Thank you. Several years ago at the European Society of Cardiology, I was one of four people that were designated as a legend a modern legend in cardiology, and the other was well known to many of you. John Kamm And he got up and he said, You know, the only thing about being designated a legend in your lifetime is the alternative. And so thank you. So it's a pleasure to be here. And I always love coming back to London so that you took on upstream therapy and atrial fibrillation. And the question is, does it work? Can we with various drugs and risk factor modification, prevent atrial fibrillation? Can we prevent progression from paroxysmal to persistent atrial fibrillation? Now, the essence of my talk is this and this is work that we've been involved with in Mayo Rochester for probably the last 20, 30 years. And that started off as the following the epidemic of atrial fibrillation, because it is an epidemic. There's no question the commonest arrhythmia, but the epidemic of atrial fibrillation, is it a vascular disease and the hypothesis was that risk factors like obesity, hypertension, age and atherosclerosis increase arterial stiffness. That in turn causes diastolic dysfunction, left ventricular hypertrophy that in turn increases the volume of the left atrium and a big left atrium has a larger degree. And big left atrium is electrically unstable and can lead to atrial fibrillation. And then somewhere out there is the role of inflammation left. I've left that as a question mark that keeps rearing its ugly head. We never quite have sorted out what the role is, but there probably is a role. And so this led to a whole series of studies, 2007 and then over the next ten years where we were able to show clearly that all of these risk factors were associated with atrial fibrillation, whether they cause atrial fibrillation, a little more uncertain, but they were associated and the clinical implications of the study were this, our first paper published in the Journal of the American College of Cardiology 2002 by Teresa Sang one of our colleagues. We showed that a dilated left atrial was a predictor of atrial fibrillation, an independent predictor irrespective of age and other things that just left atrial volume as a predictor of atrial fibrillation. But what really surprised us was a year later was this paper where we showed it is as much a predictor of stroke, MI, and cardiovascular death and coronary revascularization as it is of atrial fibrillation. And left atrial volume was almost like a barometer of the vasculature and the accompanying editorial from Dr. Pamela Douglas said LA. volume is the haemoglobin A1 c of diastolic dysfunction. And then I added to that and vascular disease. So I think left atrial volume is telling us quite a lot about the stiffness of the left ventricle and the size of the diastolic function in the ventricle and the stiffness of the arterial vasculature, which in turn is the result of atherosclerotic risk factors. So this is an abstract we're going to just has been sent to be presented at the American Heart Association meetings in November, 4900 patients, 27 not countries, counties in the Midwest. And these are patients with incident atrial fibrillation. And if you look at the number of chronic conditions in patients three years prior to the diagnosis of AF matched controls, 35% had no chronic condition, only in those with AF only 4% had no chronic condition. And by these chronic conditions already mean hypertension, diabetes, vascular disease and so on. And if you look at patients with three chronic conditions, 69% of those with AF matched controls 32%. So I really think that although atrial fibrillation is an arrhythmia and we treat it as an arrhythmia, we need to really think of it as a vascular disease. And that's important if we're going to try and prevent atrial fibrillation. And this was a paper written with Dr. George Weiss from Canada, who sadly recently died, but a very prominent electrophysiologist in North America. And we postulated here or that if you look at atrial fibrillation, it's not one disease at all. On one end of the spectrum, it's a disease that triggers triggers in the pulmonary vein. And these are patients that we used to call lone AF that means AF without any other disease. And although that term has fallen away, these tend to be young people. Maybe with a family history increased vagal tone. And then on the other end of the spectrum, you've got the majority of people that we all see with atrial fibrillation where age, obesity and atsclerotic risk factors are present and now you have a trigger, but you also have shown in grey a disease substrate atrial dilatation fibrosis leading to atrial fibrillation. And it's not just a disease of triggers, it's also a disease of a fixed substrate on the left and mainly paroxysmal on the right, mainly permanent. And somewhere in between is what's called persistent AF, and that is it's persistent, but you can call your victim out of it and then patients on the left very suitable for catheter ablation. But things have changed. Now as we were talking earlier, we now do catheter ablation earlier and earlier in the course of this disease. But these were most of the trials that have been published or in these patients in the seventies and eighties with atherosclerotic risk factors and a dilated left atrium. So let's look at the risk factors and their association with atrial fibrillation. This large national database from South Korea of a million subjects. And if you look at the adjusted rates for new onset atrial fibrillation and body mass index, pink is under the age of 60 blue over the age of 60. And there's a very strong association starting around about the age of the body mass index of about 25. And you can see an unequivocal association with atrial fibrillation. The other was smoking, particularly in pink in younger patients, very strong. And this is a very strong association with atrial fibrillation. And basically what this study showed was the emphasis on modifiable risk factors like weight and smoking and a greater impact in patients under the age of 60. And the guidelines in the US, the ACCAHA guidelines similar to the European guidelines said that it is weight loss. This is the 2019 update for overweight and obese patients with AF weight loss. Combined with risk factor modification is recommended and they made it across. One indication based upon B.R. is some randomised data and meta analyses and emphasised that there was no new data that demonstrate the beneficial effects of weight loss and risk factor modification and controlling AF. And I personally, when I send a patient for ablation, if they really are overweight, I like to try and see them lose weight over the next three months and may even use some of the ketogenic diets. But I've got a feeling that there is good evidence that if you can't get the weight down, that may reduce the risk of recurrences. There is a very strong association between obstructive sleep apnoea and atrial fibrillation. And if you think if you want to get an idea of the frequency of obstructive sleep apnoea, get on a plane in the Midwest, in the United States and you will see it's pretty frequent. These are papers that not all of them written by us, but the majority where we showed an association with the incidence of atrial fibrillation, the prevalence showed that of the direct current cardioversion patients with sleep apnoea are much more likely to relapse. Higher recurrence after RFA is radiofrequency ablation and the response to antiarrhythmic drugs was much is significantly poorer in patients with sleep apnoea. The mechanisms It's difficult to study sleep apnoea because when you study sleep apnoea, you've got a minimum. Most people with sleep apnoea have other comorbidities, so you're looking at obesity, metabolic syndrome, high inflammatory markers and it's very difficult to tease out patients with pure obstructive sleep apnoea and no other risk factors. But all of these factors can play a role in the development of atrial fibrillation. The other thing I think that happens if you think of sleep apnoea, it's a tremendously hyperactive autonomic milieu. These patients have both increased parasympathetic tone, increased vagal tone and sympathetic tone, and then when they obstruct, they get huge changes in the entire intra thoracic pressure, which results in increased wall stress, increased left atrial volume and atrial stress, atrial electrical and structural remodelling. And that leads to atrial fibrillation. And I think there is a very close relationship. Unfortunately, it's only really been one trial. And this trial, 579 patients with paroxysmal AF apnoea, hypoxia index of 15 or more. So they have moderate to severe obstructive sleep apnoea and they were randomised to usual care and CPAP and on the left it shouldn't be usual CPAP, it should be just usual care. And what did it show? Nothing. If you look at the CPAP group on the left at baseline and then three months, absolutely no change in the burden of atrial fibrillation. And if you look at the mean change in AF burden, this is the CPAP group in the last three months, usual care group, no difference. So rather disappointing. I've talked to my colleagues who really study sleep apnoea and they said pointed out it's a small trial. We don't actually know how well these patients adhere to therapy in a large number of people who put on CPAP just don't use it properly. So for what it's worth, there is a strong association with obstructive sleep apnoea, probably related in part due to obesity, but at least the one trial we have didn't show a benefit in terms of atrial fibrillation. That doesn't mean that we don't use CPAP. Obviously there are other benefits from sleep in patients with paroxysmal AF and obstructive sleep apnoea. Treatment with CPAP did not result in a statistically significant reduction in the burden of AF. But CPAP certainly plays a role in terms of quality of life. This is quite an interesting study that we did a few years ago. We looked at 15,000 patients who had exercise testing and where we had a measurement of the predicted functional aerobic capacity compared to what is predicted. And if you look at the these patients, the blue or those who had an excellent functional aerobic capacity of 104% or greater, the yellow with the least fit FAC less than 75%. And really what the study showed was that if you look at the freedom from atrial fibrillation over a 15 year period in people who are physically fit, there's a much lower rate of atrial fibrillation. Now, the many explanations for that, it may be that people who are physically fit or slimmer, they may smoke less than exercise more and so on. So it's confounded data. It's not direct proof, but it's pretty suggestive study considering it's 15,000 patients. So for whatever reason, physical fitness, which is good for you anyway, may reduce atrial fibrillation, but it's a j-shaped curve. And there are four studies that have shown in highly competitive aerobic athletes who have probably big left atrial because of the stroke volume they've got to generate particularly cross-country skiers. And there is an increase in atrial fibrillation. And later with age and these are just a number of studies. Marathon runners versus controls, hazard ratio for atrial fibrillation, 8.8 fold over time. And then one of the best studies, I think from Scandinavia, 52,000 long distance cross-country skiers participating in a 90 kilometre cross-country skiing event and the hazard ratio for AF in looking at the highest number of completed races. Vs those who only completed one race, 1.29 30% increase. And again those who had the fastest finishing times had a much higher late rate of atrial fibrillation many years later. And I think it's probably because of big left atrium and we seeing this in NFL football players. The problem with NFL players is when they stop playing, I mean, these are giants. And so when they stop playing and you've got a £300 man, you can almost be sure they have sleep apnoea. So it's but we are seeing more atrial fibrillation in the sports medicine clinic. What about blood pressure lowering? This is from one of the larger trials of Antihypertensives where patients were randomised to systolic blood pressure of less than 120 versus a pressure of less than 140 And the yellow was intensive, intensive treatment to get the blood pressure below. 120 This is 140 and if you look at incident cases of atrial fibrillation over a follow up of five years, significantly fewer in those with intensive blood pressure control hazard ratio of 0.74 P-value .037. And then in this analysis, it looks as though those patients with a blood pressure of less than 132 these are tertiles of blood pressure have the greatest reduction in subsequent atrial fibrillation. So it makes sense to control blood pressure. And we've actually looked at this in a different patient population in a registry at Duke University, and we've shown the same thing in a lot of talk about omega three fatty acids and vitamin D supplementation. This is a sub study of a trial called the vital trial. People over the age of 50 and embedded into their trial was another trial of with an endpoint being incident atrial fibrillation. Suffice it to say there was nothing there, no difference at all. P 0.19 for omega three fatty acids and vitamin D three which has had some kind of resurgence of interest in the era of COVID. Again, no effect, No effect on Atrial fibrillation. This is a this is a criticised trial for a number of reasons. The Prettyman trial, where people were randomised to a mediterranean diet enriched with nuts and extra virgin olive oil, 6700 for prevention patients, primary prevention. These were the Mediterranean diet and nuts group versus control in yellow. And if you look at extra virgin olive oil, there was a significant difference for what that's worth. But it's a trial that was criticised for a number of reasons in terms of crossovers and enrolment. And so what about caffeine? And this is, you know, when I was at nursery school in Zambia and primary school in South Africa, I was told that I learned that coffee causes atrial fibrillation, just part of we all knew that. So then along came a couple of epidemiological studies in the US, large studies that didn't show an association with caffeine consumption. In fact, the largest showed that people who drank more than three cups a day had less atrial fibrillation, which is a bit confusing. This is a really good trial and it's now published in the New England Journal. And about a month ago by a doctor, Greg Marcus, 100 patients smartphone mobile application and they were randomised to 14 days of caffeine consumption versus absence for 14 days and monitored during that time. So coffee consumption increased PVCs by 54%, reduced sleep by 36 minutes a night, increased Fitbit based steps, no effect on blood glucose and no effect on atrial arrhythmia. It is pretty impressive. Most of my and most of my cardiology friends love this study that just love it, and so do I think so. But it is a sting in the tail. If you look at patients who never had AF no history of AF that does not appear to be in association with caffeine consumption and atrial fibrillation. But in patients with a history of established AF caffeine is a has been shown to be a trigger 25 to 28% of the time. And I take care of a couple of colleagues at Mayo and if I called out and not one of them is urologist and he gets called out at night, he has a couple of cups of coffee and he's back in a food the next morning. So if you've never had a history, I would say moderate caffeine consumption is fine. But you will find patients who are adamant that caffeine will cause atrial phenomena. I'm not surprised by that. Alcohol UK Study UK Biobank 400,000 individuals. And whichever way you look at the data, it is clear that although there may be some reduction in atrial fib in people with mild alcohol consumption once it goes above 14 drinks a week is a very strong relationship. I don't know. You know the difference. Certainly it seems that beer and sin and spirits are more harmful than red wine and white wine. But be that as it may, I think there is a relationship between alcohol or at least moderate to severe alcohol consumption and atrial fibrillation. What about periodontitis and atrial fib the problem of looking at periodontal disease And any condition is that people with bad oral hygiene have many, many other risk factors. So it's difficult like sleep apnoea, to tease out pure effects of pure poor oral hygiene. And in the Appalachian states, in the stroke belt, in the states, West Virginia and some of those states where there is a very high incidence of cardiovascular disease, very high incidence of risk factors and really poor socioeconomic status, they talk about the ratio, the 2 to teeth ratio. So if you go to more tests and you have teeth, that's not a good thing. And it's probably, I do think that if you look at the data, there is a there's certainly a very plausible biological mechanism to explain why poor oral hygiene causing inflammation could result not just in atrial fibrillation but into other cardiovascular diseases, but difficult to study because this population is just a walking conglomeration of risk factors that this is an interesting study. I think it was from Japan, where they looked PISA, reflected the quantification of active inflammation of periodontal tissue, and then it correlated and doesn't look like such a strong correlation if you just look at that curve. But it is p .001 and it correlated with the degree of atrial fibrosis. Just really interesting study. And the clinical perspective is periodontitis can be a modifiable risk factor play if dental specialist should participate in comprehensive AF management. That was their recommendation. Well, this Danish prospective study also looked at chocolate intake and hey, you want anything to the left of the line is a reduction in atrial fibrillation. So what spoils this this relationship is really good. And if you. Keenan and you like eating chocolate this is a little bit worrying so what I would do is just simply just delete that from the paper. But accumulating evidence suggests that moderate chocolate intake may be inversely associated with AF risk. Well, there, like all of these studies, there's the potential for confounding. So to summarise and conclude, if we look at the modifiable risk factors, I think this curve, what this figure shows is the effect of the risk factor on AF and to the right, the effect of risk factor modification on AF. I think there really is good evidence for body mass index and AF and there is shown in green, there's pretty good evidence that if you can lose that this may have a favourable effect on recurrences of AF, although not everybody has been able to show that I might add. But very good study from Australia, although some people have not been able to repeat it, physical inactivity is a risk factor and as I showed before, I think that moderate reasonable levels of fitness reduce the incidence of atrial fibrillation, very high physical activity such as in competitive athletes may have a bimodal effect with maybe a reduction early on in AFib. But AFib in later life, sleep disordered breathing and obstructive sleep apnoea, I think there's no question that it's a risk factor, but whether we can modify it is open to question because at least the one trial was negative. Diabetes is a risk factor. Hypertension is a risk factor. And as I showed you, rigid control of blood pressure does appear to reduce the incidence of risk factors. Coronary disease. We just don't know. It's probably a risk factor, but we cannot say that modifying it would change the rate of atrial fibrillation, alcohol, clear data, cigarette smoking. We just don't have any data on smoking cessation. But there's no doubt that it increases. Yeah, atrial fib for whatever reason. And then I'm showing you the data with caffeine. But to close, irrespective of the strength of evidence linking specific risk factors to atrial fibrillation, what we treat when we treat these risk factors, we're not just trying to prevent atrial fibrillation, we're trying to prevent cardiovascular death and the overall benefits of controlling respect is indisputable. And quite frankly, I think this is a talk that often asks us to give. But the point is not to prevent atrial fibrillation. All of these risk factors should be modified because of common sense. And if you look at the Eric study, 13,000 patients, I don't know what the AHA is. The simple seven risk factors that contribute to cardiovascular health and and these are them stop smoking, eat better, lose weight, get active, manage blood pressure, reduce blood sugar, control cholesterol. And, you know, if you're able to do that, you get two points for each one of these three and six in. So if you were able to do that to a pretty large extent, look at the cumulative incidence of atrial fibrillation over 15, 20 years and inadequate would be in green where you have a score of you only actively reduce two of these risk factors and look at their incidence of atrial fibrillation. I mean, it is about 50% higher and the same applies to heart failure, same thing in independent predictors of incident, heart failure of the same respective and depending upon how many risk factors you had. So was this an effect on the relative risk of of heart failure? So the number of low risk lifestyle, lifestyle factors, a greater the less the risk of heart failure. And so the relationship really applies as well, I think, to atrial fibrillation and that is control risk factors for multiple reasons. So my final slide is in a we got a dog that behaves like this. We love love the dog dearly, but you can teach an old dog new tricks sometimes and it makes sense to control the risk factors. And I think they will reduce the incidence of atrial fibrillation, but they'll and they'll do other things that are beneficial as well. So I'll stop at that point.