Hello, everyone. Welcome to Core Concepts in EP. I'm Ed Gerstenfeld, University of California, San Francisco, and today we'll be talking about mechanisms, pharmacologic, and non-pharmacologic treatment of atrial fibrillation. These are my disclosures. So today, this talk is really going to be a whirlwind talk about all things AFib. We're going to talk about AFib mechanism. We're going to talk about pharmacologic therapy. We'll talk about anticoagulation. We'll talk about catheter ablation of paroxysmal and persistent AFib. We'll talk about risk factor modification, AF and congestive heart failure, and then some clinical trial results as well. So going back to the very beginning, there were two conflicting theories about the mechanism of atrial fibrillation. Based on publications by Scherff and colleagues where they stimulated the atrium in animal models with a conatine and caused a rapidly firing focus shown on the left, they theorized that atrial fibrillation was focal, was driven from a rapid focus with fibrillatory conduction to the remaining atria. An alternate theory was proposed by Gordon Moe based on computer simulations where he developed a multiple wavelet reentry model that AFib was due to multiple reentrant wavefronts that interacted, split off daughter wavefronts in a self-sustaining manner but without any new focal input. And these two groups published back and forth, these two conflicting theories. It was really until the 80s when Moritz Alessi in the Netherlands in an animal model was actually able to map AFib in the dog with two egg-shaped electrodes. And what he found was actually validation of the multiple wavelet hypothesis that there were multiple wavefronts, but he didn't see any focal drivers. Although again, notably his electrode, egg-shaped electrodes did not extend into the pulmonary veins, but at this time it pretty much put to rest the concept of focally driven AF and everyone accepted AF as due to multi-wavelet reentry. That really was the basis for the maze procedure, right? The surgical procedure that cut initially as a cut and sew procedure, cut the atrium into multiple segments and sewed it back together so that none of these re-entrant wavefronts could re-enter one another. And importantly, as shown in this slide, was the incision around the pulmonary veins that actually isolated the pulmonary veins and the back wall of the atrium. I mean, I don't realize that, but that probably was a very important lesion as part of this maze procedure. But again, this is open heart surgery, high rate of pacemaker implantation and other comorbidities, but it did validate the hypothesis that multi-wavelet re-entry likely was important for AFib. And then all that kind of turned on its head in 1998 when Hasegira published New England Journal, this now seminal paper showing that regardless of how AFib is maintained at the onset of AF, the trigger typically comes from muscle sleeves, myocardial sleeves that extend into the pulmonary veins. If you look at the onset of AFib, nearly all the time the triggers come from the pulmonary veins. And that's really, you know, revolutionized the treatment of AFib and led to the pulmonary vein isolation procedure that we perform in the lab today. You know, other important concepts, I think, were this idea of the more AFib you have, the more AFib you end up with in the long term. So in this study, looking at patients who were in AFib and cardioverting them, you know, the ones, example in yellow, who were in AFib for more than 12 months had a much higher recurrence rate than those who were only in AFib for three months. So patients with longer lasting AFib tended to have a higher rate of recurrence after cardioversion. This was shown experimentally in a famous paper titled AFib Begets AFib, it's a common phrase. And again, done by Wiffels and Alessi in the Netherlands, where they had a chronically instrumented goat model. And they actually developed a stimulator that would stimulate the animal into AFib and then stop. And then if they were still in sinus rhythm, it would re-stimulate and continue with this burst stimulation. And you see, initially the AFib only lasted a few seconds, but after 24 hours of stimulation, it lasted longer. And after weeks eventually led to sustained AFib, just as we see in humans, that the more AFib the animals had, the more sustained AFib they ended up with. This is the whole concept that the more AFib you get, it leads to this process of atrial remodeling that tends to perpetuate AFib. And when they looked at the two common electrophysiologic measurements that contribute to AFib, conduction velocity and refractory period, but they found that in this model, there was not really much change in conduction velocity, as shown on the left, but with the longer episodes of AFib, there was a shortening of refractory period. And this shortening of refractory period shortens the wavelength of reentry because more re-engineer wavefronts can take place in any area of the atrium. And this contributes to the maintenance of atrial fibrillation. Now, why does this happen with rapid stimulation of the atrium? Again, this has been looked at by Bosch and Stendhal and others. And it seems like, you know, the primary reason is a decrease in the L-type calcium current that leads to shortening of the action potential and therefore shortening of refractoriness. There's some other changes. I don't think they're as relevant in recognizing that the main current that plays a role in electrical remodeling due to persistent AFib is down regulation of the L-type calcium channel. But what was noted is then when you restore sinus rhythm in patients or animals, that this electrical remodeling, this shortening of the refractory period actually reverses pretty quickly over a few days. Yet it seems like in humans that the process persists much longer, right? You cardiovert someone and they can still have recurrent AFib six months later. Why is that? And that's kind of the second part of remodeling, which is not the electrical remodeling, but the structural remodeling that you see myelinolysis and uncoupling of cells and fibrosis. And this fibrosis interrupts homogeneous conduction, leads to zigzag, heterogeneous activation and re-entry. And that once this fibrosis takes place in the atrium, it does not reverse with restoration of sinus rhythm. So again, with AFib you get both electrical and structural remodeling. Electrical remodeling reverses, the structural remodeling does not. And that may be why AFib becomes so persistent. So, you know, we still today, even though we spend many days in the lab ablating AFib, do not really have a good understanding of the actual mechanism, right? There was the original shown in the upper left multiple wavelet hypothesis. And perhaps I added that this is contributed by occasional firing in the pulmonary veins. You have the Scherff original model of a purely focally driven AFib. We've had some hypotheses about rotors driving atrial fibrillation, kind of a mother rotor that then drives the fibrillatory process. Waldo has shown in animals evidence of multiple foci driving AFib. And then there are the Leslie, DeGroote, and Schotten models, which highlight the three-dimensional nature of the atrium that there's endo-epi re-entry. And that contributes to an increase in the volume of the atrium and perpetuation of AFib. It may be different patients with AFib have different mechanisms. It may be some combination of these, but these are sort of the predominant mechanisms that we think of. We don't really know which one is true in human AFib. The other important part of AFib mechanistically we've learned are the autonomics, right? We all know about, you know, vagal AFib. Patients tend to have AFib when they're sleeping. The main extrinsic autonomic stimulation of the heart comes from the paravertebral ganglia, both the stellate ganglia and the vagal trunk. And then there's also an intrinsic autonomic system on the atrium itself, these ganglionated plexi. And these plexi are made up of, everyone thinks of them as vagal, but they're made up of both vagal and sympathetic nerves. And we think about AFib, we have both the trigger and the substrate, and the sympathetic nerves would tend to drive the trigger. So again, I don't think the actual ion channel changes are important to remember, but, you know, all the potential mechanisms that might trigger AFib, enhanced automaticity, EADs, early after depolarizations, and DADs are contributed to by sympathetic or adrenergic stimulation. With a vagal or cholinergic stimulation, you tend to, vagal stimulation of the atrium tends to shorten refractoriness, but the vagal stimulation is not even, it's heterogeneous. So you end up with a spatially heterogeneous shortening. Some areas have short refractoriness, others don't. And that again, tends to lend itself to unidirectional block and re-entry. So sympathetic stimulation tends to accentuate the trigger and vagal stimulation tends to accentuate the substrate. It's important to realize that it's not one or the other. Again, we often think about vagal AFib, but it usually takes both the sympathetic stimulation to start AFib and the vagal stimulation to maintain it. So in terms of actual pharmacologic management of AFib, we know about the typical class 1A, class 1C, and class 3 drugs. Again, brocainamide not really commercially available, so a cross that went off, but these are all drugs that we can use to maintain sinus rhythm if warranted. Again, how these drugs work. So class 1Cs, fluconide and propafenone primarily are sodium channel blockers. They work on phase zero of the action potential to slow conduction that may prevent re-entry and wavefront turnaround. The class 3s, bufetalide, sotalol, and ibutalide work primarily to block the repolarizing currents that lengthen action potential duration and lengthen refractoriness. Then finally, there's amiodarone, which we know blocks multiple channels and is also fairly effective at maintaining sinus rhythm. Now, we all use these. I think we tend not to use them enough, which are pharmacologic acute medicines to pharmacologically acutely convert someone to sinus rhythm. In the hospital, typically used for patients in the ICU. I wouldn't trust personally our emergency room, but in the ICU or in the lab, we can give intravenous ibutalide, right? It's a class 2 drug only approved for IV use. Milligram over 10 minutes, wait 10 minutes and give the second milligram. Pretty good at converting flutter, 65%, about 40, 45% for AFib. Again, this is a QT prolonging drugs. You want to make sure the QT is less than 440. You have magnesium on hand that you can treat. Torsado, if it occurs, it's going to occur in 2% to 3% of the population, but for someone in the ICU, particularly if they're not NPO and you're trying to convert them, it's a good trick. Then as outpatients, again, patients with recurrent, infrequent recurrent persistent AFib. They may have episodes once a year, twice a year, but when they go into AFib, they stay in AFib and need a cardioversion. We can use this pill-in-the-pocket therapy with 1C drugs. And this has been well described in the literature. So a single dose of 3 to 600 milligrams of propafenone. In the usual size person, I'll often start with 450, 3, 150 milligram tablets. You know, smaller person, you might start with 300. Flaconide, 2 to 300 milligrams. These are given with an AV nodal blocker. So either a beta blocker or a calcium channel blocker, because you don't want to organize the fib into flutter and have them conduct rapidly. But these can be used as a pill-in-the-pocket method out of the hospital for a patient to convert themselves out of AFib. Typically we like to watch them the first time they do this, because some patients may have a long pause with symptoms. Once they do that, then patients can treat their AFib out of the hospital. And this is a nice therapy for infrequent episodes. Now, when do we really want to keep people in sinus rhythm versus just leaving them in AFib and controlling the rate, right? This is kind of the age-old question for AFib. And the first, you know, large trial to address this was the AFIRM trial. You know, over 4,000 patients, and they were randomized to rate a rhythm control with up to three years or more of follow-up, and basically followed for the hard endpoint of mortality, with the question of, does maintaining sinus rhythm reduce your mortality? And as we all know, in AFIRM, in fact, there was no difference in mortality. In fact, if you look at the rhythm control arm, if anything, it trended to be higher. But, you know, this, I would say, led some people perhaps overenthusiastically to just say, well, rate control is fine, even for your first episode of AFib. We know there are some other symptomatic benefits to being in sinus rhythm, but it's important to realize from AFIRM that there isn't any clear mortality benefit to maintaining sinus rhythm. An important part of this study, though, I think, was recognizing these findings in terms of stroke rate, that actually patients in the rhythm control arm, those in sinus rhythm, had a higher stroke rate than those in the rate control arm, right? That seemed counterintuitive at the time, but the reason we realized is some, many people stopped their warfarin because they said, oh, you know, you are on a drug, you're a clinic visit, you're in sinus rhythm, and then those patients off warfarin had strokes. And so we know that, you know, once you have AFib and are treated with pharmacologic therapy, that you can be having asymptomatic episodes at night and other times when you're not in the office. So in general, you know, other than studies looking at implantable monitoring, once you have an indication of anticoagulation, you should continue on anticoagulation regardless of apparent maintenance of sinus rhythm, even if the patient feels like they're in normal rhythm all the time. And I think that's an important point because strokes are probably the worst complication for AFib. It's important to realize, you know, there are two other large randomized studies, RACE, STAFF, and AFIRM. All three have shown no mortality benefit to rhythm control, maintenance of sinus rhythm over just rate control. So the main reason to maintain sinus rhythm, at least at this point in time, was for symptomatic benefits. There really hasn't been evidence of a mortality benefit with all these studies. In terms of which antirethmic drugs we use, we know in patients without structural heart disease, particularly coronary heart disease, that 1C drugs like flecainide and propafenone are well tolerated. If those are ineffective, we can move on to class 3 drugs. Although this is a 2017 guidelines, this will likely be changed with the next guidelines based on data that I'll show you. But once you fail an antirhythmic drug or break through an antirhythmic drug, catheter ablation is a class 1 indication for maintaining sinus rhythm if it's thought that sinus rhythm is important. And the odorone, again, because of all the side effects, is the last option. Again, what I think may change is that catheter ablation may become at least a 1A first-line indication based on the data that I'll show. But again, it's important to realize that it depends on the patients. Some patients may want to start with antirhythmics. That's fine. Some patients may want to start with catheter ablation. If you have coronary artery disease, you know, based on increased mortality in casts, you should not use 1C drugs. And so then usually we'll start with defedolide, dronetarone, or sotolol. Again, if patients break through antirhythmics, catheter ablation is a second-line option. Amiodarone reserved for the last line if there are no other options. Patients with heart failure, dronetarone is kind of indicated, so you're left with options of defedolide or amiodarone. It should be pretty standard for all of us treating AFib. Again, I always keep in mind no drug is expected to have 100% efficacy. I tell all my patients this, an occasional breakthrough is not a, quote, failure of a drug. And it drives me crazy when patients get admitted to the hospital and someone writes in the chart, you know, fail propafenone and stops it completely. It may be, if that's their one episode a year, that it's totally fine. Continue on the same dose, you can adjust the dose, but we have to have reasonable expectations, goals to reduce AF burden and frequency, and again, breakthrough on an antirhythmic should not be considered a failure, and just cardiovert people and keep them on the same drug, and it may be doing okay, especially if they had some kind of exacerbating illness. Now, there was a recent study that I think was really nicely done and very helpful and enlightening in terms of, you know, contemporary rate versus rhythm control of AFib. This was the East AFNet4 study, 2,700 patients, mean age of 70, 46% female, 26% persistent AFib, and a third asymptomatic, so pretty representative of the average AFib patient that we see, and they were randomized to usual care or rhythm control, and what I like with this study was it was practical. Most of these patients were actually treated with antirhythmic therapy, but compared to a firm where ablation wasn't really an option when that study was done, ablation was added as a potential option to help maintain sinus rhythm, and you can see the drugs used here on the left. Majority were 1C drugs, propafenone and flaconide. Some got amiodarone, some got dronadarone, and about 8% initially underwent catheter ablation. By year two, it was about 20% that had catheter ablation, but again, the reason I like this study is it's practical, and it really is an antirhythmic drug study with adjunct ablation when needed, again, in about 20% of patients. The patients randomized to usual care, predominantly rate control ab nodal blockers. They looked at a composite primary outcome of cardiovascular death, stroke, or hospitalization, and this is really, you know, looking at this composite endpoint, the first study to show a clear benefit, so about a 5% benefit in this composite endpoint of early AFib. Again, these were all patients treated in the first year of their AFib onset, so that may be one of the important differences to affirm, but a clear 5% difference in this outcome, importantly, without any difference in hospital nights per year, so some patients argue it, you know, much more expensive to undergo a rhythm control strategy with multiple admissions and cardioversions, but here they showed that basically the majority of this can be done as an outpatient. So again, the overall outcome, primary outcome was significantly reduced with early rhythm control. This statistical analysis, you have to realize they use a denominator of events per 100 person years, so you'll see the denominator is much larger. That increases the difference and may enhance the statistical difference between groups, but it's published in the New England Journal, so I assume the reviewers, you know, picked up on this, and this is a reasonable way to analyze the data, but it's important to realize that there weren't 6,000 patients in the study. It's looked at by person years, but looking at this analysis, when you look at cardiovascular death and stroke, important to realize, again, for the first time, rhythm control showed both cardiovascular mortality and stroke benefits compared to usual care, and again, by the end of the study, about 72 to 74 percent of patients were actually asymptomatic, so may even have a role for asymptomatic patients, but again, keep in mind the clinical relevance that these differences are small from 1.3 percent per year to 1 percent for death and 0.9, so a 0.3 absolute difference in terms of stroke benefit, so there are clear differences, but the differences are small, so how do I, you know, factor this in when I'm talking to patients? Well, again, I think you could say that if you treat 300 AF patients a year with rhythm control and anticoagulation, you'll save one life, you know, one cardiovascular death and one stroke per year, and I didn't show all this data, but at the expense of three serious but non-life-threatening drug or ablation complications, things like tamponade, syncope, pacemaker, drug toxicity, so again, it depends on the patient, depends on their preferences, but if they don't have dramatic symptoms, there is this kind of benefit, although you have to weigh that against some small risk of a procedure. Again, if patients have symptoms, I think it's pretty easy that if they feel better in sinus rhythm, it makes sense to try and keep them in sinus rhythm. I also think the study shows that depending on the patient preference, either starting with an anti-rhythmic drug or ablation is fine. Some of these patients started with drugs and then went on to ablation. If the drugs didn't work, someone went right to ablation, and either is a clinically reasonable option. I'll talk briefly about anticoagulation. This is just a summary of these studies. We rely on Rocket AF and Aristotle and the appropriate drug that was used, Engage AF, which looked at doxaban. Again, compared to warfarin, we know all these drugs had fewer bleeding events and fewer strokes compared to these newer anticoagulants. Fewer strokes, fewer bleeding events than warfarin, and these days, they're really preferred, again, unless cost prohibits their use. First-line therapy for anticoagulation should be the newer anticoagulants, the factor Xa or thrombin inhibitors. These are the brief characteristics. Again, the bigotrin is a thrombin inhibitor. The others inhibit factor Xa. They all have similar half-lives. I'll leave this chart here for you. There's only a couple of things I'd highlight. One is that, again, the half-life is actually a little similar, but a little bit longer for apixaban compared to rivaroxaban. Yeah, rivaroxaban, we know, was dosed once a day. Apixaban is twice a day. Why is that? Because in the clinical trial, that's the dosing that they chose, and it was at least equivalent to warfarin. It just has to do with the clinical trial, but it's important to realize that the half-lives are similar. I'll also point out that the bigotrin has the fewest drug interactions. For patients, for example, on multiple HIV medicines, that may be CYP3A4 inhibitors. The bigotrin is preferred, but I'll also note that it's the most renally excreted. For patients with renal insufficiency, apixaban is preferred because it's the least renally excreted. I think everyone realizes that we should be using, when we decide who needs thromboprophylaxis in a patient with atrial fibrillation, we use now the CHA2DS2-VASc score, which is shown here. Again, I think clinically, the main thing to distinguish among patients is CHA2DS2-VASc0 patients. You want to identify those at the lowest risk who don't really benefit from anticoagulation. At CHA2DS2-VASc0, none of those risk factors, their stroke risk per year is less than 1%. There's some bleeding risk from anticoagulants, so no clear benefit to anticoagulation. For CHA2DS2-VASc2 or higher, anticoagulation is clearly recommended. For one, there's some difference, although personally, I would still recommend anticoagulation. This slide shows the difference in the U.S. with AHA, ACC, HRS guidelines compared to the Canadian and European guidelines. Everyone agrees no anticoagulation for CHA2DS2-VASc0 patients. Everyone agrees oral anticoagulation for two or higher. The main difference is one, where according to the U.S. guidelines, you have the option of aspirin, nothing, or oral anticoagulation, whereas in the Canadian guidelines, they recommend oral anticoagulation. European guidelines say oral anticoagulation for men, because I think everyone would agree that gender alone, female gender, is not a good indication for anticoagulation. But I think these will get more uniform over time, and with the safety of the DOACs, CHA2DS2-VASc1 is certainly reasonable to offer anticoagulation. Okay, so we talked about drugs, talked about anticoagulation. Let's talk a little bit about ablation. So, again, the current 2017 guidelines are that after breaking through one class 1 or 3 antiarrhythmic drug for symptomatic paroxysmal AFib, it's a class 1 indication level of evidence A, so a pretty strong indication. But again, some people don't realize that even with the current guidelines, without breaking through a drug for symptomatic paroxysmal AF, ablicatheter ablation is still a 2A indication, meaning not backed up by multiple randomized trials, but still enough data that most people would support it. So, again, if a patient, you know, they're a triathlete and felt bad on beta blockers and doesn't want to try an antiarrhythmic drug, they can go directly to ablation with good support in the literature. The standard approach for AFib ablation should be electrical isolation of the preliminary veins, and that, at a minimum, requires demonstration of entry block into the preliminary vein. These are all from the guidelines. You shouldn't just ablate flutter because you're there, but if the patient has a history of typical flutter or inducible flutter, then K-vitracuspid isthmus ablation is recommended. And again, can't emphasize enough, when you do decide for whatever approach to do linear ablation, you should use pacing maneuvers to document completeness of the line and block across the line. You know, I can't overemphasize how many re-do procedures I'm doing from other centers where people just, if you ablate a line but don't prove block, then you're just creating the substrate for re-entry. So, very important. In terms of anticoagulation during ablation procedures, again, studies using all the current drugs have basically shown that uninterrupted anticoagulation, no interrupted doses, including the morning of the procedure, is actually safer than uninterrupted anticoagulation with warfarin. So, that's the standard approach, I would say, today. Again, shown here, for patients who've been anticoagulated with warfarin or DOACs, performance of the ablation procedure without interruption is recommended. So, I think that's important. So, again, I think, you know, when we started doing catheter ablation, we started ablating initially the focus out deep in the pulmonary vein. Then we started with more osteoablation. Now, we've realized the importance of the antrum taking the part of the left atrium proximal to the pulmonary vein. So, taking the part of the left atrium proximal to the pulmonary veins, which also has pulmonary venous tissue, is also important to ablate. We know that the triggers that start AFib can be present in the antrum in addition to distally in the pulmonary veins. We know that the meandering wavefronts, meandering re-entrant wavelets can anchor at the pulmonary vein left atrial interface. And we talked about the GPs, the local autonomics, which are also present at the pulmonary vein left atrial junction. And that's why this, you know, so-called antral pulmonary vein isolation ablation that includes the pulmonary veins and the proximal left atrial tissue is really the standard for pulmonary vein isolation. So, when we have some kind of multipolar catheter in the left atrium and in the pulmonary vein, we'll see these signals, in this case, to the left pulmonary vein, the pulmonary vein signals kind of overlapping with the left atrial signals. And as we gradually ablate around that pulmonary vein, we'll see delay of the pulmonary vein signals and block from the left atrial signals. And then we'll see abrupt disappearance representing entry block or isolation of the pulmonary vein. And if you're seeing pieces of the pulmonary vein go away, well, this electrode goes away, then another one, then another one, you're probably too close to the pulmonary vein ostium. When you're proximal, you really should see the whole vein isolate at once. This is an example of lesions around the pulmonary veins leading to pulmonary vein isolation. Now, although it's not mandatory in the guidelines, what you really care about is that triggers won't get out of the pulmonary vein to start atrial fibrillation. So, we also like to prove exit block. So, we pace from a catheter inside the pulmonary vein and show that that does not get out to the remaining atrium. So, in this case, we're pacing in a pulmonary vein. We can see with the red arrows that we're capturing this local pulmonary vein sleeve with a circular mapping catheter and that that is at a separate rate and not conducting to the rest of the atrium. So, now we have entry block, we have exit block, and that is our standard endpoint for pulmonary vein isolation. Now, an important adjunct to that can be looking for acute pulmonary vein reconnection with adenosine. It's also frequently used as a board question because, you know, again, there's not that many questions you can ask about AFib, and this actually has some mechanistic understanding. So, here is a circular catheter in a pulmonary vein showing isolation. You also see coronary sinus catheter, an ablation catheter, and a catheter in the right atrium. We're giving adenosine, and what we see is transient reconnection of the pulmonary vein. Why does that happen? So, we know, again, perhaps due to catheter movement, contact, that some cells may be injured but not completely destroyed. And so, those cells have an elevated resting membrane potential, perhaps above or near threshold, so that when the next stimulus comes along, they don't depolarize, and the vein appears blocked, but then those cells can heal and recover. What adenosine does is hyperpolarizes the cell membrane, so then these cells can conduct again before they wash out. So, adenosine leads to hyperpolarization of the cell membrane via the IKADO channel that leads to recurrent PD conduction. Should you ablate these areas of recurrent conduction? There's some controversy. There was a Canadian study that showed better outcome when you ablated them. There were some Japanese studies that did not show a difference. Again, I think you want to…anyone can acutely isolate a pulmonary vein, I would say. You want to keep them chronically isolated, so anything you can do to help prevent chronic reconnection, I think, is probably helpful. Now, differential pacing, again, another important concept, and something that you'll see on board-style questions, but it's important clinically, just in practice. So, as you're ablating, you may see some very complex potentials, and you need to sort out which potentials are due to which structure, because the left…particularly around the left pulmonary veins, as shown here, there's multiple structures that can cause electrical signals on your catheter, the left atrium, the pulmonary vein, the appendage, the ligament and marshal, adjacent pulmonary veins, and some combination. This is a nice review article from St. Master of Botham, but basically, with a catheter in the pulmonary vein, you've got these three signals you'll record, the left atrium, left atrial appendage, far field, and the pulmonary vein potential, right? So, shown here, on the top, or I'll say the middle, you're pacing from the left atrium, you'll pull in the left atrial potential, and you'll see the pulmonary vein signal light, and that tells you the signal C that the vein is not isolated. You can also pace from the left atrial appendage, right, because that often overlaps with the pulmonary vein signal. You'll pull that signal in early, and you'll see the left atrial appendage late. If all the signals get pulled in early, and you don't see anything late, then you know that the pulmonary vein is isolated. Let's just look at an example. So, here we have a circular catheter in the left superior pulmonary vein. You know, there's some sharp deflections there, so, you know, you might say, well, is that still connected? Do I need to ablate more, or is that pulmonary vein still isolated? And so, what you can do is pace, so move the ablation catheter, in this case, into the left atrial appendage, and we pace from the appendage, and what we see is we're bringing in all these sharp signals early. There's no late signal. So, in fact, the pulmonary vein is isolated, and these are just fractionated signals related to ablation, and again, it's important because you're not just ablating signals that are there that aren't really related to the pulmonary vein, and that could lead to additional issues. Here, different case, but again, now we're pacing again from the appendage because we had some overlapping signals, and now we see this small late signal that's not brought in. It's actually late. So, that is a pulmonary vein signal, and tells us that we still have more to do to isolate the pulmonary vein. So, these differential pacing maneuvers are kind of an important part of proving entry block into the pulmonary vein. Again, what I've been talking about so far is ablation using heat or radio frequency energy. Another common approach is using the cryo balloon or freezing. There are different manufacturers now that have different balloons and generally they come in different sizes. This is one particular balloon that comes in 23 and 28 millimeters. Most people exclusively use the bigger balloon with an over the wire balloon that inflates and then the Freon is injected into the balloon causing freezing simultaneously around the ancient of the pulmonary vein. This was compared in a prospective randomized study the cryo balloon to drug therapy. You can see that again, this is patients who have already broken through one drug that drug therapy has very poor efficacy and allowing some redos in the blanking period the first 90 days at about a 70% freedom from AFib at a year. So really no comparison to drug therapy. The cryo balloon approach is fairly fast but does have some additional morbidities to know about. One is the risk of injury to the phrenic nerve, small risk potentially of pulmonary vein stenosis. This is a test x-ray again, you may see this in the patient with shortness of breath after cryo balloon ablation. You can see obviously hopefully that the right hemidiaphragm is elevated. This can happen after any type of ablation RF or cryo but a little more common with cryo. And there's certain maneuvers you can take to mitigate this. But if you see this on a chest x-ray, this is indicative of phrenic nerve palsy. Many of these may recover over the ensuing months. Is there a difference in efficacy? Again, this was the large fire and ice study run by Carl Heinz Cooke where they compared radiofrequency ablation and cryo balloon as shown in the left panel. Important to realize really no difference in outcome both with about a 60, 65% freedom from AFib over you can see about 65% freedom from AFib at a year. The differences really were that the procedure duration and left atrial dwell time were shorter for cryo balloon. Although I should say this was before high power short duration RF ablation which is short in the time for those procedures as well. So there are two studies now that have looked at primary cryo balloon ablation for paroxysmal AF. So for patients with paroxysmal AF as first-line therapy essentially before they received antiarrhythmic drugs randomizing patients to ablation versus antiarrhythmic therapy for maintenance of sinus rhythm. Both, one by Jason Andrade in British Columbia one by Osama Wazni at the Cleveland Clinic both showing about a 30% absolute improvement in maintenance of sinus rhythm with ablation over drug therapy. You'll see some differences in the outcome. And I think it's important when you're talking to your patients about AFib ablation. So in the Wazni study there was a 75% freedom from AF at a year in the ablation arm and 45% on drug therapy. See the numbers were lower 57% freedom from AF in the ablation group and the Andrade study and 30% with drug therapy. Really the difference in these two studies was that the study used standard monitoring at six and 12 months and otherwise symptoms whereas the Andrade study implanted loop monitors with 24 seven monitoring of arrhythmia burden. So, this tells you that with intermittent monitoring you're basically getting symptomatic freedom from AFib and about 75% of patients which is good for patients to know. If you really wanna know how many people are kind of quote cured having zero AFib it's closer to 60% but either way you're gonna do better than drug therapy at a year. What about more persistent forms of AF? So AFib once it starts persists until cardioversion. Again, everyone knows that success rates are lower in this group that they have as we talked about remodeled atrial substrates or recurrence rates are much higher and people have looked at what can be done to improve outcome in this group. Some people have advocated ablation of triggers of AFib outside of the pulmonary vein so-called non-pulmonary vein triggers unmasked with isopropyl. They both talked about cafes or complex fractionated atrial electrograms. People talk about adding linear ablation, ablation of other thoracic veins, isolating entirely the posterior left atrial wall, isolating the left atrial appendage, alcohol ablation of the vein of Marshall or other signal processing guided approaches such as targeting rotors or drivers. I'll just share this one study, STAR-AF2, which was done by Atul Verma in 2015. They looked at three different strategies for persistent AF, PV isolation alone, PV isolation plus fractionated electrograms which was a common approach at the time or PVI plus linear ablation including a left atrial roof and mitral isthmus line. They actually randomized patients one to four to four because most of the investigators didn't think PVI alone was really a good approach. But it turned out as we know, of course, that there's no difference in outcome. In fact, the PVI alone group shown here in black actually trended a little bit better than the other groups. So that pretty much put to rest, I would say, the idea of ablating electrograms or empiric linear ablation for AFib. And honestly, we still don't really know what the best targets are outside of the pulmonary veins. There have been two other, I would say, important positive studies. One is the BELIEF trial by DiBiase and colleagues. They looked at electrical isolation left atrial appendage and shown here found a significant improvement in outcome compared to patients who didn't have that ablated. Again, my personal view is that isolation of the appendage is not a good approach because of the increase in stroke risk and the need for uninterrupted anticoagulation or appendage closure. I think strokes, again, are the worst outcome of AFib, but it's important to realize from a data standpoint, there is some data supporting better freedom from AFib and persistent AF. Again, it might be reserved for very refractory cases. The other, I think, important study was Miguel Valderrabano who looked at alcohol ablation into the vein of Marshall as part of the initial strategy in persistent AF in addition to pulmonary vein isolation. And you'll see, again, about a 10, 11 percent benefit in people who got the additional vein of Marshall ablation. Again, this uses tools that may not be as familiar to many of us, but there is data clearly supporting vein of Marshall ablation and persistent AF as having about a 10 percent outcome improvement. The only thing that made it into guidelines, though, because these studies were a little more recent, is ablation of non-pulmonary vein triggers so that if a focal trigger that initiates AFib is identified outside the pulmonary vein, that should be targeted. Posterior wall isolation may be considered, but still the data is unclear, and the guidelines at least say that other approaches really don't have well-supported data. Finally, I did want to point out this important group with Tachybrady syndrome. So patients with AFib and either conversion pauses or concomitant bradycardia, where in the distant past, someone might have considered a pacemaker plus antiarrhythmic drug therapy, and that is still an option, but I think most people would argue in otherwise young, healthy patients that an AFib ablation is a better option. The AFib ablation, in addition to the fact that if you remove the AFib, they often won't have the bradycardia, but there's also vagolitic effects of AFib ablation that seems to limit these bradycardic episodes, and so this seems to really work well for these patients with Tachybrady syndrome, and I think for most patients where AFib ablation is an option, that's a better option than pacemaker plus drug therapy. Again, if patients either don't prefer or maybe for comorbidities can't undergo an AFib ablation, then certainly pacemaker and drug therapy is reasonable. Are there other things beside all these different ablation approaches that we can do? This was from when we actually had courses in person, the research that John Miller undertook, and one thing we've learned from Pross Sanders and his group in Australia is the importance of weight loss for AFib. These studies looked at the intervention in these studies is weight loss, and they showed both in terms of the number and duration of AFib that there's a dramatic decrease in AFib episodes in patients who lose weight. This was the AREST-AS studies looking at single and multiple procedure success in two groups, and this is after ablation, so groups, so patients who were overweight and had at least one risk factor, hypertension, diabetes, hyperlipidemia, sleep apnea, smoking, or alcohol excess, and then patients who are randomized to just getting advice or more stricter risk factor modification, including treatment of sleep apnea, weight loss, treatment of hypertension, and you can see the dramatic difference in AFib maintenance. Both of these groups got ablation, right? If you said RFM was a new catheter, everyone would buy it because look at the improvement in outcome, but this is just with a risk factor modification after single ablation and multiple ablation. The multiple ablation's only 48% if you're not treating these risk factors, so important lesson for us and our cardiology, I think, and associated professional colleagues is that if we're just treating obese hypertensive patients with ablation and not treating these risk factors, we're really not doing patients a service. So did make it into the guidelines that weight loss is important as a strategy for patients with AF. You have to consider the patient's BMI when discussing AF ablation, and screening for sleep apnea, very important in AF patients. To briefly touch on AFib in congestive heart failure, because we see this frequently, this slide shows that in patients with heart failure, about 30% over 10 years will develop atrial fibrillation. It was important, a CASEL-IS study run by Nasir Maroosh, where these were a specific group of patients with an EF less than 35%, NYHA-2 or greater heart failure, who had an ICD present and were randomized to either rate control primarily or catheter ablation. And in addition to better reduction in AFib, they actually found a mortality reduction. Again, one of the few studies that showed a mortality reduction with treatment of AFib, pretty impressive. I mean, a 12% absolute mortality reduction. And if you look at other studies that have come up with treatments that are pretty standard for heart failure, for example, treatments like beta blockers, ACE inhibitors, prophylactic ICDs, the mortality benefit from CASEL-AF was actually greater than many of these studies. So in patients with heart failure, again, not that they've been in AFib for 20 years, but heart failure. And then especially if it's exacerbated with a recent onset AFib, treatment of AFib can be an important adjunct strategy for them. Finally, I have to mention the CABANA study, large contemporary study run by Doug Packer. You know, this has been out a few years now, so it is potential for questions. For example, if you're taking the boards, but important to know for practice as well. So more than 2000 patients, right? They had to be either over 65 or have a transvascular risk factor, and they were randomized to catheter ablation versus drug therapy, which could have been rate or rhythm control, but the vast majority in drug therapy were actually under rate control. All patients in both arms importantly were anticoagulated. And in terms of the primary endpoint, death, disabling stroke, bleeding or cardiac arrest, again, no difference overall between drug therapy and ablation, although at least in this case, the hazard ratio for ablation leaned towards improvement as opposed to as we saw in a firm where it leaned towards harm. Again, in terms of all cause mortality for the intention to treat arm, there was no difference. Again, we can talk about on treatment arm and differences and the risks, you know, the caveats of undoing the randomization strength of the study, but I think this is the important outcome to drive home. It was no difference in mortality. And, you know, but if you look at AFib control, again, as we saw with most of the studies, significantly, you know, ablation is gonna be much better than drug therapy in terms of freedom from AFib about 50% better. So less AFib at four years, but no clear improvement in mortality, although as again, EAST-AFNet4 suggests early treatment, whether it's drugs or ablation, may have a small benefit in cardiovascular mortality. So, you know, what can we conclude from Cabana? Which of these statements? I would say, we can certainly say that AF, ablation reduces AF burden significantly more than medical management, and that if ablation reduces hospitalization significantly more than medical therapy, but we can't conclude, at least from Cabana, that mortality was reduced or the composite was reduced. Last thing is, again, if we're gonna talk about ablation, we have to mention complications. These are important, particularly as we're dealing with patients who may be minimally symptomatic from their AFib, pericardial effusions and tamponade, some mechanical complications, obviously the risk of stroke, embolic events, pulmonary vein stenosis, again, less common, but still happening out there from ablating too far in the pulmonary veins, the kind of dreaded worst complication of left atrial esophageal fistula or other vascular access complications. The oldest slide from 2010, just a survey showing that there was a 0.1% mortality from AFib ablation, so patients have to know that coming in, and you can see the various types of complications, including stroke, TAA, pulmonary vein stenosis, and atrial esophageal fistula, about 0.04% of the time. This becomes very important in clinic when you have ABPs or colleagues who are following patients after ablation, and we teach them all as they're learning about various symptoms. We tell patients the first month you really need to call us with any complaints, and this is a nice chart from actually the guidelines that we put together with symptoms, what the possible diagnoses are and evaluations, so for example, shortness of breath after ablation, volume overload could be pneumonia from intubation, pulmonary vein stenosis from ablation, or phrenic nerve injury, and so a physical exam, chest X-ray, and fluoroscopy, and so you have this slide, which I think is useful for clinical practice. Again, late fever, dysphagia, and neurologic symptoms are a real red flag where you worry potentially about alveolar esophageal fistula. Avoid endoscopy, which can insufflate air into the esophagus. Chest CT or MRI is really the diagnostic tool of choice. Okay, so to summarize all that information, we know that AF is typically triggered by pulmonary vein firing, and that's exacerbated by sympathetic stimulation and maintained by pulmonary vein left atrial reentry, and that is stimulated by parasympathetic stimuli. We know that AF tends to promote more AFib or AF begets AFib through both structural, which is not reversible, and electrical remodeling, which is reversible. We know that antiarrhythmic drug risks and benefits, in particular drug, should be carefully considered and used generally to improve symptoms and minimize side effects. We know that use of the novel anticoagulants is preferred over Warfarin, and pretty much should be used in anyone with a CHA2DS2-VASc greater than zero. The cornerstone of AF ablation, whether it's parasympathetic or persistent, remains pulmonary vein isolation. Other targets, I'd say, are still investigational. Important to use pacing maneuvers to distinguish near-field from far-field signals on our mapping catheters to judge when we have achieved pulmonary vein isolation. While there hasn't been clear mortality, overall mortality benefit with maintenance of sinus rhythm, in patients with heart failure and AFib, there is evidence of lower mortality with maintenance of sinus rhythm. And for recent AF onset, less than a year, there is more recent data that I showed you from Beast-AFNet4 that does support maintenance of sinus rhythm for reducing cardiovascular mortality and morbidity. So I will stop there. Obviously, feel free to email or attend the discussion sessions if you have any questions. Thank you very much.

atrial fibrillation

mechanisms

pharmacologic treatment

non-pharmacologic treatment

catheter ablation

pulmonary vein isolation

risk factor modification

East AFNet4 study

CABANA study