Hi, this is Eric Prostowski. Welcome to another segment of EP on EP. I'm delighted to have with me today Dr. Ann Gillis, who's been a past president of the Heart Rhythm Society and is a professor of medicine at the University of Calgary in Canada. We have a Canadian, wonderful. So Ann, you have expertise in many areas, but what I'd like to ask you today is give us your insight and the data on the effect of sex in atrial fibrillation. Can you talk about that a bit? Sure, Eric. Well, as you know, yesterday I gave a presentation at one of the sessions on sex differences in terms of the electrophysiology, epidemiology, differences in clinical presentation and some outcomes. And first and foremost, we need to emphasize that sex hormones have important different effects on cardiac electrophysiology. The action potential duration in the ventricle is increased in women because estrogen suppresses some of the repolarization currents and so they have less repolarization reserve. That affected QT, right? Yeah, that results in lengthening of the QT. And there's some data to also suggest that there are differences in the action potential duration in the atrium as well, although the magnitude is probably less than in the ventricle. I was not aware of that. Because of estrogen or testosterone? It's really a combination of both and it's really a complex interaction because in part some of it is due to the concentration of testosterone or the concentration of estrogen or the ratio of estrogen to progesterone. So for instance, during the cycle of 28 days in a female, you see increased concentrations of estrogen in the follicular phase and increased concentrations of progesterone in the luteal phase and that can impact the electrophysiology of the atria and ventricles. So before you go on to give us more detail, one of the well-known observations is that certain arrhythmias tend to become more prevalent five to seven days before menses. Is that, you think, related to what you're talking about? Yes, because the estrogen concentrations are increased then and it certainly has been reported that some of the electrophysiologic parameters are different and lead to perhaps a circuit that could sustain re-entry. Because I've seen that in practice over the years, patients come in with that. All right, so we have those differences. So how does that affect what's going on in AFib between the two genders, between the two sexes? Well, that is a little more complex because women develop atrial fibrillation almost, there's about a decade lag in terms of looking at the prevalence of development of atrial fibrillation in women compared to men. And part of that is probably the protective effects of estrogen pre-menopause where they're less likely to develop important heart disease. But then post-menopause, they begin to catch up in terms of developing coronary artery disease. They then start to develop more hypertension. Women have more hypertension as a risk factor for developing atrial fibrillation than men. They also tend to experience some weight gain, increase in abdominal obesity that translates into an increase in epicardial fat. And adipose tissue in the epicardium, particularly around the atria, secretes cytokines that can trigger signaling processes that lead to fibrosis in the atria. It's interesting that if you look at MRI images that have been specifically aimed at quantifying atrial fibrosis, women at each age group except over the age of 80 have more atrial fibrosis compared to men. And these are patients with atrial fibrillation. With atrial fibrillation. So does that also, so, but women tend to, like you said, if you look at just men versus women with the percentage of AFib until later ages, it's usually men more than women, right? That's correct. So where does the, has that been looked at also, fibrosis, do women have, in other words, if they have AFib, they have more atrial fibrosis, is there any data on just comparing a group of women and a group of men with and without atrial fib if that's also true? I haven't seen, I haven't seen that data specifically. We're looking in the group who have AFib. That's correct. So would that mean then it's going to be harder to treat women theoretically, or are your approaches to them, like ablation and drugs, different? It may well be. It's well recognized that women have triggers for atrial fibrillation within the atria. They have more triggers within the atria apart from the triggers within the pulmonary veins. So if your initial ablation approach is just to electrically isolate the pulmonary veins, that may be one of the reasons why women are more likely to have recurrence of atrial fibrillation following ablation. But it's more complex than that because, because women tend to be older when they're referred for ablation, and so it may be, and they tend to have more comorbidities such as hypertension. And so there really has not yet been a direct, direct comparison of age-matched women versus men and their outcomes following ablation. And hopefully CABANA, because they've had a reasonable population of women, will be able to address that. So also, I know you, I've heard you talk about this before, women have, are more prone to diastolic compliance problems. You know, that has to play somewhat, doesn't it, into the AFib? I mean, the pressure changes in the ventricle. Absolutely. I believe that developing diastolic dysfunction, the elevated left ventricular and diastolic pressures translate into left atrial hypertension stretch, but also triggering the fibrosis. And it's pretty clear from some of the studies that have been done that women are more likely to have diastolic dysfunction compared to men. And part of that, I think, gets back to whether they have hypertension, whether it's been appropriately managed, and if not, then more likely to progress on. Well, one of the things you've mentioned, I'm going to start looking at. I was not aware of the fibrosis issue is actually quite important, like you said. Because if that's true, then I think if you take a woman to the EP lab for sort of a PVI, you have to look a lot more, from what you're suggesting, maybe, we have to look a lot more carefully for triggers also outside of the veins. I think that's fair, at least to start considering it. It may be important, more important to look, particularly if women have persistent atrial fibrillation or also a higher burden of paroxysmal atrial fibrillation. Maybe they experience more adverse remodeling that leads to the fibrosis. And whether it's related to burden, again, we don't understand that quite yet. But to me, logically, it makes sense that that's part of the issue. From what you just said, it sounds like we've woefully under-investigated these issues. Is that fair to say? I think so. It's very fair to say. And this is an area that's ripe for further investigation. Looking at the temporal, like, it'd be nice, maybe I'll try to do this as a research project, but take a cohort of patients and look at the temporal evolution of atrial fibrosis as atrial fibrillation progresses. Well, this has been a great discussion. You're going to have to promise me to come back and talk about the sex differences and ventricular arrhythmias next time. I will. Thank you. Thanks, Anne.

sex

atrial fibrillation

estrogen

cardiac electrophysiology

fibrosis