 Thank you for that kind introduction and for inviting me to speak today. I'm going to share my screen now and put myself on presentation mode. Hey, great. So today I'm going to talk to you about prevention and early intervention of atrial fibrillation. These are my disclosures, not particularly relevant to the topic that we're discussing today. So what we are discussing today is atrial fibrillation. And as you all know, the prevalence of atrial fibrillation is increasing and it is quite high globally across the world with the highest rates in North America, as you can see here. In a recent estimation back in 2014, it was estimated that 33.5 million people worldwide were afflicted with atrial fibrillation in 2010. And this was estimated to be 442 million in 2016. Now, atrial fibrillation prevalence and incidence is increasing. And one of the reasons that it's probably increasing is that our population is aging. And you can see here that there's an exponential rise in the incidence of atrial fibrillation at age 60 or so. And these are several different cohorts. It's found pretty much in every cohort. Now this is clinical. There's also this entity of subclinical AF, which is AF that we don't actually diagnose unless we put a monitor on patients. And there are several studies that have looked at this, trying to estimate that prevalence. And if you take patients in the stroke stop study that had, there were aged 75 or older, about 30% have undetected atrial fibrillation. And that rate will increase to 7.4% if you take patients who are over 75 and have greater than one stroke risk factor. And again, these are handheld tools that you screen just once a day. If you actually do 30 day monitoring, which is continuous, and you take a patient population who had cryptogenic stroke, you'll get up to 60%. And if you take patients who have had ILRs in it, like this, this study, the reveal AF study, where they took patients with a lot of risk factors for atrial fibrillation, put ILRs in and you can see that you can see a pretty high burden of short durations of atrial fibrillation. But, you know, almost 30% had at least one hour of atrial fibrillation in a day. We don't know the clinical significance of those undetected atrial fibrillation events. And I'll talk a little bit more about that later. But we do know that clinical AF is associated with a high morbidity. We always think about stroke, it's the most feared complication, four to five fold increased risk of stroke, stroke ends up being 20 and strokes due to atrial fibrillation ends up being 25% of all strokes. There's also potentially a link between atrial fibrillation and dementia. And some of that could be actually independent of stroke or it could be due to sort of microimpfacts but infarcts but there does seem to be a relationship. The strongest relationship between atrial fibrillation and an outcome is actually for heart failure with a five to 10 fold increased risk of heart failure once you develop atrial fibrillation and we'll talk a little bit about that later. There have been associated risks of myocardial infarction that have been shown in several studies associated risks of CKD against small risks and recent studies have found associations between atrial fibrillation and cancer. And this again has been found in multiple studies. We reported on this in the women's health study that over 10 years there was about a 40% increased risk of cancer. And this was all translated into, well, this is a study that we did about a decade ago now, where we looked at women who had no cardiovascular disease. So their only cardiovascular disease was atrial fibrillation. And you can see even in that setting, there's an association with all cause mortality with cardiovascular mortality, and actually with non cardiovascular mortality as well, arguing that some of these outcomes, such as associations with cancer dementia, could be driving some of that mortality. Now, how, how, how much have we been able to make a dent on this mortality and on these adverse outcomes. Well, these are data from the Mayo Clinic, and you can see on the left hand side of the slide that we really haven't made much of a dent between 1984 and 1984 in mortality. But again, you could argue that this is before the NOACS. And, but there is, at that same time, a benefit on stroke. And again, this is when warfarin became, you know, utilized routinely, but we weren't able to make any of our failure or mortality because warfarin really just targets stroke. Now the novel and or the anticoagulants have now come of age. And we know that in four seminal studies put together in this meta analysis that they are associated with lower rates of hemorrhagic stroke, possibly lower rates of ischemic stroke, although non significant, and actually lower rates of all cause mortality. And again, the dreaded intracranial hemorrhage which also which often leads to much of this mortality. So, how has this benefited us? Well, again, when you look at some of the randomized trials, you know, about this is the Dibigatran trial, which was one of the first published on the NOACS. You can see that the majority of death in these patients is due to vascular causes, where you would think that the minority, I'm sorry about a majority, a minority of deaths are due to vascular causes, where you think that the NOACS would have a benefit. Some of these other causes such as non cardiovascular may not be benefited by the NOACS. And in this study by the Framingham Heart Study which encompasses some of the time that NOACS have become available but not all of it. You can see that there is some reductions compared to 1972 to 1985 in excess mortality due to atrial fibrillation. But when you control for all kinds of risk factors, you don't see anything that impressive. So, again, by anti-quagulating patients, we have made a huge impact on stroke, but we are still left with a lot of other morbidity that possibly relates to this mortality. So our current approach to atrial fibrillation is to wait for atrial fibrillation to become clinically apparent and then to treat it. Now, the problem with that is that some of our pharmacologic and invasive treatments for maintaining sinus rhythm have significant risks. And until recently have been used quite late in the course of the disease process. So there's been much more emphasis on using these earlier on recently and we'll talk a little bit about that. And although anticoagulants significantly reduce the risk of stroke as we talked about, they don't entirely eliminate it. So there are still patients that have strokes on oral anticoagulants, as we know, and they do not impact other causes of morbidity and mortality. Now, we do have left atrial appendage closure now. And again, there will be trials looking at that. But again, these are mostly going to be targeted towards stroke. And AF is often silent and complications may be the first manifestation and, you know, about 10% or so present with a stroke. So it can be quite devastating. And a significant fraction will present with persistent AF, AF that doesn't come and go but since. And the problem with that is that persistent AF tends to be less amenable to our treatment strategies. So that's why today I'm going to talk a little bit first about primary prevention, which is preventing the AF to start with, and preventing progression, preventing AF from being persistent so that it can be better treated. So there are several modifiable risk factors that influence AF risk. And these are data from Marco Perez from the Women's Health Initiative just showing sort of the attributable risk or the prevalence of these risk factors in the population. And in current population, the most prevalent risk factors tend to be hypertension and being overweight. Again, a sedentary lifestyle, alcohol, smoking, diabetes, sleep apnea, all of these things have been related to atrial fibrillation. So it is assumed from these studies that a 50 to 60% reduction in AF risk could occur when they're associated with optimal risk factors. So if everyone had optimal AF risk factors, perhaps we would see a 50 to 60% reduction in AF risk. So risk factor modification is indeed quite important. Now just to provide some evidence about sort of more subtle aspects of risk factor modification. This was a study a while ago in the Women's Health Study looking at systolic blood pressure and finding that even low, you know, high normal blood pressures of 130 to 139 were associated with significantly elevated risks, almost 40% increased risks of atrial fibrillation. In the sprint trial which looked at this, unfortunately didn't have atrial fibrillation as an endpoint and it would have been great had they had that. But ideally, we think about maybe managing tight control for atrial fibrillation might, blood pressure might reduce the risk of atrial fibrillation not proven in randomized trials, but several observational studies including this leading to that possible conclusion. So risk factor which is incredibly important in atrial fibrillation probably more important in atrial fibrillation than most other disease processes is obesity. And these are data from six prospective cohorts, looking at the relationship between observational reported body mass index and atrial fibrillation, and you can see how consistent the results are. There's a difference across the board that for every one kilogram of per meter squared of body mass index. There's a 4% increased risk of atrial fibrillation. And again in epidemiology when we see things over and over again that makes us think that yes this possibly could be real. In addition, we performed a Mendelian randomization experiment, where we in the same cohorts took the genes that were associated with BMI, and then look to see whether they are associated with atrial fibrillation and indeed they were and in fact more strongly than the association that was seen observationally so a 9% increased risk of incident atrial fibrillation versus the observational estimate which was 4%. So suggesting that there could be some reverse confounding such that people who are sick start to lose weight that leads them to become to get atrial fibrillation so you lose that association that you might see if you just look at the genetics from from birth. Now we also have data from observational studies that if you change BMI, you might change that that risk of atrial fibrillation so it's not set in stone. And these are data from Ushetedro from the Brigham looking at when you were able to reduce your body mass index to less than 30 having been obese before. You had a risk of atrial fibrillation the same as if you had never been obese. And if you were stable obese, you still had a risk. And if you became obese during a time period this was over 60 months, you actually then had the same risk as those people who remained obese so suggesting that that reducing your weight could lower the risk. Again, you can see from the study how difficult that might be, and that we have 24,000 people in only 600 of those were able to reduce their body mass index to less than 30. So again, it's an of the 5000 that actually had that was about 6000 so about 10% were able to reduce their risk. So, in addition to predicting incident AF obesity also predicts whether you will present with persistence AF so patients who are obese tend to have more recalcitrant forms of atrial fibrillation. And these are data from Dr. Sandy who's now here at see your sign I showing that there was an elevated risk of persistent AF for patients with non proxysmal AF so that this was a higher risk of developing non proxysmal than proxysmal AF and those who had a BMI greater than 30. And hemoglobin A1C was also related to developing persistent atrial fibrillation. And again, this brings up all kinds of ideas about potential therapies that we now have the SGLT tube inhibitors therapies to for weight loss that that are coming out that could be potentially useful for preventing atrial fibrillation. And there was actually a meta analysis looking at atrial fibrillation in some of the randomized trials of SGLT to inhibitors. And again, this was not a pre specified endpoint and points that were deemed most of the time to be adverse events so it has some imperfections, but at least in this data it looks like there may be a lower risk of of of atrial fibrillation in patients who were randomized to SGLT to inhibitors. Now, in addition to weight exercise has its own individual benefit on atrial fibrillation. And there's actually an interaction between weight and exercise. So you can see in these obese women in the women's health initiative. If they were more active and participated in physical activity, they had lower risks of developing atrial fibrillation than if they weren't active. And same here for those with normal BMI so there was a significant interaction. The, not everything that we like to do, like exercise is beneficial and unfortunately multiple studies have also shown that alcohol is strongly associated with atrial fibrillation. You know, there were studies suggesting that alcohol may be beneficial for cardiovascular disease in general though there are some debate about this now in the literature. So with alcohol it is always shown a fairly adverse association on all studies but most, and this is one man analysis putting it to all together, suggesting that one drink per day was associated with that 8% increased risk of atrial fibrillation. And a recent study in a very large population of 100,000 people over a median fall of 3.9 years showed that almost any amount of alcohol has some elevation in the risk and you see this sort of plateau at higher risks of alcohol. And the good news is that caffeine does not really seem to be associated with atrial fibrillation. And this is one observational study, in addition to many others that have been done that we did in the women's health study that showed that there was not a significant relationship between caffeine or coffee or tea or chocolate. And, and there was a, in fact, maybe a U shaped inverse association with people with moderate amounts of caffeine intake having lower risk of atrial fibrillation. And recently Greg Marcus did a triggering trial where they looked at least APCs and patients who had, who took caffeine young patients and did not see any association between acute caffeine intake and increase in APCs. So, in general, this is not something we have to tell our patients to avoid. As far as diet, there's not been a lot of data on on multiple aspects of the diet, but there have been a lot of data on fish intake. Because there was a big interest in omega three fatty acids being anti rhythmic drugs potentially because they do have some anti rhythmic properties in in cellular models and electrophysiologic models. So, the data for fish intake is pretty much all over the map. There are some studies that suggest that it's beneficial the cardiovascular health study which is on the left side slide. The Rotterdam study suggested that it was unrelated to AF incidents, and then in Danish diet cancer and health study suggested that there was actually a adverse trend. But the studies that looked at blood levels of omega three fatty acids had found an inverse association between omega three fatty acid level and atrial fibrillation. So suggesting that if you were to supplement with omega three fatty acids, perhaps you could lower the risk of atrial fibrillation. And in addition, similarly, there were many studies looking at vitamin D deficiency so again patients who had low blood levels of vitamin D tended to have a higher risk of atrial fibrillation. So again, suggesting that maybe vitamin D supplementation would be useful. I remember that when we talk about primary prevention for atrial fibrillation atrial fibrillation like heart failure doesn't occur like from one day to another. The substrate develops possibly over years where you have some structural remodeling of the atrium that may be detectable on the echocardiogram we know the left atrial size is associated with atrial fibrillation. Some electrical atrial remodeling, mechanical dysfunction, and then eventually having clinical atrial fibrillation. So what we wanted to do was we wanted to see whether if you supplemented with omega three fatty acids and vitamin D, would you actually prevent atrial fibrillation in the long run based upon the observational data. So this is data that we published last year on the vital trial. The vital trial is a large trial that was a primary prevention trial of cardiovascular disease and cancer that was performed in 25,000 men and women in the United States. This is an ancillary study of that. And it was a double blind placebo controlled randomized trial that tested a two by two factorial design 2000 units of vitamin D three and 840 milligrams of omega three fatty acids. So some patients were on both some patients were just on one and some patients were just on placebo. In conclusion, men were required to be at least 50 years of age and women were required to be at least 55 years of age, and all required for this study to have no AF, and for the main trial to have CV, no, no history of CBD or cancer. And it was a pragmatic male based design where participants were mailed questionnaires that asked them about their health status and they were male pill packs with their study agents and this is all distributed through the mail. The end point in this study was done prospectively. So when participants were reported new diagnosis of AF on annual follow up questionnaires, we contacted them through additional questionnaires and asked for permission to review their records. We also linked the patients to CMS so that we could identify patients who maybe did not self report their atrial fibrillation. And again, those AF events we tried to confirm by medical record review as well. This is the population, the mean age was 67. And I have to congratulate the the PIs of the study Dr. Manson and Dr. Bering for having 50% women in the study actually over 50% women. The principal investigators were also successful in in recruiting at 20% African Americans and 50% had hypertension, 13% with diabetes and very few were current smokers. So the number of incident AF events that we had over 5.3 years of treatment and follow up with 900. So that was about 3.6% of the entire population had a confirmed AF event. And most of these were confirmed by ECG or medical record report. The type of AF actually fair number of them presented and this is their first report we actually really tried to go back and make sure that we got the first report because we want to make sure it didn't happen before the beginning of randomization and 38% of people presented with persistent AF despite it being their first report of atrial fibrillation. And the symptoms presented diagnosis only 60%. So it shows that the doctors are screening a bit for atrial fibrillation, or there's more recognition of atrial fibrillation from patients because a fair number of these did not present with symptoms at the time of their diagnosis. And we had a 92% power to detect a 20% reduction or increase in the observed has a ratio for incident AF. And you can see there was a small sets, smattering of patients who had post AF post cardiac surgery or atrial flutter only. Now the results were for the EPA plus DHA were not significant. The hazard ratio is 1.09 so tending toward hazard, but again not significant but with curves that were separating. And the same thing with vitamin D in fact the exact same hazard ratio. So no benefit. And really the competence interval show you that we've ruled out most benefit that could possibly, you know, maybe there could be a very small benefit. But these results ruled out that there was a significant benefit of these agents in primary prevention. Several sensitivity analyses, where we excluded AF events that might have had symptoms prior to randomization so that maybe there were some that, you know, began before randomization no change. We excluded AF events detected by CMS linkage because you know they're only certain fracture the cohort had CMS linkage. We excluded atrial flutter alone and post operative atrial fibrillation. We performed it on treatment analysis, and we looked at the secondary endpoints of proxysmal and non proxysmal atrial fibrillation and again no benefit in any of those groups, and no significant increased risk. Now for vitamin D, we did the same analysis and found the exact same results, no benefit in any of these sensitivity analysis and no significant increased risk. Now at the same time or right before these results came out, the reducent trial also came out with the results of icosapental ethyl for hyper triglyceridemia and you can see that this was a positive, we all know that this was a positive trial on their primary end point which is cardiovascular disease. There were several tertiary endpoints and there was a benefit on sudden death which I'm not talking about today, but there are also observational studies, including some that we have done that's just omega three fatty acids might prevent sudden cardiac death. But they found that those that had icosapental ethyl had more atrial fibrillation and and they and their endpoint was hospitalization for atrial fibrillation or atrial flutter. Now the strength trial found a different result on the total endpoint and we won't go into the debate on those two trials being different, but what they both showed is that there was an increased risk of atrial fibrillation and the strength trial as well. In addition, there were several other trials just an increase in risk. So we actually put these together in a meta analysis with the vital trial and other trials that were long term trials testing omega three fatty acids over at least five to seven years you can see here. The shortest follow up was about four years. And, and when you put them all together in meta analysis you do come up with a very modest increase risk of atrial fibrillation which is significant. And it does appear to possibly be dose related, because when you look at the relative risk estimates for those that had low doses like one gram like vital, you don't see such an increase in the hazard ratio but when you look at those with the higher doses, you see more of an increased risk and when we do a dose response curve it's it comes out significant. Now, why would that be well we have looked at some of the ECG is in these vital participants and we do see changes in those who are randomized to make a three fatty acids in the PR interval. P wave duration and the P wave amplitude in such a direction that would tend to predispose patients to atrial fibrillation. We also see differences in autonomic tone, again very subtle, but increases in bagel tone and again this potentially in some circumstances could predict could could lead to an increased risk of atrial fibrillation. And then finally ending up in the prevention and intervention. So part of this, the pretty med study also suggested that olive oil might be beneficial against atrial fibrillation and currently some investigators in Spain are randomizing some patients who have been referred for ablation to olive oil. But again, this was not a pre specified hypothesis af was not a pre specified event, but suggesting again that there could be some sort of benefit. So that's prevention. What about early intervention, and there has been much more of a lean towards that and part of it is looking at early diagnosis and a up screening. And there are multiple ways to screen for atrial fibrillation. You can see here are the different ways you know you can go from just palpating the pulse to, you know, monitoring with a live core device or a handheld device. You know every once in a while, you could have a watch on that would alert you and then you could have continuous patches, and the amount of atrial fibrillation is going to be directly related to the amount that you screen. Now the Apple Watch study showed that you know if you screen a pretty healthy young population with the Apple Watch, you end up with about half a percent of patients who will have a detection for atrial fibrillation by their Apple Watch, and this will vary by age significantly. So what you can see here when you do a patch, you actually put a patch on then of those patients and again they had 2000 they only got patches on 34 on a small fraction of them 450 or so it got a patch. And those that got a patch, they were 34% were detected so they ended up detecting 153 cases of atrial fibrillation after screening that entire population of 500,000 individuals. We may not pick up a ton of atrial fibrillation this way. They did do some positive predictive values suggesting that when you do have a detection and you have a patch on that the positive predictive value was relatively good for actually having atrial fibrillation underlying this. So to worry about the overall the positive predictive value depends upon the prevalence in the population. So if you take a very low, low likelihood population to develop atrial fibrillation, you're probably going to have a lot of false positives with this type of technology. In the Huawei study found about a similar number of a little bit less 0.23% had AF detected with this type of monitoring again, bearing significantly by age. And then when they went to actually find who actually had AF by investigating all of these and they did a little bit more of an intense investigation. And they found 0.12% of the population had AF and the overall positive predictive value was 54%. So half the time it's going to be a false positive. So what about incorporating it into our care, our usual care so this is the vital trial, another vital trial but a different vital trial vital AF where they incorporated screening with these technologies in a primary care practice, they found that it really didn't help to increase the amount of AF detected, maybe in those over age 85, which suggests the doctors are doing a pretty good job, just with the technology that they have available to them in the office. Now, we can detect atrial fibrillation does it mean anything when we do it can we intervene and change endpoints and we do have two studies now on that topic. One is the stroke stop study, which was was these the follow up to that initial study that I showed you about screening in the population. Again, using patients who are 75 to 76 using a handheld device, two times daily. People were randomly assigned to screening or control group once they had AF detected they were referred to a primary cardiologist, and their primary endpoint was a combined endpoint of a schematic or hemorrhagic stroke systemic hemilism bleeding, and they were followed for a median of 6.9 years huge trial of 28,000 individuals really have to congratulate the authors on completing this trial. Now, the proportion of individuals with diagnosed AF and on anti coagulation in the invited to screening and the control groups are seen here. You can see that there were more people that did get on anti coagulation in those invitees, but a lot of the controls got on anti coagulation so again, were they being screened in some other way so that AF was being detected. And so, when you look at the absolute result, you see a very modest benefit, again, a 4% reduction and because it was such a huge trial that actually was marginally significant. The need to screen would be 91 in order to prevent one of these primary outcomes. Looking at a schematic stroke alone, it was 0.92, and it was not significant. And this just shows again that the, the non participants those that did not want to be screened that were randomized screening. So not everybody who was, you know, participated so this intention to treat. If you look at them, they did poorly like the controls. So those who who adhere to screening seem to do better but as you know in randomized trials we always have to look at the intention to treat. So there's probably some benefit of screening and there's probably some benefit of screaming on stroke, but it's not large. And the loop study was similar kind of similar results in 6000 individuals that were assigned to an ILR versus control, and found that their primary outcome which was stroke or systemic Emelism was not significantly reduced but it was reduced. And again, none of these other outcomes were significantly reduced. That's for screening so at this point there isn't the recommendation to screen for atrial fibrillation in order to intervene, although there are some promising data for stroke and we'll have to see how guidelines, guideline writers deal with that information. But what about early treatments to try to reduce AF recurrence and burden. And I'm going to go back to risk factors because naturally this is something that we should do and can be easily done early on with minimal risk. And so there's a fair amount of data for this. This is from the Australian group showing that if you lose weight and actually follow another number of healthy lifestyle habits in this respect to modification clinic. There are reductions in symptom burden symptoms severity score, and also in AF mentioned, measured by culture monitor. And these data from Melissa middle Thorpe who's also now here with us at Cedars show that there was people who lose weight and lost a significant amount of weight like 10% of their weight loss were also less likely to progress, and might have a reversal of their weight loss so that persistent would now become proxysmal. So both for symptoms and for the amount of atrial fibrillation. And as far as aerobic training they're also randomized trial suggesting that aerobic training may reduce the burden of atrial fibrillation very small. So looking at this 51 patients study and patients with permanent atrial fibrillation exercise reduced the burden of atrial fibrillation from 8.1% to 4.8% while it increased in the control population. Now alcohol abstinence does decrease atrial fibrillation and these investigators did a randomized trial on alcohol abstinence finding a significant reduction in risk. It was very hard to enroll these patients in the study and very hard to keep patients in the state because it's very hard to do abstinence, but it does work and so this is good for us to understand for our patients when we talk to them about reductions in alcohol intake. So just putting patients on the type of medications that they should be on for their comorbidities may also have a reduction in the burden of atrial fibrillation that's seen on a one year Holter monitor. And I mentioned before data regarding SGLT two inhibitors. I'm sorry, and maybe even some of the other agents that may be coming along. So what about ablation? Well, again, you know we used to think about ablation is when you fail drug therapy and that's really when you basically have your AHA, ACC, HRS guidelines which say that it's a class one indication if you have symptomatic AF refractory or intolerant to antirhythmic drugs. However, there have been several randomized trials of first line ablation. These are shown here in in the meta analysis and also the stop AF trial that all show a reduction in AF recurrence and symptomatic AF when you use ablation rather than drug therapy as a first line. So that has a class two a indication for paroxysmal atrial fibrillation. And since those guidelines, the this early AF trial have been published again arguing for early ablation with respect to AF recurrence. Here you can see they had ILRs in everybody. And they actually did a really good job of not allowing patients to cross over. And they still found a very significant reduction in the recurrence of atrial fibrillation but you can see that there's still a fair amount of atrial fibrillation that occurs after ablation, even when you think you are successful and freedom from symptomatic AF. So this really is the end point. This is really the reason we're doing ablation at this point. And there is a significant benefit. Now, if you combine that with risk factor modification, you may even get more of a benefit. And so this is again the arrest AF study done by investigators in Australia, showing a significant benefit on procedural recurrence of atrial after procedure recurrence of atrial fibrillation. And if you look at people who reduce their weight significantly, like lose greater than 10% versus people who you actually do an ablation on, you see basically the same rate is if you lose weight greater than 10% versus, you know, you do an ablation and you don't lose anyway. So, so it is really important to incorporate weight loss with ablation. And this is made it into guidelines. These are the European hearts of European ESC guidelines, recommending modification of all these risk factors. And in the HA guidelines they updated supplement focused a lot on weight loss. And again, these are some of the more specifics on from the ESC guidelines again, you know, specifically recommending specific targeted interventions on lifestyle. Now, finally, are we able to impact outcomes based upon reducing AF recurrence and burden and symptoms. We've shown those things or we have good evidence for that. What about outcomes? Well, we did an observational study on heart failure. And this was in the women's health study just showing you the strong relationship between AF and heart failure in this really healthy cohort of women that had previously not had cardiovascular disease, with really significantly higher rates of all cause mortality, cardiovascular disease mortality, and myocardial infarction in patients, you know, who develop heart failure who have atrial fibrillation. So it seems like it would be good to prevent the heart failure. And in these data, if you had optimal risk factors such that you had a systolic blood pressure that was normal, less than 120, a BMI that was less than 30, no diabetes and you did not smoke. The risk of developing heart failure if you had atrial fibrillation was markedly reduced, greater than 80%. So suggesting that if we modify these risk factors in our patients with atrial fibrillation we may prevent heart failure. And most recently, the yeast trial looked at the strategy of using early rhythm control with, primarily with anti-rhythmic drugs and with ablation on long term outcomes. And this trial was a high risk trial. It was a high risk population. They were older than 75 years of age and they had to have one of the following criteria. They had to either be older than 75 years of age, have a previous TIA or stroke, or have two of the following criteria. So they were at significant risk of stroke and for complications from their atrial fibrillation. And this shows you the characteristics. The mean age was 70. They also were very successful recruiting women, 46% women. And they also found that a significant proportion of patients presented with persistent AF as their first diagnosis of atrial fibrillation. And what they found overall, you know, they basically, like I said, this wasn't an ablation trial, but they did use some ablation. A lot of the anti-rhythmic drugs in the rhythm control arm were drugs like propanum and flecanide 1C agents. They also used a fair number of adrenetorone, but didn't use a lot of the drugs that are often used in the United States, such as amiodarone and didn't see a lot of sotolol at all. So they found the proportion treated and that there wasn't too much crossover in the usual care, but some of the patients in the usual care did get treated probably for symptoms. And overall, they found a significant result on their primary outcome over five years of death from cardiovascular causes, stroke or hospitalization with worsening heart failure, suggesting that if we intervene and we try to suppress atrial fibrillation, we could have a benefit. Now this goes counter to what we've always thought about with rate control and the affirm trial and also counters the guidelines right now. So these will have to be incorporated. But I do want to point out that when you look at the absolute outcomes, you can see reductions in the individual outcomes of most of these death from cardiovascular causes, stroke, hospitalizations from heart failure, but there wasn't a reduction in mortality. And so if you go back to a firm and you look at a firm, you learn that a firm had a mortality as its endpoint, not these other outcomes. So again, maybe mortality isn't going to be necessarily the goal, but it's the goal to, or, you know, at least not in five years, but it's the goal to prevent some of these other comorbidities that are significant in early atrial fibrillation. So in summary, cardiovascular risk factor and lifestyle modification are critical for both prevention and management of atrial fibrillation. And management of comorbidities also improves the maintenance of sinus rhythm and regression of persistence of paroxysmal atrial fibrillation. So risk factor modification should be used as an adjunct catheter ablation, because it also reduces AF recurrence and persistence in this setting, and may also reduce cardiovascular morbidity in patients who have atrial fibrillation. And there should be greater emphasis on early treatment with rhythm control strategies. This is emerging to perhaps reduce the long-term consequences of atrial fibrillation. And multiple modalities are effective for AF screening, but positive outcome studies are still lacking so that hasn't really made it into guideline. And to make an impact on morbidity and mortality, we need to have a more comprehensive focus beyond just stroke prevention, and it needs to occur early in the disease process. So I want to thank you all for your attention, and I'm going to stop sharing.