 That way I get a better signal upstairs. So you're good to go. Good morning, everyone. Welcome to Grand Rounds. This morning, we have the honor of hearing two of our rotating medical students present. Our first student is Taylor Fields. He's joining us from the Medical College of Georgia. He's born and raised from Georgia and experiencing his time out here in Utah in the West. And from what I've heard, he's really liked it. He will be presenting on pseudo-expoliation syndrome and atrial fibrillation. Good morning, everyone. As really said, Taylor Fields from the Medical College of Georgia. I was able to get involved in some research while I was here with Dr. Worosco. She's currently working on pseudo-expoliation syndrome and atrial fibrillation. So lucky enough to help. So just the purpose to start off, we really wanted to find, want to explore the connections between pseudo-expoliation syndrome and atrial fibrillation using the University of Utah Center of Moran Records, linked to the Utah population database. And we're hoping to search the state of Utah using Medicare CMS database to find a larger or broader patient base. So the background, pseudo-expoliation is one of the most is the most common cause of secondary open-angle glaucoma. It's also a very easily identifiable cause. You can see it on exam, whereas many other causes of glaucoma or the apathic are unknown. We were able to use the ICD-9 code, which is very specific for pseudo-expoliation, to identify the patients that we were setting. Possible other associations are pelvic organ prolapse and hernias, which are two associated conditions that Dr. Worosco is setting. And in the literature, it's been reported that it also has connections to aortic aneurysms, erectile dysfunction, and coronary artery ectasia. So based on the underlying common pathophysiology, with the help of Dr. Ravi Rajan of the cardiology department, we hypothesized that atrial fibrillation and pseudo-expoliation had similar pathophysiology, and thus could be connected. So a little background on pseudo-expoliation is caused by a variant of the loxal 1 gene. This is a lysol oxidase, like 1 protein. It basically, oh, that's complicated, it deeminates elastin polymers so that they can connect with collagen in the extracellular matrix of tissues throughout the body. It has incomplete penetrance, so just because you have this variant, which is actually an up-regulated variant, you have more loxal 1 in these patients, doesn't mean you'll get the disease. It's a multifactorial process. Age seems to be the greatest risk factor. Those that are about 52 to 64 only have 0.6%. Once you get over 65 is when is the typical presentation of pseudo-expoliation. And those 75 to 85 are about 5% in non-Glokoma patients. Glokoma patients is obviously more. Race Caucasians, it's been said that Scandinavians actually have the highest prevalence of pseudo-expoliation, somewhere around 25% amongst Icelanders in one study, above 65. And African-Americans have some of the lowest rates. Conflicting data. So sunlight, there's been studies in India specifically showing that patients that live in rural communities or illiterate actually have higher rates of pseudo-expoliation. And it's hypothesized that these are actually labors outside and direct higher exposure to sunlight has been the root cause of this. Gender. Some studies show that females may be at higher risk of pseudo-expoliation. Others show no connection. So all in all, pseudo-expoliation leads to the fibro-material deposition in the anterior segment of the eye, which was initially where people thought it was the only place they found it. But through other studies, it's been shown to be in the vascular chair, muscles, and visceral organs throughout the body. So here's the common slit lamp presentation of pseudo-expoliation. You can see a clear, up on the top left, a clear central disc, and then a surrounding ring of the pseudo-exfoliative material. You can see the edges kind of roll, which becomes significant in cataracts. So as you get these pseudo planes for capsular access, and you can remove not the entire lens capsule. And then down below you just see higher definition. So what's the big deal? So open-angle glaucoma, obviously one of the highest risk factors for pseudo-expoliation. These patients, this fibro-material gets stuck and adjusts the canolecular canals adjacent to the Schlimm's canal, and basically form choke points so that aqueous fluid can't get out, increasing the pressure. You also get backodinesis or the lens wobbles. This is because the pseudo-exfoliative material actually sits at the, or it gets deposited, where the zonules connect to the capsule, as well as the ciliary body, and make these zonules unstable, which can lead to lens displacement. And that ultimately can lead to angle closure glaucoma, where the lens actually just forward into the pupil, and this is more common in myotic patients that are under myotic therapy. It also leaves iris rigidity just because the fibro-material deposited in the iris. Moth heat and appearance and melanin dispersion have to do with the zonules actually rubbing the back of the iris, and spontaneous introsomal hemorrhages is because the vessels are deposited with this fibro-material and kind of break-like twigs when you dilate them. Complications during cataract extractions, that has a lot to do with the zonular instability, and as well as the capsule kind of pseudo-planes that are formed by this material. So you can get a lot of, you can get lens dislocation during cataract surgery. Higher incidence of retinal vein occlusions. So a little bit about atrial fibrillation. It affects about 1% of the general population. It's a fairly common disease. Increases with age starting at about 50, and then it goes up to about 8% of it. It goes older than 80. You can see up here, oh, it doesn't do it. Okay, well, at the top right, you can see normal sinus rhythm with P waves for the QRS complex, and then atrial fibrillation, no good P waves. It's associated with an increased all-cause mortality and morbidity, so it is a significant disease. Complex pathophysiology, so you can see this five-ring kind of diagram down at the bottom right. All these are involved in atrial fibrillation. One doesn't lead to the other, but they're all sort of, well, it's unknown what leads to what, so we're chicken and egg. But of importance here is the fibrosis of the extracellular matrix is a big theme of atrial fibrillation. So current literature, Diaz et al in 2008. They showed that loxal1 had been, had a role in biliary atresia in mice, so it actually, they stained it for loxal1. You can see on the top right, that's a mouse with biliary atresia. It's stained brown, so you can see brown loxal1 proteins within the biliary canals, and then on the bottom right, that's a normal mouse without so much brown staining. Yeah, this is a dull picture. So basically the importance of that study was that loxal1 is found outside of the body and causes pathophysiologic fibrosis. Platonavut al in 2011, they showed histologic evidence that patients with persistent atrial fibrillation have consistently more fibrotic change in the left atrial wall. So on the left, it's stained blue, the fibrotic tissue. So persistent AF shows a lot more blue, a lot more fibrotic tissue, a lot more cardiomyocyte apoptosis with fibrotic tissue replacement, and then on the right you can see normal with much less and much more and controlled typical line of the ECM. So what ties this all together? In 2011, Adam et al demonstrated that the lox, one of the five lysoloxidases, all five lysoloxidases have the exact same, basically, catalytic domain. The difference is their first exon, the first part of the protein, actually decides where they go. Lox will want to specific to the ECM where his lox is kind of throughout the body. But they demonstrated that lox was upregulated in atrial fibrillation and contributed to the structural remodeling of the cardiac tissue. And it's stained red in these pictures, and I'm sorry, I guess it doesn't really come through very well in the bottom left picture. The bottom picture is atrial fibrillation, top or sinus rhythm. You can see greater blue immunofluorescence, more lox protein. So this is kind of one of the big tying factors. Methods that we used. We analyzed all the Moran patients since 1996, about 225,000 individuals. Identified 1,497 patients, age 65 and up. The reason we chose 65 is because that's the typical presentation of pseudo-exfoliation. Anything below that would be atypical. And we didn't want to include them in the study. Unexposed controls from the University of Utah, healthcare, hospitals, and clinics were matched five to one, same age. They were matched on gender, race, and age. These individuals were then screened for the ICD-9 codes corresponding to atrial fibrillation. So what were our results? So that's actually easier to read than I thought it would be. You can see that it's stratified by age, 65, 65, 74, 75, 84, so on. And there's men and women, men only and women only. So I'll zoom in on this in a second. But the important thing here is that the men and women, you can see the odds here actually. I'll just get to that in a second. So the odds ratio of a patient with pseudo-exfoliation having atrial fibrillation is about three, a little over three, and the confidence intervals were inclusive of this and did not include one. So there is a greater risk it shows, or it is presumed that pseudo-exfoliation leads or is associated with increased risk of atrial fibrillation. I didn't show the male and female parts of this diagram because their confidence intervals actually overlap quite a bit so it's not significant. There's no significant difference between the two genders in our study. So discussion, the prevalence of pseudo-exfoliation was consistent with other studies of Caucasian populations, so Miranda's an under or over-diagnosing pseudo-exfoliation. It's completely logical that we have these numbers. And this analysis shows positive correlation between pseudo-exfoliation and atrial fibrillation, suggesting a possible genetic link, loxal one, the pathogenesis of these disease processes, possibly loxal one. So in the future, we wanna confirm this association on a larger, broader population statewide database. Again, the CMS Medicare, Medicaid databases and the Utah public database. Assess the presence of XFS or pseudo-exfoliation contributing to higher morbidity and mortality. So it's been postulated that there is a genetic link to the pseudo-exfoliation. You would get atrial fibrillation earlier and it may be more severe, so you might need a blade of therapy more often than those without pseudo-exfoliation. So we wanna study that. And we plan to submit this to AGS in the fall. So acknowledgments, I would like to acknowledge the Department of Ophthalmology and Visual Sciences and Moran Center for Translational Medicine, Dr. Gregory Hageman, John A. Moran, Presidential Professor and Executive Director, the Utah Public Database of Patient Database. University of Utah Huntsman Cancer Center Foundation and the Huntsman Cancer Institute Cancer Center Support Grant from the National Cancer Institute. I would especially like to thank Dr. Karen Curtin of the Department of Medicine, HCI Pedigree and Population Resources. You did a lot of the heavy lifting as far as population database, database searching and statistical methods. Dr. Borosco, the PI, for allowing me to jump in and come up with these great associations. And Dr. Ravi Rajan of the Department of Medicine, Cardiology, for really helping with the connection between the two. Here are my references. Thank you, any questions? Yes, actually Dr. Borosco has already found connections between pelvic organ prolapse and hernias. Other researchers have found connections to coronary artery ectasia, erectile dysfunction. But yes, it's very recent that it's probably 2011 and forward that they've made these connections. Yes, sir. So the rate in those with pseudo-exfoliation was 41 out of, so a little less than 1%. 41 out of, yes, Dr. Curtin, please. Yes. So, right, so I guess what goes into the referral would there be significant changes? Would, I mean, is it worth, you know, what's the number needed to treat? I don't know. It would seem logical, right? Or at least patients with pseudo-exfoliation, maybe they, and if there's a genetic link, their siblings, children may need to seek cardiac or maybe EKG after the age of 50, something like that. Dr. Peggy, it's pretty, it's still rare.