Hi, this is Eric Prostowski, and welcome to another segment of EP on EP. I'm delighted today to have Dr. Jared Bunch with us, who is the Division Chief of Electrophysiology at the University of Utah. Jared, welcome to the show. Thank you. It's a pleasure to be here. So this may surprise you, Jared, but I'd like you to talk about dementia and atrial fibrillation. Oh, it's a pleasure. So let's start with some older data that you presented. I've been very impressed with your work in this field, and I think it was, at least for me, back in around 2010, I read a paper, the date may be slightly off on, this whole area that you introduced us to where there seems to be a tie-in with aphibid dementia. Can you go through that with us, please? I can, and that is correct. About 12 to 15 years ago, we became interested in this area, and it really came from an observation at bedside, and I think this has a lot of inroads to everything we've done. I was at Intermountain Medical Center, and the patient was next to us, and behind us was his telemetry, so you could see his rhythm as he spoke. He was this outgoing salesman, and he told these elaborate stories. What was interesting was he would speak freely, and then he would go into atrial fibrillation. At that time, his wife, who had heard these stories a million times, she would start filling in for him, because there was this train of thought, and then when he would go back into sinus rhythm, he'd say, I had a senior moment, and circle back, and he would do this over and over in this patient interview, and at that point, he started to say, what's going on with the brain, and how does atrial fibrillation influence it, and so that led to that first large survey in Utah looking at the role of atrial fibrillation and dementia. We've long known that atrial fibrillation is associated with dementia related to multiple strokes, but our interest was more in this patient, and that could it cause idiopathic dementia or senile dementia due to alterations of the blood, the blood perfusion in the brain, and so we were able to find at that time, really from the first time, that atrial fibrillation associated with all forms of dementia, and it raised the risk anywhere to two to three times compared to people without atrial fibrillation. Yeah, I remember that when I showed that paper off, and you showed that, all of them, I'm not as facile with the neurology differences between Alzheimer's versus other types of dementia, but is this still held up with your more recent research, that it goes across the field of dementia? It does, yeah, and we had some challenges with that from an epidemiology standpoint because, you know, if you express cognitive decline in a medical record system, they may say potential dementia, so we initially had to restrict a lot of our analysis to those that were specifically diagnosed by neurology, and we're able to find that, but there is some overlap, and obviously, in recent, and the two can coexist, and recent data has shown that people with a diagnosis of Alzheimer's, if you do MRI imaging or pathology of the brain, you'll see infarcts in some of those patients. So you're a perfect example as a wonderful clinician of chance favors the prepared mind. I'm sure you know that very famous quote. That clinical observation at the bedside is something others might have missed, so congratulations on your sharp clinical skills. That's a wonderful pickup. You know, there was a paper, I've never been able to find it, and I'm, you know, a lot of people know I'm a student of the literature, but there's a paper decades ago that I read where people did a mental exam on patients, and then after cardioversion, repeated it, and found that everything was better. And I was always impressed by that. I didn't know what to do with it, but it was like, okay, there's something about AFib that clouds the mind, you know? So obviously, this is an observation that you've put into science, you know, versus the work you're doing, but let me take you to go to another area. When I used to read about this, there was some literature suggesting that it was maybe microbleeds with warfarin. Where do we stand now with the participation of anticoagulants in this syndrome? That's a great observation, and one we're still interested in, because the most obvious cause causing Alzheimer's disease in mediopathic dimensions is the fact that we know what causes vascular dementia with big strokes, and so what is the role of macro and microbleeds in clots and trying to sort those out? What we found, we found three things, that the timing and efficacy of use of anticoagulation is critical, and the durability of use. And so, the group out of Sweden, Freiburg and colleagues, found that anticoagulation in patients with atrial fibrillation lowers risk. And in addition, they found that that benefit really was in those that had very good time in therapeutic ranges, but what was interesting in their work is, with the sub-analysis, all the benefit was when they received anticoagulation within the first year of diagnosis. And we found the same thing throughout Utah, that it was only when it was started early that there was benefit. Once you go out three to five years of waiting, you don't see a benefit at all. And then, we were interested in that concept of efficacy, how well we're controlling anticoagulation, so we looked at a pharmacy anticoagulation service, and in people that were screened for cognitive, intact cognitive function, and started on morphine at day zero. And there was a strong association with your time in therapeutic range in morphine and risk of dementia in people that interviewed to have no over-cognitive dysfunction at start. Not only did we find that with morphine, we found that actually in other people that required long-term anticoagulation without atrial fibrillation, such as valvular heart disease or chronic pulmonary embolism, that atrial fibrillation still augmented risk beyond those. So that speaks to some of that. And of course, you can see that both on people that are under-anticoagulated, but even more so on people that tend to be over-anticoagulated. So that gets at that micro-B-lead hypothesis, and we know that 8% to 10% of people experience that on anthonic lung anticoagulation. So Jerry, this is a pretty complicated area, right? Because let's look at three things, and let you parse it for us, please. We have a population that's aging in the AFib population with multiple comorbidities. I've heard some people say these are just things that occur naturally because they have overlapping risk factors, hypertension and all that sort of thing. Then you have the AFib component, and then you have the anticoagulation component. Well, before we get into other mechanisms, some of your recent research, how do you put this together as far as, like, for example, let's say I was a patient who said to you, I don't mind staying in AFib, Dr. Bunch. Well, am I okay as long as I take my anticoagulation? You know, you're starting to be the first month that I had it. Or is AFib going to do something even though I'm well anticoagulated? That's a great question, too, and that was our biggest concern initially was this just epiphenomenon. We were just looking at two diseases that they were aging, and we found the correlation. What's really interesting with the correlation, idiopathic dementias in atrial fibrillation, it involves the younger AFib patients. And we found that our people under 70 were at the highest relative risk. A large study out of the UK found people under 65 were at higher risk. And then recent meta-analysis that was published in Trends of Cardiovascular Medicine showed in aggregate, younger atrial fibrillation patients tended to have the highest risk match. So I think there's some teeth to it. We do know that anticoagulation use obviously is really critical, but we're really starting to want to understand what does the rhythm do, and how does it participate? We match people chronically anticoagulated for other reasons in those atrial fibrillation across all spectrums, anticoagulation efficacy, atrial fibrillation-raising risk. So we think it participates in this, at least in retrospective studies. And then the most important thing to me is anticoagulation could do nothing to explain my first patient. And so going back to that first idea, he didn't have multiple small strokes to dynamically change the conversation. His brain had to function acutely from perfusion changes. And so that other separate pathway has really become an interest as we move forward. What can we do with the rhythm, and how does atrial fibrillation affect perfusion? How does its treatment affect perfusion long-term and function? So Jared, I couldn't ask for a better segue. So let me hold this up to the audience. Let's see if we can get that up there. Now, this is from a recent paper that work you're doing on in the canine. People can take a look at it, and I suggest everyone read it. I'll take it down and ask you to go through your research, because for me as a clinical scientist, everything you said up to this point, I'm in. But I want a pathophysiologic link, and this paper of yours begins to give us that link. So why don't you educate us on your recent research? Oh, thank you very much. And I think this is really interesting to say. So we used a canine model, and the dog's unique because they have this vascular network in their neck. It really filters out stroke, and so it's not perfect, but it's one of our animal models that we can study the physiology without strokes. And so we looked at what's called cerebral vascular reserve, and when you expose an animal, a human to acetazolamide, they get this large augmentation of blood flow to the brain, and it's easy to quantitate on MRI imaging. And so we took dogs at baseline, and then we measured their perfusion and their white matter, gray matter at baseline, and then with acetazolamide exposure, and they markedly increased. They almost doubled, or 50% increased in their perfusion of their brain. And what's interesting is that same healthy animal, you pace into fibrillation without heart failure, and in three months, you repeat the experiment, and they actually don't augment. They actually have a maladaptive response. And so it goes the other way, acetazolamide, and then at six months, you repeat the testing and it somewhat improves, but it never becomes adaptive. And one, it kind of explains this patient, but it also explains sometimes why patients over time say the symptoms have lessened perhaps, because there is some adaptation. And then there's a second study that I think is fascinating with CO2 in the brain. If you take people and you measure their brain flow, and then you expose them to hyperjapnia, where you hold their breath at higher CO2 levels, the brain dilates and you get more perfusion to preserve the brain. And people with atrial fibrillation, their response, their auto-regulation of CO2 is 30% worse than controls, and people that have chronic hypertension. So it's not just the vascularity of the brain. It's something to do with the lid on them. And their response is on par with people that have had a stroke. So what's happening in the brain is not only we lose some of the perfusion response, but we also lose our auto-regulation. Well, this is fascinating stuff. And you know, your patient being one example, but you often hear, right, Jared, from patients that they just don't feel good. And now their rates aren't fast, their blood pressure's fine. I mean, I know it's irregular, but even patients who have a pacemaker, even a blatant pace type things, where they have a nice regular rhythm, when they go in AFib, there's a whole group of people, right, that sort of fit your thing, your research, where suddenly they're just... I mean, they're not with it, right? They're just cloudy. They talk about being cloudy-headed and stuff. And then you get them in sinus, and suddenly, like your patient, like, wow, I'm feeling great. Which brings me to my last point, which is very controversial, but I'm going to ask you anyway. Is this a reason we should be doing our shared decision-making with patients to say that this is a possibility, this is where research is headed, and why sinus rhythm may be the better choice for you, especially if you're younger? I think so. The data's lining up that way. There's a nice study of cognitive testing in patients ablated and that weren't, and they tested the MOCA testing baseline six months, 12 months, and the domain that improved the most in those that had sinus rhythm after ablation was in memory processing. There's also a really interesting study that looked just at brain perfusion, and they took patients that were ablated and not, and the doubling of perfusion was seen in those patients that actually had persistent ablation, so the sicker patients, and they just tended to do much better. That group didn't do cognitive testing, which would have been nice, but they showed that the group that perhaps was sicker, the one that we may have had more of an inclination to do rate control, they actually, the one from a brain perfusion standpoint, that did the best. And then I tend to use the EAST-AFNP trial a lot, saying, you know, we now have a trial where rhythm clearly won, but it won when it was done early, whether it was medications or ablation, and I think that's really important. And it fits our use of anticoagulation, that if we're going to do it, we need to do it earlier. That's sort of become the foundation of my discussion with patients, you know, whether it's medicine, whether it's ablation, we need to get you on anticoagulation if you qualify urgently and quickly and make it efficient, and we need to talk about rhythm control strategies. Well, I totally, Weldon, I totally agree with you. I wrote this piece, this small little piece, Bridge to the Future, because we want to let patients know, at least, that if they want to stay in sinus, you have to approach it relatively early. It gives them that bridge to the future, but, Jared, you've done great research in this area. Thank you so much for all your hard work over the years, and thank you for being on the show. Thank you. It's my pleasure.

electrophysiology

atrial fibrillation

dementia

blood perfusion

anticoagulation