arrhythmias in congenital forms of LQTS.

Several studies from the International LQTS Registry have shown that this gender-related difference is age dependent (Figure 50-2, A to D). Locati et al found that before puberty, boys were at higher risk for cardiac events (syncope, cardiac arrest, or SCD). Another study from the same registry found that during childhood, boys who were LQT1 carriers had a significantly higher risk of cardiac events compared with girls, whereas no gender-related difference existed among those patients who were LQT2 or LQT3 carriers. In a more recent analysis from the registry, in which the endpoint of aborted cardiac arrest or SCD was assessed in 3015 children with LQTS, boys were found to have a threefold increase in the risk of these lethal arrhythmias during childhood. Hobbs et al studied 2772 registry patients who were followed up between the ages of 10 and 20 years and found that boys age 10 to 12 years had a fourfold higher risk of SCD compared with girls, but found no significant gender-related difference in the age range of 12 to 20 years (see Figure 50-2, B).

FIGURE 50-2 Risk of aborted cardiac arrest (ACA) or sudden cardiac death by gender during childhood (A), during adolescence (B), during adulthood (C), and after age 40 years (D).

(From Goldenberg I, Zareba W, Moss AJ: Long QT syndrome, Curr Probl Cardiol 33[11]:629–694, 2008.)

Sometime between the end of puberty and the beginning of adulthood, a reversal of gender-related risk occurs. Adult women in the age range of 18 to 40 years have been found to have a 2.7-fold higher risk of aborted cardiac arrest and SCD compared with men (Figure 50-2, C). The cumulative probability of aborted cardiac arrest or SCD in this age group is higher among women (11%) than among men (3%).⁷ Even after the age of 40 years, when patients with LQTS are expected to have a lower rate of arrhythmias and when the increased prevalence of acquired cardiac diseases should overshadow the effects of LQTS, patients with this entity still experience a high risk for life-threatening cardiac events. This was recently shown by Goldenberg et al, who studied 2759 subjects from the registry and found that the hazard ratio (HR) for affected (QTc >470 ms) individuals versus unaffected (QTc <440 ms) individuals for aborted cardiac arrest or SCD among patients between the ages of 40 and 60 years was 2.65. In this age group, women are affected by a marginally but significantly higher rate of aborted cardiac arrest and SCD compared with men (Figure 50-2, D).⁷ The difference in the timing of events is likely related to the shortening of Q-T intervals in boys after puberty, as discussed earlier. In patients carrying the common LQT1 genotype with mutations that impair the slowly activating delayed rectifier potassium (K⁺) current (I_Ks), 79% of lethal ventricular tachyarrhythmias are associated with exercise and faster heart rates. Since boys tend to perform more intense physical activities compared with girls, they could be exposed to a greater risk of arrhythmic events during childhood. After puberty, testosterone shortens the QTc interval in boys, whereas estrogens may modify the expression of K⁺ channels and have a dose-dependent blocking effect on I_Ks. These hormonal influences provide relative protection to postpubertal boys and to men, whereas they predispose female patients to lethal arrhythmias, particularly during menses and pregnancy.⁷