Sex Differences in Arrhythmias

Cellular Electrophysiology

Differences between female and male cardiomyocyte electrical properties have been documented in various species, including humans. In addition to genetics and sex hormones, many factors modify cardiomyocyte structure, cardiomyocyte function, ionic currents, and AP morphology. These factors determine susceptibility to arrhythmias by affecting the depolarization and repolarization process and by causing changes in conduction intervals. Sex-based differences in clinical arrhythmias are essentially based on these cellular dissimilarities.

Ion Channels

Sex-based differences in function, structure, quantity, and currents of cardiomyocyte ion channels, including sodium (Na ⁺ ), potassium (K ⁺ ), and calcium (Ca ²⁺ ) channels and their components, have been defined ( Fig. 107.1 ). Sex hormones affect Na ⁺ channel function and the transmural distribution of Na ⁺ channel current (I _Na ). In the canine left ventricle (LV), I _Na amplitude is smaller in female epicardial and endocardial layers. In rabbit atria, there is a large difference in late I _Na current in male and female cardiomyocytes. Nonhomogeneous transmural dispersion of I _Na increases the risk for ventricular arrhythmias in females. In castrated male dog hearts, I _Na amplitudes are similar to those in female hearts.

A study on healthy human transplant donor hearts showed reduced expression of a variety of delayed rectifier K ⁺ currents (I _K ) subunits, including hERG, MinK, K _ir 2.3, K _V 1.4, KChIP2, SUR2, and K _ir 6.2, in women compared with that in men. In female mouse hearts, total I _K , transient outward K ⁺ current (I _to ) and slow delayed rectifier K ⁺ current (I _Ks ) densities are lower in a higher estrogen state, reflecting a direct effect of estrogen on K ⁺ currents. This lower current density is associated with downregulation of K _V 4.3 and K _V 1.5 transcript levels. In female canine ventricles, total densities of I _to , I _Ks , and L-type Ca ²⁺ (I _CaL ) currents are different and lead to transmural variation in cardiac repolarization. This finding is species dependent. In guinea pig hearts, expression levels of the different K ⁺ channels are similar in both sexes. Larger I _CaL currents are present in all layers of female canine ventricles compared with those in males. The required Ca ²⁺ for maximum contractile force is significantly lower in males. Cellular Ca ²⁺ transients have been measured in rat epicardial myocytes. Ca ²⁺ reuptake was smaller in magnitude and longer in duration, with greater local variability, in females. The rate sensitivity of Ca ²⁺ alternans was higher in females without significant heterogeneity in cellular responses.

Electrocardiography: Baseline Intervals

Sex-based differences in baseline electrocardiographic (ECG) intervals and HR are summarized in Table 107.1 . Conduction intervals, as well as P wave and QRS morphology, have been noted to be different in men and women (see Fig. 107.1 and Table 107.1 ). Women have shorter PR intervals, QRS and P wave durations, and RR intervals than men but have longer QTc intervals. ^, P wave amplitude is greater in women than in men of all ages. The differences in PR interval and P wave duration progressively increase with aging, whereas P wave amplitude progressively decreases in both sexes with aging. The QRS complex is shorter in duration and lower in R wave amplitude in women after adjustment for LV mass and body weight. Thus the diagnostic accuracy of ECG criteria for LV hypertrophy is significantly lower in women than in men.

Adult women have longer QTc intervals than men (see Fig. 107.1 and Table 107.1 ). QT prolongation is associated with sex hormones. ^{, ,} During childhood, QTc intervals are similar in boys and girls, but they shorten in boys at puberty. Among adults, men with higher testosterone levels continue to have shorter QTc intervals than women. Athletes who take large doses of anabolic steroids have shorter QTc intervals too. In parallel, women with virilization syndromes have shorter QTc intervals than castrated men and healthy women. After the age of 65 years, QTc gradually increases in men and becomes comparable with that in women. Hormone replacement therapy, however, does not have an effect on the QTc intervals of postmenopausal women. Thus, compared with estrogen, testosterone modulates QTc more effectively. Significant seasonal variation in QTc intervals has been found among adult men but not in women. QT dispersion is greater in men than in women and demonstrates prominent circadian variation. Data derived from the Women’s Health Initiative Study show that nonspecific repolarization changes are more frequent in women and predict cardiovascular events. Repolarization inhomogeneity, as reflected in variations in the mean RR intervals and beat-to-beat QT intervals in an established time domain, is higher in women. Women adapt the QT interval to changes in RR interval faster than men. The QT/RR relationship is steeper and more curved in women.

Electrophysiologic Study

Intracardiac electrophysiologic measurements in men and women have demonstrated fundamental differences in the electrical properties of the heart, including sinus node function, AV conduction, and atrial and ventricular myocardium (see Table 107.1 ). Sinus node recovery time is significantly shorter in women than in age-matched men with structurally normal hearts. ^, Similarly, corrected sinus node recovery time remains shorter in young and adult women than in men.

AV conduction properties are also different in women, as reflected by shorter PR, atrial-His (AH), and His-ventricular (HV) intervals, as well as shorter AV block cycle lengths. Overall, men develop AV block more often than women. The incidence of dual AV nodal pathways is similar in both sexes, but women with symptomatic AV nodal reentrant tachycardia (AVNRT) have shorter slow pathway effective refractory periods (ERPs) and tachycardia cycle lengths than men. ^, The anterograde fast pathway ERP has been found to be similar to or shorter in women than that in men. During ventricular pacing in the absence of pharmacologic stimulation, women more often have ventriculoatrial (VA) conduction; men are more likely to exhibit VA dissociation. Also, women have shorter atrial ERPs but longer ventricular ERPs than men. The atrial ERP is similarly shorter in girls without structural heart disease than in age-matched boys. ^{, ,}

Sinus Node Dysfunction/Tachycardia

Women are more frequently affected by sick sinus syndrome, sinus tachycardia, inappropriate sinus tachycardia, postural orthostatic tachycardia syndrome, and sinus node reentry tachycardia than men. On the other hand, carotid sinus syndrome occurs more often in men ( Table 107.2 ). Inappropriate sinus tachycardia is diagnosed much more often in women younger than 40 years. Abnormal autonomic regulation of the sinus node or a related immunologic disorder involving cardiac β-adrenergic receptors has been speculated to be the cause of this condition in women.