Gender-Based Differences in Atrial and Pulmonary Vein Substrate
Gender-Based Differences in Atrial and Pulmonary Vein Substrate
The central result of this study is that we observed no systematic between-gender differences in PV or atrial electrophysiology, either in those with or without a history of AF.
This result was contrary to our hypothesis. Indeed, it is well established that there are differences in the clinical nature of cardiac arrhythmias between men and women. Clinically it is known that atrioventricular nodal reentrant tachycardia has a 2:1 female-to-male predominance, while atrioventricular reentrant tachycardia in patients with accessory pathways is twice as prevalent in men than in women. Similarly, large population studies have demonstrated the prevalence of AF to be higher at all ages in men than in women, with AF found to be 1.5 times more common in men than woman in the Framingham study. In contrast, when women do develop AF, the clinical course is often more complex with faster ventricular rates, longer episodes of AF, greater difficulty in maintaining sinus rhythm after cardioversion, and an increased stroke risk.
Although we observed no difference in parameters of atrial or PV electrophysiology measured invasively, gender-based differences in other electrophysiological parameters have been described. These include higher resting heart rates and a longer corrected QT interval in women, lower heart rate variability in men, shorter PR and QRS intervals in women, and a shorter atrioventricular nodal ERP in women. Given that in most studies most changes appear around puberty and at least partially resolve at the menopause, it is likely that sex hormones play an important role.
In this context, receptors for both estrogen and androgens have been identified in cardiac tissue. An acute effect of estrogen on cardiac tissue has been demonstrated in multiple molecular studies, employing estrogen levels far higher than those found physiologically, and with the primary effect being calcium antagonism leading to both a negative inotropic and chronotropic effect. In human electrophysiology, the acute administration of estrogen into the RA has been shown to slow RA conduction and to prolong RA refractoriness. Progesterone, enhancing activity of the slowly activating delayed rectifier potassium current and inhibiting the L-type calcium-channel current, is thought to oppose the effect of estrogen. The clinical result of these molecular effects is seen in the observation that in premenopausal women with SVT, episodes of arrhythmia are more likely to occur during the luteal phase of the menstrual cycle, in the context of high progesterone levels and in inverse relation to estrogen levels.
In a large European study analyzing temporal trends in the age at which menopause is reached, 25% of women were reported to be postmenopausal by the age of 50 years and the median age of menopause was reported to be 54 years. In this study, the mean age of the female cohort in the non-AF arm was 49 years and in the AF arm was 62 years. Certainly in the latter the great majority would be expected to be postmenopausal and therefore less affected by the effects of sex hormones identified in the premenopausal population. Nevertheless, in the postmenopausal population overall between-gender differences in electrophysiology and clinical behavior have been reported to persist to a degree.
Our data suggest that the increased prevalence of AF in men compared with women may not be secondary to differences in the atrial or PV substrate, with other factors playing a role. In particular, cardiovascular comorbidities that are more prevalent in men than women, such as hypertension, obesity, obstructive sleep apnea, and the metabolic syndrome, may contribute to the increased AF prevalence seen in men. These comorbidities would be expected to induce more advanced remodeling of the atrial substrate at any given age. In this study, gender groups were matched for the prevalence of major cardiovascular comorbidities and there was no difference in atrial size as a marker of remodeling. This may account for the absence of observed differences in atrial and PV electrophysiology in this study.
Discussion
The central result of this study is that we observed no systematic between-gender differences in PV or atrial electrophysiology, either in those with or without a history of AF.
This result was contrary to our hypothesis. Indeed, it is well established that there are differences in the clinical nature of cardiac arrhythmias between men and women. Clinically it is known that atrioventricular nodal reentrant tachycardia has a 2:1 female-to-male predominance, while atrioventricular reentrant tachycardia in patients with accessory pathways is twice as prevalent in men than in women. Similarly, large population studies have demonstrated the prevalence of AF to be higher at all ages in men than in women, with AF found to be 1.5 times more common in men than woman in the Framingham study. In contrast, when women do develop AF, the clinical course is often more complex with faster ventricular rates, longer episodes of AF, greater difficulty in maintaining sinus rhythm after cardioversion, and an increased stroke risk.
Although we observed no difference in parameters of atrial or PV electrophysiology measured invasively, gender-based differences in other electrophysiological parameters have been described. These include higher resting heart rates and a longer corrected QT interval in women, lower heart rate variability in men, shorter PR and QRS intervals in women, and a shorter atrioventricular nodal ERP in women. Given that in most studies most changes appear around puberty and at least partially resolve at the menopause, it is likely that sex hormones play an important role.
In this context, receptors for both estrogen and androgens have been identified in cardiac tissue. An acute effect of estrogen on cardiac tissue has been demonstrated in multiple molecular studies, employing estrogen levels far higher than those found physiologically, and with the primary effect being calcium antagonism leading to both a negative inotropic and chronotropic effect. In human electrophysiology, the acute administration of estrogen into the RA has been shown to slow RA conduction and to prolong RA refractoriness. Progesterone, enhancing activity of the slowly activating delayed rectifier potassium current and inhibiting the L-type calcium-channel current, is thought to oppose the effect of estrogen. The clinical result of these molecular effects is seen in the observation that in premenopausal women with SVT, episodes of arrhythmia are more likely to occur during the luteal phase of the menstrual cycle, in the context of high progesterone levels and in inverse relation to estrogen levels.
In a large European study analyzing temporal trends in the age at which menopause is reached, 25% of women were reported to be postmenopausal by the age of 50 years and the median age of menopause was reported to be 54 years. In this study, the mean age of the female cohort in the non-AF arm was 49 years and in the AF arm was 62 years. Certainly in the latter the great majority would be expected to be postmenopausal and therefore less affected by the effects of sex hormones identified in the premenopausal population. Nevertheless, in the postmenopausal population overall between-gender differences in electrophysiology and clinical behavior have been reported to persist to a degree.
Our data suggest that the increased prevalence of AF in men compared with women may not be secondary to differences in the atrial or PV substrate, with other factors playing a role. In particular, cardiovascular comorbidities that are more prevalent in men than women, such as hypertension, obesity, obstructive sleep apnea, and the metabolic syndrome, may contribute to the increased AF prevalence seen in men. These comorbidities would be expected to induce more advanced remodeling of the atrial substrate at any given age. In this study, gender groups were matched for the prevalence of major cardiovascular comorbidities and there was no difference in atrial size as a marker of remodeling. This may account for the absence of observed differences in atrial and PV electrophysiology in this study.
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