Review Article: Gender Differences in Atrial Fibrillation

Abstract

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia that is diagnosed in clinical practice, leading to increased hospitalizations, morbidity and mortality, as well as escalating healthcare costs. AF affects two to six million people in the United States and over 30 million people worldwidAe.¹ AF, due to the increased risk of stroke and heart failure, along with the need for treatment with anticoagulants, often complicates the management of other chronic diseases.² AF is known to increase the risk of dementia in the elderly,³ stroke,⁴ heart failure⁵ as well as sudden death.⁶

Upon initial diagnosis of AF, gender differences are quite evident, with women presenting with more symptomatic AF, hypertension, and other comorbid conditions such as diabetes and thyroid disease. In the Copenhagen City Heart Study, it was shown that AF is a greater risk factor for stroke and cardiovascular death in women than in men.⁷ Older age groups have higher rates of AF. Males in the age range of 75–79 years have a fivefold higher prevalence of AF compared to males in the range of 55–59 years old. Adjusted to age, risk of AF is 1.5 times higher in males than in females.⁸ Higher risk in males can be partly attributed to the increase in male hormones, androgens, after puberty, which shortens the heart's QT interval.⁹ However, the absolute number of women with AF is greater due to the fact that there are more women over 75 years of age compared to men in the general population.⁹ Understanding the etiology of these statistical differences requires close study of the gender specific physiological effects of AF.

Electrophysiological changes in AF

It is known that AF causes profound cardiac remodeling such as atrial enlargement and atrial fibrosis. In-depth understanding of AF pathophysiology is necessary to formulate and improve therapeutic approaches using pharmacological and invasive strategies. Current drug therapy for AF management has major limitations such as lack of efficacy and inducing life-threatening pro-arrhythmic events. Many previous theories such as multi wavelet, leading circle models and more recently rotor models of AF have been proposed to explain the mechanism of cardiac remodeling. Though the modulations in the cellular electrophysiology that transforms normal sinus rhythm to arrhythmia is precisely unknown, reentry is generally accepted as the mechanism to sustain AF after having the triggering event. Triggers are thought to arise from the pulmonary veins or posterior wall. Maintenance of reentry is dependent on tissue substrate and its properties such as slowed conduction and shorter refractory periods. The triggering event, such as ectopic activity, is initiated by either calcium-handling abnormality that cause delayed afterdepolarizations or prolonged action potential durations that cause early afterdepolarizations. Prolonged episodes of AF alter the ionic properties of the atrial myocardium and increase the likelihood of ectopic activity and reentry. The refractory period depends on the action potential duration (APD) and is the key factor governing the likelihood of reentry. Ion transport processes (involving various channels, exchangers and pumps) determine APD. Any changes in these processes lead to alterations in action potential properties that influence the occurrence of AF. Sodium current (I_Na) governs the phase 0 (upstroke) of the APD and corresponds to the depolarization of the myocardium. The sodium current determines the conduction velocity and abnormalities in phase 0 contributes to the reentry. Studies on the ion channel remodeling, and how it leads to AF are mostly conducted in animal models. Yue et.al, first demonstrated that atrial remodeling in the tachy-paced dogs has action potential properties similar to that of humans with AF.¹⁰ The group demonstrated the critical role played by I_Ca,L in remodeling and AP morphology in these tachy-paced dogs. I_Ca,L density decreased over the duration of AF, thus shortening the APD. Ca²⁺-independent transient outward current (I_to) was reduced similarly, while T-type Ca²⁺ current (I_Ca,T), delayed rectifier (I_Ks, I_Kr, I_Kur) and inward rectifier (I_K1) potassium currents and the Ca²⁺-dependent Cl^– current were not altered.¹⁰ In a sustained AF goat model, expression of the L-type Ca²⁺ channel, and of Kv1.5 was shown to be reduced, and expression of Kv4.3 and Kv4.2 was not altered.¹¹ I_Na and gap junctions determine conduction velocity in the heart¹² and in the dog model, conduction velocity is decreased in the atria due to the reduction of I_Na current density.¹³ Prolonged tachypacing also caused a decrease in the amplitude of the Ca²⁺-transients, leading to decreased contractility.¹⁴ In humans with AF, shortening of APD, effective refractory period¹⁵ and triangular action potentials¹⁶ were reported. Chronic AF decreased I_Ca,L densities while no such effect is seen in paroxysmal AF.¹⁷ Other changes observed include reduction in the I_to¹⁸ and increase in I_K1 and I_KACh.¹⁹ Data on remodeling of connexins in human AF is limited and one study pointed the reduction in Cx43 expression.²⁰

Estrogen's effect on cardiac ion channels

Gender differences in electrophysiological properties are well known. Healthy men and women tend to show notable differences in surface electrocardiograms, such as in QT_c interval, heart rate and QRS interval.²¹ These variations can be partly attributed to the effect of sex hormones on cardiomyocytes at the cellular and ion channel level. In the early 80's, McGill et al. provided conclusive evidence that cardiac myocytes possess both androgen²² and estrogen receptors.^23,24 Later, they also demonstrated that these receptors’ binding is isoform specific—myocytes have receptors only for dihydrotestosterone (DHT) and not testosterone.²⁵ These receptors are functional and, depending on the stimulus, can modulate gene expression and non-genomic signaling pathways.²⁶

Nuclear estrogen receptors (ERs) come primarily in two types: ERα and ERβ. In addition to their expression in the uterus, ERs are widely expressed in the heart.²⁷ ERα is mainly located on the cardiomyocyte membrane.²⁷ Both receptors are found abundantly in myocyte mitochondria and regulate mitochondrial function.²⁸ Estrogen receptors are translocated to nuclei after exposure to 17β-estradiol.²⁹ Estrogen also has a direct effect on the conduction properties of cardiac myocytes. Chronic estradiol treatment has shown modulatory effects on the coronary smooth muscle K⁺ channels³⁰ and the cardiac calcium channels.³¹ In a canine model of ventricular arrhythmias induced after ischemia/reperfusion, estrogen administration significantly reduced the arrhythmia burden.³² These antiarrhythmic properties are due to estrogen's effect on opening K_Ca channels³³ and inhibiting Na⁺/H⁺ exchanger³⁴ during ischemia/reperfusion injury. Estrogen also plays an important role in the excitation-contraction coupling by regulating calcium homeostasis in the heart^35,36 and regulating membrane density and expression of L-type Ca²⁺ channels on the cardiac myocytes.^37,38 Ovariectomy caused significant myocardial dysfunction in the rats.³⁹ 17β-estradiol inhibited occurrence of early afterdepolarizations and depolarization-induced ectopic-triggered activity such as in myocardial ischemia, potentially acting as an anti-arrhythmic agent.³⁸ Estrogen is shown to inhibit I_CaL in a voltage-dependent fashion. This is particularly of importance in myocardial infarction, in which myocytes in the ischemic zone are partially depolarized and estrogen prevents triggered activity from these partially-depolarized surviving ischemic myocytes.³⁸ Further studies are needed to demonstrate the long-term effects of estrogen on the other cardiac channels.

Progesterone's effect on cardiac ion channels

Several clinical studies have shown the protective role of progesterone in LQTS-associated arrhythmias.^40–42 This protective role is due to progesterone's actions on cardiac repolarization. Progesterone modulates ion channels through a nongenomic pathway that induces eNOS activation. It enhances IKs and inhibits I_Ca,L, which reduces the QT interval and thus is beneficial in patients with LQTS.⁴³ Inhibitory action on I_Ca,L occurs only when I_Ca,L has been activated by sympathetic stimulation.⁴⁴ This genomic and non-genomic regulation of cardiac ion channels by sex hormones may contribute to the development of gender differences and dynamic fluctuations of QT_c interval and arrhythmic risk in women.

Normal levels of circulating ovarian hormones influence baseline cardiac repolarization. Both estrogen and progesterone exhibit a modulatory effect on cardiac repolarization either directly by altering potassium channel expression and conductance^45,46 or indirectly by influencing the autonomic tone.⁴⁷ On the genomic level, estrogen downregulates the expression of I_Kr and I_Ks ion channels, thereby affecting the cardiac repolarization and prolonging the QT_c interval.⁴⁸ Jiang et.al demonstrated in the isolated cardiac myocytes from guinea pigs that both estrogen and progesterone play an important role in regulating calcium levels in the sarcoplasmic reticulum.⁴⁹ Estrogen and progesterone have opposing effects on cardiac repolarization—estrogen prolongs the QT_c interval while progesterone shortens the QT_c interval. There is controversy regarding the effect of these hormones at their physiological concentrations, which are usually in the nanomolar range). Studies at micromolar concentrations⁵⁰ have shown cardioprotective effects whereas studies at physiological nanomolar concentrations did not show any significant cardioprotection.⁵¹ During the menstrual cycle, progesterone reverses the effect of estrogen-induced QTc prolongation.⁵²

Testosterone's effect on cardiac ion channels

Testosterone acts similarly to progesterone by accelerating the repolarization and thus providing protection from drug-induced arrhythmias.⁴³ McGill et al. first described the presence of androgen receptors in atrial and ventricular myocytes, leading to the discussion of sex hormones’ possible effect on myocardial function.²² Testosterone is generally considered to increase cardiovascular risk. Recent studies have shown that the acute effects of testosterone are beneficial and are different from the effects of chronic testosterone exposure.⁵³ Cardiac L-type calcium channels (I_Ca,L) have a major role in maintaining intracellular calcium homeostasis and thus play a critical role in the induction of arrhythmias. Chronic exposure of rat cardiac myocytes to testosterone for 24–30 hours increased I_Ca,L, mainly by increasing the expression levels of the alpha 1C subunit of L-type calcium channel and open probability of the single channel. Frequency of calcium sparks increased without any increase in the SR calcium load. In contrast, acute treatment of the myocytes with testosterone caused a decrease in the I_Ca,L. These differences are thought to be due to activation of nuclear receptor-mediated pathways⁵⁴ in chronic treatment and the direct blocking effect with acute treatment.⁵³

Despite the well-known physiological distinctions and outcomes between men and women with cardiovascular disease, sex-specific treatment strategies are not well studied. Further research on sex hormones and their role in the heart is key to developing personalized therapies.

QT interval affected by sex hormones

The electrocardiogram (EKG) is a simple and powerful tool used for diagnosis and prognosis in a wide range of cardiovascular diseases. An EKG is a representation of the electrical activity of the heart and consists of a P wave (atrial activation and recovery), QRS complex (ventricular activation) and T wave (ventricular recovery). The QT interval represents ventricular activity and is calculated from the beginning of the QRS complex to the end of the T wave. Corrected QT (QT_c) is calculated by taking the heart rate into consideration using Bazett's formula. Prolonged QT_c interval (long QT syndrome) is an important marker to evaluate the risk of ventricular arrhythmias such as torsades de pointes (TdP). Long QT Syndrome (LQT) can be either hereditary or acquired. The hereditary form is a result of various genetic mutations on channels involved in the cardiac action potential⁵⁵ and the acquired form is usually a reversible condition that is induced either by drugs such as antihistamines, antibiotics, antipsychotic drugs and gastrointestinal prokinetics⁵⁶ or metabolic conditions such as hypokalemia, hypomagnesemia, hypothyroidism, and hemodialysis. While these latter risk factors can cause LQT in both males and females alike, female gender is an independent risk factor for drug-induced LQT. Sex hormones such as estrogen, progesterone and testosterone have been shown to affect the QT_c interval. Bazett first described the gender difference in QT_c interval, with women's QT_c interval 24 ms greater than that of men.⁵⁷ Gender differences do not exist at birth and males tend to have a shorter QT_c interval throughout puberty and adulthood.^58,59 However, by the age of 50, gender difference disappears again.⁶⁰ This is attributed to the testosterone in males associated with shorter ventricular repolarization. Several interventional studies have demonstrated this direct association. QT_c intervals decreased with increased endogenous testosterone in the males from the Rotterdam study cohort and Study of Health In Pomerania (SHIP).⁶⁰ Zhang et al. showed that middle-aged men with the highest testosterone levels had significantly shorter QT_c intervals.⁶¹ A negative linear relationship between QT_c and the level of testosterone was demonstrated in hypogonadic men after a single injection of testosterone. QT_c interval tended to be shorter (mean difference of 13.6 msec,p=0.0007) with the higher dose of testosterone in the injections.⁶¹ Geraldi et al. studied QT_c intervals in the hypogonadic males and compared them with the age matched controls. QT_c was shown to have a higher prevalence in the hypogonodal men.⁶² All these results demonstrate that both endogenous and exogenous testosterone show similar effects on shortening QT_c interval.

The effect of endogenous estrogens on the QT_c interval is conflicting. QT_c in mice with endogenous estrogen is found to have prolonged QT_c than in ovariectomized mice with no endogenous estrogen. QT_c in ovariectomized mice with estradiol injections tend to restore to that of the normal mice.⁶³ This is in contrast to what has been observed in humans. A study in premenopausal women before and after bilateral oophorectomy showed significant decrease in the estradiol post-surgery but there was no significant change in the QT_c interval.⁶⁴ Another study by Saba et al. showed that the QT_c does not vary between premenopausal women (405±21 msec) and postmenopausal women even though the estrogen levels were significantly lower in the postmenopausal women (419±30 msec).⁶⁵ Progesterone, like testosterone, shortens the APD and QT_c interval in women.⁶³ During the menstrual cycle, progesterone levels have the dominant effect on ventricular repolarization. Progesterone levels are higher in the luteal phase, during which the QT_c interval is shorter in women.⁴¹ This is also evident from studies done on women treated with menopause hormone therapy. Women placed on estrogen alone therapy have QT_c prolongation compared to women on estrogen plus progesterone therapy. In the latter case, estrogen and progesterone tend to have a counterbalancing effect on the QT_c interval.⁵⁰

LQT in women

It is well known that the QT interval is longer in women and that there is a female predominance among patients with symptomatic LQT syndrome.⁶⁶ The effect of testosterone in men may explain the lower incidence of related cardiac events in men compared to women. Furthermore, during pregnancy, hormonal changes can cause subsequent variations in QT interval. It has been previously shown that there is prolongation of the QTc in pregnant women.⁶⁷ In this study, EKGs were recorded in healthy pregnant women (36–40 weeks of gestation) and in healthy non-pregnant women. In addition, women with established LQTs have a higher risk of developing TdP in the first nine months after the pregnancy⁶⁸ and after which the risk level returns to baseline as in before the pregnancy.⁶⁹ This higher risk of arrhythmias immediately after pregnancy can be partially explained by changes in heart rate. After delivery, heart rate returns to baseline and this protection is lost, resulting in prolonged QT intervals and thus increasing the risk of having arrhythmias.⁷⁰ In addition, the associated increase in stress and lack of sleep due to child care could increase the incidence of cardiac events postpartum. β-blocker use during pregnancy and postpartum was independently associated with the decrease in cardiac events.

Pregnancy and arrhythmias

During pregnancy, incidence of supraventricular tachyarrhythmias (SVT) is increased. In a study on 60 consecutive women with SVT, it is shown that the risk of exacerbation and new onset of SVT is increased during pregnancy.⁷¹ The risk level however was not affected by the stage of pregnancy. The exact cause of increased arrhythmias during pregnancy is unknown, although changes in autonomic tone, hormonal levels, and hemodynamic alterations have all been speculated as causes. Management of arrhythmias during pregnancy is often complicated by the possibility of fetal injury. Current antiarrhythmic drugs are not specific enough and can pass through the placenta to injure fetus. Abstaining from the treatment could also put the fetus at risk with the resultant hypotension from hemodynamically significant arrhythmias. Extreme care in selecting the drugs is necessary and long-term drug treatment should be avoided except in the cases of severe arrhythmias.

Sex-based differences in presentation, treatment and outcomes in women with AF

Sex differences studies in the arrhythmias have relatively received less attention compared to coronary heart disease.⁷² Large registry studies including Registry on Cardiac Rhythm Disorders Assessing the Control of Atrial Fibrillation (RECORD AF)⁷³ and Eurobservational Research Programme—Atrial Fibrillation General Registry Pilot Phase,⁷⁴ focused on the AF symptoms, but there was no detailed analysis on sex differences in symptoms and quality of life. As discussed previously, women have lower incidence of AF, but the number of patients with AF above age 75 years is about same due to the fact that women outnumber men in the group with the highest percentage of AF.^75,76 In the few studies available, it is reported that women present with higher heart rates during AF than men.⁷⁷ Women also have higher incidence of paroxysmal AF after successful cardioversion, which is attributed mainly to the greater number of reported AF episodes.⁷⁸ A study that analyzed Canadian Registry of Atrial Fibrillation (CARAF) data showed that despite its proven efficacy, warfarin is not commonly used in women with AF because of higher susceptibility to major bleeding (about 3.35 times more likely than men).⁷⁹ Stroke Prevention in Atrial Fibrillation III (SPAF III) data identified women as a high risk group for bleeding complications, especially for women above 75 years of age.⁸⁰ In the Swedish Atrial Fibrillation Cohort Study, the risk for stroke or systemic embolism was shown to be 20% higher in women.⁸¹ Thus, while considering anticoagulation treatment, female sex should be accounted. Dagres et al. in their EuroHeart survey report, noticed that compared to men, women with AF had a lower quality of life with higher comorbidities and reported more palpitations, dyspnea, and fatigue. However, long-term quality of life changes and other morbidities and mortality were similar in both men and women.⁸² Data from the EORP-AF Pilot registry, managed by European cardiologists, showed females to have a higher proportion of ischemic heart failure and preserved ejection fraction.⁸³

Symptomatic females with AF more often received rate control than rhythm control while asymptomatic females received mostly rate control management.⁸³ Initial management of AF did not differ in men and women with AF. Digoxin is the first prescription at the baseline visit followed by antiarrhythmic drugs such as amiodarone, propafenone and sotalol. Women are less likely to undergo catheter ablation for AF. Though permanent AF is less common in women, there is a higher rate of AV nodal ablation, which is usually a last resort for drug refractory and symptomatic AF.⁸⁴ There is also the notion of depression associated with increased AF symptoms. However, the effects of depression on the presentation of and quality of life in men and women is not clearly understood.⁸⁵ Clinicians should be aware of these sex differences while considering AF treatment strategies for women. The American Heart Association (AHA), in its 2011 guidelines, highlighted the need for reporting sex-specific analyses in cardiovascular interventions to aid in the development of future sex specific guidelines.⁸⁶

AF management during pregnancy is a concern for the wellbeing of both mother and fetus. The onset of episodes during pregnancy can be either primary or a recurrence of previously diagnosed AF. Most of the primary episodes are benign and thus appropriate advice and reassurance is helpful. In the episodes that are highly symptomatic and occur as a recurrence of previous AF, judicious use of antiarrhythmic therapy is required. It is a delicate balance to consider both the benefits of arrhythmia treatment and the maternal and fetal side effects of antiarrhythmic drugs. The first trimester, during which fetal organogenesis occur, possess a major risk to use any antiarrhythmic drug. If AF is associated with valvular disease such as severe mitral stenosis, it is advantageous to consider terminating AF using antiarrhythmic drugs to avoid the need for anticoagulation, because pregnancy in particular is a pro-thrombotic condition. Sotalol, atenolol, flecainide or procainamide are the preferred drugs in such cases. These drugs should be administered in the lowest effective dose and constant monitoring of mother and fetus during the treatment is recommended. Electrical cardioversion is usually safe in pregnancy irrespective of the trimester. However, it has been reported that there is remote possibility of initiating fetal arrhythmias which require emergency caesarean section.⁸⁷ There are also reported incidents where electrical cardioversion lead to fetal death, contracted uterus, and loss of fetal heart rate.⁸⁸ Hence it is advised to use electrical cardioversion only in facilities that have equipment to monitor fetal heart rate and conduct emergency caesarean section. Ibutilide can be considered for pharmacological cardioversion and it is shown to be safe in pregnancy in a case report by Kockova et.al.⁸⁹ Cardioverter-defibrillators (ICDs) may be another safe alternative and reports show that women with ICD during pregnancy did not risk fetal health.⁹⁰

Pharmacological Intervention for AF

Therapy for AF includes antithrombotic drugs for stroke prevention in all patients with more than 1 moderate stroke risk factors according to the CHADS2 score, which allocated 1 point for congestive heart failure, hypertension, age>75 years and diabetes mellitus) and 2 points for history or stroke. In 2009, the CHA₂DS₂-VAS_c score was developed after identifying other stroke risk factors in patients with atrial fibrillation. The CHA₂DS₂-VAS_c scoring system assigns one point for age 65–74, and 2 points for age ≥75, 1 point for female sex, 1 point for congestive heart failure, 1 point for hypertension, 2 points for history of stroke, transient ischemic attack or history of thromboembolism, 1 point for vascular disease, and 1 point for diabetes mellitus The study shows that o score of 0 to be low risk for thromboembolic events, score of 1 intermediate risk (0.6% rate at 1 year), and greater than 1 high risk (3% rate at 1 year). It also highlights that the female sex is an independent risk factor for increased risk for stroke.^91–93

As an alternative to oral anticoagulation, aspirin (81–325 mg) can be used in low risk patients such as those with lone AF, who do not have comorbidities as listed above or those with contraindications to oral anticoagulation. Options for oral anticoagulants include warfarin, a vitamin K antagonist. However, newer anticoagulants, which do not necessitate frequent blood testing and adjustment of doses have increased in popularity in usage and prescribing preferences. Factor Xa inhibitors such as rivaroxaban, apixaban and edoxaban, have been increasingly used over the usage of direct thrombin inhibitors, such as dabigatran.⁹⁴

Women, compared to men, have increased risks of deleterious arrhythmias with usage of antiarrhythmics, since they have longer QT intervals and it is known that longer QT intervals increase the risk of torsades de pointes. In a study of D,L sotalol women had 4.1% incidence of torsades compared to 1% for men. This gender specific increase was seen also in the SWORD trial and the DIAMOND-CHF trial, which evaluated usage of dofetilide. It has also been noted that women have a higher incidence of sick sinus syndrome due to antiarrhythmics such as flecainide, sotalol, and amiodarone, thus leading to increase implantation of pacemakers.⁸³

Invasive catheter ablation as treatment for AF

Restoration and maintenance of sinus rhythm after ablation has been known to improve quality of life, symptoms, exercise tolerance and left ventricular function. Catheter ablation for AF may be a curative therapy for patients who are refractory to pharmacological therapy. The success of catheter ablation can be variable from 60–85%, and highly dependent on duration of AF and structural abnormalities such as burden of atrial fibrosis and left atrial size. Paroxysmal AF is known to be more amenable to successful catheter ablation then permanent AF. Women tend to have longstanding AF, larger left atrial size and a history of not responding well to antiarrhythmics, conferring poorer outcomes.^93,95 Women are also referred 3 times less often then men for AF ablation which may be reflective of sex bias in referral patterns, even though women with AF report poorer quality of life and have a higher risk of stroke and increased mortality. AF ablation in women may also be more technically challenging as women often had a higher incidence of nonpulmonary vein sources such as from the superior vena cava compared to men. Women also suffer from higher procedural complications. Incidence of cardiac tamponade, femoral vascular complications such as hematomas, and pseudoaneurysms are higher in women compared to men. In addition, women are often underrepresented in clinical trials of invasive procedures such as catheter ablation. Women who are enrolled in single center or multicenter trials have usually been less than 30%.^91,96,97

A novel transgenic mouse model used to study gender differences in AF

In many diseases, the mouse model is critical for basic research because of the ease of genetic engineering and the large number of pre-existing genetically altered mice for cross-breeding. Studies of AF have been hindered by the lack of a mouse model that accurately recapitulates the spontaneous initiation and sustained periods of AF observed in humans. Most, if not all studies use non-physiological methods including high-frequency burst pacing to induce very short episodes in mice, typically lasting several seconds, of AF compared to hours, days or longer for humans. A novel transgenic mouse model with spontaneous and sustained atrial fibrillation is the first step to understanding the pathophysiological differences in females and males with AF. Wan et al.⁹⁸ generated transgenic (TG) mice with doxycycline-inducible and titratable, cardiac-specific expression of FLAG-epitope-tagged human Na_V1.5 with a mutation (F1759A) in the local anesthetic binding site⁹⁹, which causes window current and persistent Na⁺ current. We found that two founder lines with doxycycline-independent low expression of the mutant Na⁺ channels had the phenotype of atrial enlargement, cardiomyopathy, frequent, relatively long episodes of spontaneous AF, and non-sustained polymorphic ventricular tachycardia, observed as early as 5 weeks of age. These mice phenocopied gain-of-function human SCN5A mutations that have been implicated in dilated cardiomyopathy and hypertrophy, and arrhythmias such as long QT syndrome, torsade de pointes and AF¹⁰⁰. The sustained and spontaneous nature of the atrial arrhythmias enabled the exploration of mechanisms by which dysfunctional Na⁺ channel inactivation causes cardiomyopathy and arrhythmias. Their study showed that the primary effects of incomplete Na_V1.5 inactivation on cardiomyocyte electrophysiology, namely prolongation and dispersion of the APD, and the secondary downstream effects on chamber enlargement, fibrosis and mitochondrial necrosis/reactive oxygen species (ROS) synergistically cause the unique phenotype of spontaneous and prolonged episodes of AF in mice, mimicking human disease. In the vast majority of previously reported mouse models of AF, atrial arrhythmias could only be elicited by very aggressive burst pacing, suggesting that whereas there may be a substrate for atrial arrhythmia, this can be well tolerated and undetected in the absence of a triggering factor¹⁰¹. AF is defined in these studies by a duration of at least 1 sec and most previously reported mouse models demonstrated these relatively short episodes of AF¹⁰¹ A new therapeutic approach for AF was identified by pharmacologically targeting the downstream effects of enhanced Na⁺ entry, using a relatively specific inhibitor of the Na⁺-Ca²⁺ exchanger (NCX).⁹⁸ This model can be used for future further understanding of the gender specific differences in male and female mice with AF, and how those differences may reflect gender specific cardiac remodeling, structure and electrophysiology in men and women with AF.

Conclusion

AF is one of the most commonly-diagnosed cardiac arrhythmias, affecting millions of people worldwide. With the availability of a mouse model to test AF treatments, there is new research to support specialized treatments. While it has long been understood that AF presents differently in men than in women, expansion of this research leads to better personalized treatment. Because AF pathophysiology at even the cellular level are significantly different in men than in women, specialized regimens are essential to improving knowledge about proper diagnosis, prognosis and treatment.

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