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EP on EP Episode 65 - Atrial Fibrosis and Stroke R ...
EP on EP Episode 65_ Atrial Fibrosis and Stroke Ri ...
EP on EP Episode 65_ Atrial Fibrosis and Stroke Risk
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Hi, this is Eric Prostowski. Welcome to another segment of EP on EP. With me today is Dr. Nazem Akoum, who is Associate Professor of Medicine at the University of Washington, and he's also the director of their AFib program. Welcome Nazem. Thank you so much. It's such a pleasure to be with you, Dr. Prostowski, and with the entire HRS audience. We're going to discuss, I think, a very exciting area, and you've been one of the leaders in this area. For many years, I've been very disappointed with the CHADS-VASc scoring system for stroke risk. I think you and I have both seen patients who had a score of zero, yet come in with a stroke, and there are others who have a very high score who never get a stroke. I've always felt there's got to be ways to make it better, but your work on fibrosis, I think, is really, really interesting. What I'd like you to do is explain to us some of your recent research in the use of atrial fibrosis to help predict stroke. Thank you so much for the opportunity to share our research with you. I completely agree with you, the CHADS-2-VASc score, and before it, the CHADS-2 score, were very good clinical tools. They're easy to use. However, everybody who uses them understands that they are very poor in predicting strokes in patients with atrial fibrillation. The main reason for that is because currently, we still lack an understanding of the mechanism by which any of these clinical risk factors that are accounted for in these scores actually mechanistically lead to a stroke. The other limitations for these scores is that they also don't capture the entire risk profile, and there are some risk factors that have been also associated with stroke and atrial fibrillation that are not included in these scores. The other piece of background information that's also super important to talk about is, number one, the observation that there is a temporal dissociation between episodes of atrial tachyarrhythmias detected through implantable cardiac rhythm devices and actual thromboembolic events. The classic paradigm where patients go into a fib, form a clot, and embolize that clot to have a stroke is put into question with these temporal dissociation type studies and makes us wonder, well, since these patients with pacemakers, for the most part, actually don't show us a fib prior to their stroke, is a fib really a necessary component to that, or is there something that is common to both a fib and stroke that's going on in these patients' atria? Added to that, a special group of patients with stroke that is often blamed on occult a fib, and these are the cryptogenic stroke patients, where a fib is suspected but not found as commonly as we would expect. For example, in the CRYSTAL-AF study, where patients with cryptogenic stroke were offered implantable loop monitors, the rate of detection of atrial fibrillation of 30 seconds duration or longer was only 30% at three years, which means that about 70% of those patients with cryptogenic stroke actually don't show a fib and we don't have an explanation for their stroke. It led us down the path of this alternate pathway where maybe a fib, our hypothesis is that a fib may not be an essential component in the pathophysiology of stroke. The alternate hypothesis that we're gathering evidence in support of is that atrial disease underlying atrial disease, fibrosis being the hallmark of that, is the underlying mechanism for the predisposition to thrombus formation and atria independent of atrial fibrillation as a clinical arrhythmia. To further support this hypothesis, we looked at fibrosis in different populations of patients. First, patients with AFib. We know that fibrosis plays an integral part in creating a substrate for AFib in patients who have the arrhythmia. We looked in that group of patients who have had a history of stroke, whether their atria are more diseased, meaning having more fibrosis. Sure enough, patients with atrial fibrillation and a history of stroke were shown to have a higher fibrosis burden compared to atrial fibrillation patients without stroke. Then we said, okay, that is consistent with our new hypothesis. Let's go and look at the source. Let's go and look at that atrial appendage where most of the thrombi and atrial fibrillation are found. We wanted to see if there was an association between appendage abnormalities, whether it's thrombus or spontaneous contrast, which is a prelude to thrombus in most echocardiography studies. We also found that patients with atrial fibrillation who are undergoing transesophageal echoes, who are found to have thrombi, also on average have a significantly higher fibrosis burden compared to AFib patients but without a history of thrombus. The next population that we studied was those cryptogenic stroke patients. We did a case control study where we enrolled patients with newly diagnosed cryptogenic stroke. We wanted to see what is the burden of atrial fibrosis in those patients who by definition do not have atrial fibrillation in comparison to age and sex matched control groups. We recruited control groups from a healthy population without AFib and without stroke. We also enrolled patients with AFib who were also age and sex matched. What we showed in our paper was that compared to the healthy controls, patients with embolic stroke of undetermined source or cryptogenic stroke had a significantly higher atrial fibrosis burden compared to those healthy controls. However, in comparison to their AFib age and sex matched counterparts, the degree of fibrosis involvement was exactly the same. They have the exact same substrate in terms of fibrosis as that seen in atrial fibrillation. However, they don't have the clinical arrhythmia. This is another piece of evidence in support of this direct link between atrial disease and fibrosis and atrial dysfunction, thrombus formation, and stroke independent of the actual arrhythmia of atrial fibrillation. Let me- I'm sorry. I didn't mean to interrupt you. Let me jump in though, because I think this is a very exciting area of investigation. Again, you're to be congratulated leading the charge. I've been a big fan of the concept that substrate is part of the issue. As you probably know, I've talked to you about that. Absolutely. I learned that from you a long time ago. Well, I learned it from others, so I can't take the overcredit by any means. But I think there's two things I want you to address sort of quickly. One is that while you'd like to make a link, there was a study published recently where they looked at all the cryptogenic stroke patients and they anti-coagulated whether they had AFib or not, and it didn't work out. Yet we do know if you have documented AFib, you can clearly reduce the stroke burden. So there's probably, it doesn't negate what you're saying, but the story is probably more complicated, don't you think? I completely agree. The story is definitely very complicated, and we're beginning to understand that this is why this is a very exciting field of study. The studies that you are referring to in the embolic stroke of undetermined source population tested anti-coagulating patients with this diagnosis sort of in an unselected fashion. Everybody who has embolic stroke of undetermined source was randomized to either receive a DOAC or to be on aspirin, which is the standard of care currently. The unselected approach showed that there was no advantage of anti-coagulating everybody with ESUS. However, patients within that study specifically navigate ESUS where an assessment of the atrial substrate measured by atrial size actually did show that those patients with enlarged atria did benefit from anti-coagulation. So it also speaks to the fact that ESUS is not a homogeneous population. There are patients that are truly cardioembolic and the clot comes from the atria, but there are probably other patients with ESUS that are not along the same pathophysiological mechanism. Now, I will also tell you about a follow-up study that we did on our ESUS cohort, and this was a multicenter cohort from the US and Europe, where we followed patients with ESUS where we had quantified their atrial fibrosis. We followed them for two clinically important endpoints. One was recurrent stroke and the other was newly diagnosed atrial fibrillation. Within that ESUS cohort, those with advanced atrial fibrosis, so higher than the median for that group, actually had a higher incidence of recurrent stroke, which is an important clinical endpoint for secondary prevention, and independently, a higher incidence of newly diagnosed AFib. Those patients with ESUS and advanced atrial disease, measured by fibrosis in our case, but also measured by enlarged atria and navigate ESUS, seem to be a subgroup of that population that will probably benefit from oral anticoagulation. This is our next step. This is the study that we're trying to launch based on our findings. So Nazem, thank you so much, and I'm sure our listeners are going to be very grateful for the information you've imparted. We look forward to part two when you have broken the code, as it were. So thanks for joining us, and you have a great day. I appreciate the opportunity. Thank you so much.
Video Summary
Dr. Nazem Akoum, Director of the AFib program at the University of Washington, discusses his research on atrial fibrosis and its role in predicting stroke risk. He criticizes the CHADS-VASc scoring system for its poor ability to predict strokes in AFib patients and proposes that atrial fibrosis may be a better indicator. His research shows that patients with AFib and a history of stroke have a higher fibrosis burden compared to those without stroke. Additionally, patients with embolic stroke of undetermined source (ESUS) have a higher incidence of recurrent stroke and newly diagnosed AFib if they have advanced atrial fibrosis. Further study is needed to determine the potential benefits of anticoagulation in these patients.
Keywords
atrial fibrosis
stroke risk
CHADS-VASc scoring system
AFib patients
fibrosis burden
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