Hello and welcome to Core Concepts in Electrophysiology. This is Ed Gerstenfeld from the University of California, San Francisco, and for this lecture we'll be covering mechanisms, pharmacologic and non-pharmacologic treatment of atrial fibrillation. It's quite a lot to cover, so sit tight and we'll try and get to everything you want to know about atrial fibrillation over the next hour. These are my conflicts, so we're going to cover some basics about the mechanism of atrial fibrillation, we'll talk about pharmacologic therapy, anticoagulation, catheter ablation both for paroxysmal and persistent AF, we'll talk about AF in congestive heart failure, and finally risk factor modification. So atrial fibrillation was really first recognized and described in the early 1900s, and initially there were two competing hypotheses about the mechanism of AF. The first on the left proposed predominantly by Scherff was that AFib was due to rapid focal firing, firing that occurred from a cell, a group of cells, so rapidly that homogeneous conduction throughout the atrium was not possible, and that resulted in fibrillatory conduction and they had animal models to demonstrate this. The second was based on largely computer models, and that was by Gordon Moe, and that was the multiple wavelet hypothesis, that AFib was not due to focal firing, but multiple re-entrant wavefronts, some of which canceled each other out, some of which sprouted off daughter wavelets, and led to self-sustained AF without focal input. And these two groups published papers arguing each hypothesis back and forth until the 1980s, when Merzalessi's group in the Netherlands was first able to map atrial fibrillation using two egg-shaped electrodes in the atrium, initially in canines. And what they found with this relatively low-ish resolution mapping was generally the multiple wavelet hypothesis, that there were multiple re-entrant wavefronts that interacted in a self-sustaining manner. They did not see any focal firing, although notably their mapping electrodes didn't extend into the pulmonary veins, and for, you know, the next decade, this pretty much put to rest the idea of focally triggered AFib, and everyone accepted the multiple wavelet hypothesis as a mechanism of AFib. That led to the MACE procedure, a surgical procedure where there were actually incisions made in both the right and left atrium, where the atrium was actually cut up and then sewn back together, creating lines of block. And the idea was this prevented any of these re-entrant wavefronts from re-entering each other, and was effective the first time as an interventional procedure in treating AF. Probably one of the major surgical incisions was this encircling lesion set around the pulmonary veins that was without any knowledge of the pulmonary veins as triggers of AF. The problem with this procedure was it is an open-heart surgical procedure, and there was morbidity and mortality, including a, you know, roughly 20% need for pacemaking after the surgery, and a complex surgery that was really only used in a minority of very resistant cases by a few skilled surgeons. But then the field really changed dramatically in 1998, when Michel-Hazard Guerre in Bordeaux, France, first described that the triggers, you know, not during sustained AF, but during the initiation of AF, almost always came from the pulmonary veins, and there were sleeves of atrial muscle that extended into the pulmonary veins. And in this first publication in the New England Journal of Medicine, 96% of the triggers came from the pulmonary veins. And by ablating these triggers focally inside the pulmonary vein, they were able to render about 60% of patients free of atrial fibrillation, really a dramatic paradigm shift in managing atrial fibrillation. Now, the other thing that was well-described is, you know, the longer patients were in atrial fibrillation, the harder it was to restore sinus rhythm. So in this study, when you look at cardioverting patients who had been in AF for more than 12 months before ablation in yellow, compared to those who were in AF for less than 3 months, when you look 6 months later, you see that the recurrence rate is much higher in those with a longer pre-existing burden of AF. And that goes along with this other classic basic model by Maritza Lessi's group, where they took chronically instrumented goats and actually created a pacemaker that would burst paste them repeatedly into AF, and led to this paper with the provocative title that we all now use when talking to patients, which is atrial fibrillation begets atrial fibrillation. The more AFib you have, the more AFib you end up with chronically, because what they found is a burst at baseline would lead to a few seconds of AF, but after 24 hours of sustained AF, then this burst would lead to longer bursts of AF, and if they kept burst pasting-induced AF over time, after 2 weeks, you ended up with sustained AF. So just AF itself led to a progressive remodeling and the maintenance of sustained AF. When they looked at the electrophysiologic properties of why this occurs, there are two main electrophysiologic properties we look at, conduction velocity and refractory period, and they found over time, not much change in conduction velocity, but what they found was a progressive shortening of the refractory period, as well as reversal of the rate adaptation to refractory period, so that the shorter refractory period led to a shorter left atrial wavelength, and more easily inducible atrial fibrillation. Why does ERP shorten? It's been looked at in several studies, this one by Bosch and Nittel and others, and mainly it seems to be a decrease in the L-type calcium channel, which leads to an abbreviation of the action potential duration shown here in red compared to sinus rhythm in black, and that leads to shortening of the ERP over time. But what was noticed is this shortening of the ERP, once sinus rhythm is restored, it reverses relatively quickly over 2-3 days, and it doesn't seem to be what fits what happens clinically, right, where we cardioverte someone, and even weeks later, they have a higher likelihood of reverting to AF, so it's thought there must be a second factor involved, other than just the shortening of ERP that leads to this process of AF, begetting AF. When they looked histologically, what they found, that there were structural changes occurring, including, probably most importantly, fibrosis, interstitial and replacement fibrosis, and also myelinolysis, and other structural changes, and that these changes in the fibrotic changes did not really reverse at all once sinus rhythm was restored. So it seems like the electrical remodeling happens over the short term and reverses, but once you're in AF for a period of time, you know, 16 weeks in these animals, you have structural remodeling which persists, and this leads to more zigzag atrial activation and contributes to reentry, and enhances the substrate for AF. So there's still not a clear mechanism, despite all the ablation modalities we'll talk about, that we understand for why AF occurs, but several possible mechanisms. There's in the lower left, the Scherff model still, that there's a focal trigger, or more recent mapping studies from Al Waldo showing potentially multiple focal triggers that drive AF. There's a multiple wavelength hypothesis from Mo and Alessi, perhaps with pulmonary vein firing contributing now to maintenance of that multiple wavefronts. There have been studies showing the potential of rotors, sort of stable circuitous rotors that drive AF. This has been not substantiated in more recent mapping studies. And then finally, Alessi de Groot and Shotton papers showing that actually the three-dimensional nature of the atrium, that there's endocardial to epicardial dissociation and breakthrough due to intramural fibrosis that also may contribute to AF. But it may be different in different substrates as well, different patients, but there's no overlying mechanism that's clearly known. We do also know that the autonomic nervous system plays a large role in AF, and that's both the extrinsic nervous system, including the sympathetic stimulation from the stellate ganglion and parasympathetic stimulation from the vagal trunk, as well as the intrinsic nervous system of the heart, the ganglionated plexi, which contain both sympathetic and parasympathetic fibers. And just to simplify that as an overview, the adrenergic stimulation with stress tends to contribute to the triggers for AF, both through enhanced automaticity, early and delayed atrial depolarizations, whereas the parasympathetic substrate, patients at rest, for example, commonly will have AF at night when they're sleeping, and that seems to affect the substrate more. So parasympathetic fibers innervate the atrium heterogeneously and lead to shortening of the axopotential. So parasympathetic stimulation leads to heterogeneous shortening of the axopotential. Some areas are short, while others are long, and this also tends to contribute to the substrate amenable to maintain reentry. That's why some patients may have AF at night, and often it's a combination of both sympathetic and parasympathetic stimulation that triggers AF in patients. Okay, so that's the background about mechanism. Now let's jump to management of atrial fibrillation. So we know AFib tends to progress over time. That time of progression is variable. We know people on the left with frequent premature atrial complexes have a higher risk of AF, and then AF often, although not always, starts out as intermittent episodes that can progress over time to more persistent AF. This is typically defined as AF that lasts for more than seven days or requires an intervention such as a cardioversion-determinant AF. And then after a year of persistent AF, it's now turned longstanding persistent AF. We tend not to use the term permanent AF anymore because AF can be restored to sinus rhythm. But the important things to realize in terms of the substrate are that at the early stages, the substrate for AF is dominated by pulmonary vein firing with less of the fibrotic re-energy-prone substrate. But as we showed in the animal models, as AF becomes more persistent, you have a dominant substrate and the focal firing is less important but still may trigger, but maybe one PAC will put someone into persistent AF. So that substrate evolves with progression over time and with our age. The first thing we always think about clinically is controlling the ventricular rate because many patients will conduct rapidly during AF and have a rapid ventricular response that can lead to symptoms, palpitations, shortness of breath, but also in some patients, cardiomyopathy. And this is from the guidelines, but just emphasizing our common knowledge that first-line therapy typically would be beta blockers or calcium channel blockers in people with preserved LD function. If you have left ventricular dysfunction, we're not going to use the calcium channel blockers, so either beta blockers, and potentially adding digoxin if needed. It's usually not favored as a single agent these days, digoxin. And in very sick patients, ICU patients where heart rate needs to be controlled and can't, amiodarone actually is very good at ventricular rate control, although has other toxicities and also the risk of converting someone to sinus rhythm if it's not intended. What is heart rate control? At least from the firm and some studies, it's been defined as heart rate less than 80 beats per minute at rest or less than 110 with moderate exercise. How strict you need to be has been looked at and really depends on symptoms. In terms of pharmacologic therapy to maintain sinus rhythm, this is again from the latest 2023 guidelines. In patients with no structural heart disease, first-line therapy includes any of these four drugs listed. These stars are my own because I really think some with no structural heart disease, flecainide and propafenone are preferred because of the lack of other side effects and tolerability. It's important to recognize that we shouldn't use this in patients with coronary artery disease, so often a screening, a stress test is done before initiation. If none of these drugs work, amiodarone is a second-line agent to a recommendation. Sotalol has actually been moved to a 2B based on studies showing lower efficacy. In people with structural heart disease, again, this is my star, or reduce the ejection fraction. We can't use 1C drugs. In fact, they're listed as class 3, potentially harmful, so you don't want to use these drugs in anyone with reduced ejection fraction. Personally, I prefer tofetolide, which has much better long-term tolerability, but amiodarone is something that is commonly used because it's easy to start out of the hospital. With tofetolide, as we know, it's mandated on the labeling that patients have to be admitted for the first five doses for monitoring. Sotalol could also be used as a 2B. Dronetarone is another possibility in patients with structural heart disease, although if they have a recent hospitalization for heart failure in the last month or persist in AF, then there are studies showing harm and increased mortality, but in someone with a reduced EF and no heart failure, Moltac or Dronetarone is also an option for therapy. How do these drugs affect the electrophysiology? Remember flecainide and bupapenone are class 1C drugs, and mainly slow phase 0 or action potential upstroke, and therefore slow conduction in the atrium. Tofetolide, Sotalol, and Ibutelide affect repolarization by blocking IKR or IKS, that's slow or delayed rectified potassium channels, and they lengthen action potential duration, and amiodarone basically affects all the channels in the heart and has an effect on all of these channels. Obviously, the patient's in paroxysmal AF, they're converting on their own, there's no need for cardioversion. For patients in persistent AF, there's several ways to restore sinus rhythm. One is with direct current cardioversion, typically these days we'll use biphasic synchronized cardioversion starting around 200 joules. Intravenous anterithmic drugs are used less commonly these days, but for a patient in the ICU, for example, Ibutelide is a drug that's approved for intravenous cardioversion, it's infused as 2mg over 30 minutes, it does have a 2-3% incidence of Torsade, so pre-treating with magnesium is often advisable. AV amiodarone is commonly used, but really, most of the early effects are beta-blocking effects, so it has a low incidence of converting AF to sinus rhythm acutely, but can be used. Ibutelide was used in the past, but again, it's a negative inotrope, also the metabolites can build up in renal insufficiency, so probably a third-line agent. And then finally, what I think is underutilized clinically is pill-in-the-pocket therapy, so use of an oral agent, which patients can use at home, so once, assuming they're appropriately anti-coagulated, we'll talk about that, and that their heart rate's controlled, so you do want to perceive this if they're not armed one by a beta-blocker, a calcium channel blocker, but can use oral bolus dose of either Glucanide, 2-300mg, or Propathenone, 3-600mg, so patients can take this at home and convert themselves out before they develop more persistent AFib. For early-onset AF, it's actually pretty good, about 75% by 6-8 hours, it is recommended that patients be monitored the first time they use this, because there are some adverse events, including having a conversion pause, organizing AFib to slow flutter that can conduct one-to-one. But after that, then patients can take this at home. I think for patients with infrequent but bothersome episodes, where they're maybe not ready for ablation, they have episodes once or twice a year, or they're very young, fill-in-the-pocket therapy is very useful. You know, the first study looking at whether it's really worthwhile maintaining sinus rhythm versus just leaving people in AF was the AFFIRM study, big study run by Al Waldo, over 4,000 patients, randomized to either a rate control, just leaving people in AF and controlling the rate, versus a rhythm control using sequential cardioversion and rhythmic drugs to maintain sinus rhythm. And surprisingly, what they found was that at the end of about three years of follow-up, there was no difference in mortality between the two groups. In fact, the rhythm control arm actually trended to be a slightly higher mortality. But importantly, these drugs, you know, weren't so effective, so it turned out many people in the rhythm control arm ended up in AFIB, and some people in the rate control arm ended up in sinus rhythm. But this study at least did not show a mortality advantage to maintenance of sinus rhythm. One important finding was actually that there were more strokes in the rhythm compared to the rate control arm, right? If you're in sinus rhythm, why would you have more strokes? And it turned out a lot of docs, when they saw the patient in the office got an EKG and they were in sinus rhythm, were stopping their anticoagulation, which was Warfarin at the time. And we know now that even patients who are in sinus rhythm in the office are often having asymptomatic episodes of AF at night. So one important lesson we learned from AFFIRM was that even in patients in sinus rhythm on antiarrhythmic drugs, if they have stroke risk factors that merit anticoagulation, the anticoagulation needs to be continued. You don't want to stop anticoagulation, because that will lead to a higher stroke risk. So unfortunately, AFFIRM led many people to, many docs and internists to just say, oh, it's fine to stay in sinus rhythm because it's not a real benefit to being in sinus rhythm compared to leaving patients in AF. And I think that was, you know, we know now probably a disservice to many patients. But many patients still, you know, prefer drug therapy or want to start with drug therapy. Important to tell patients, you know, we don't expect 100% efficacy, but basically we're decreasing the probability of maintaining, of staying in AF. And that a single recurrence isn't necessarily a failure. You may need a cardioversion once a year. But if you're mainly, you know, staying in normal rhythm, that drug may be helpful. So a more recent study, which I think was more helpful, was EAST-AFNET4, which was a randomized study that was stopped early, sort of a modern, you know, rehashing of the AFFIRM trial. But in this trial, patients were randomized to rhythm control, which could be either antiarrhythmic drugs or catheter ablation. So that was added because, again, the problem with AFFIRM was that many of the patients didn't stay in sinus rhythm. And many of the common drugs were used, propafenone, flaconide, shown here on the left, you know, some dronetarone, some amiodarone. And again, about 8% of patients in year one into one ablation, about 20% by year two. So they were better at maintaining sinus rhythm. And usual care was primarily rate control, as seen here in gray. Most patients were not on an antiarrhythmic drug. Some of the characteristics of the patients, again, 2,700 patients, mean age of 70, about half female, about a quarter with persistent AF, and about a third who are asymptomatic. And at least based on the composite endpoint, which included death, stroke, or hospitalization with heart failure, this was the first study to show a benefit from early rhythm control. I should mention, these are patients who had AFib for a year or less. So not treating patients very late in the course of AF. But it did show a significant reduction in that composite endpoint. By about 5%, without any increase in hospitalization. So the first time showing that, in fact, there was a benefit to maintaining sinus rhythm in terms of reducing heart failure, hospitalization, stroke, and death. Not so important study. Now, what about anticoagulation? Again, we know that the left atrial appendage is this outpatching in the left atrium, and is a common source of thrombus, and therefore, stroke in patients with AF. In terms of patients' risk of stroke, we generally use, these days, the CHEDS VASc score, which has all these components, a total of nine, including things like hypertension, congestive heart failure, age over 75. Importantly, hypertension is any history of hypertension. I found patients often ask, well, I'm not hypertensive now, but it doesn't matter. It's epidemiologically determined, so that any history of hypertension counts, any history of diabetes. And for heart failure, it actually can be systolic or diastolic dysfunction, still categorized as heart failure. So you add all these up. And I think, you know, the risk of stroke obviously increases with CHEDS VASc score. To me, the most important is that CHEDS VASc zero has a low risk of stroke, less than 1%, and anticoagulation generally is not indicated. CHEDS VASc two or higher, everyone would agree on anticoagulation. Personally, I think with the CHEDS VASc of one, guidelines differ, and sometimes aspirin or oral anticoagulation is recommended. But personally, I think anything above zero anticoagulation is recommended because strokes can be really consequential for patients. But it's the CHEDS VASc zero patients where anticoagulation isn't required outside of, you know, just around the cardioversion or ablation. We'll often start them in anticoagulation beforehand and continue it for a month after. You know, obviously, we've moved from warfarin now to the direct oral anticoagulants. These are shown here along with their characteristics. I think everyone's familiar with these. Just to mention, Dabigatran is a direct rombin inhibitor, so it's a bit different than the other drugs. Main difference is a high percentage of renal excretion, so not great to use in patients with renal insufficiency, but it has the least drug-drug interactions. So, for example, in patients who are on multiple HIV drugs that interact, this can often be safest. I'll point out between rivaroxaban and apixaban are both factor Xa inhibitors. Rivaroxaban and doxaban also are dosed once daily. Apixaban is dosed twice daily. I'll just point out that the half-lives are quite similar. So, the reason that, you know, rivaroxaban and doxaban are dosed once daily is just that that's what was chosen in the clinical trials. Both were found to be non-inferior to warfarin, but again, the pharmacokinetics could support twice-daily dosing if that's how they were dosed. And I'll point out that apixaban has the least renal excretion. So, in patients with renal insufficiency or even renal failure, apixaban is probably the best choice. And again, all of these drugs can interact with CYP3A4 inhibitors. Again, in this original, all these studies comparing warfarin and the direct oral anticoagulants that are found in terms of stroke risk, not just to be non-inferior, but overall superior to warfarin. And same with bleeding, particularly eloquence, which was found to have significantly less bleeding than warfarin. So, really, other than patients with mechanical valves or rheumatic heart disease, the DOACs are favored over warfarin and certainly easier for patients to manage since it's just a single dose and there's no serial blood testing needed. Patients often worry about bleeding risks, and there are reversal agents now for all these drugs. Idaricizumab is a monoclonal antibody to reverse dabigatran, and adnexadalpha is a reversal agent for the Factor Xa inhibitors. So, all these can be immediately reversed, and there are other options as well as outlined in this table. You know, what to do about device-detected AF in terms of anticoagulation has been a long-standing question. Someone gets a pacemaker, you know, they have 30 minutes of AF detected that's asymptomatic. What's the risk-benefit of anticoagulation? We got a lot more data recently that could be important for you to know about, but also could be asked about on the boards. These two big studies, NOAAFNet6 and Artesia, both randomized patients with a CHA2DS2-VASc score of at least 1 to anticoagulation for Artesia with epixaban versus aspirin, and NOAAFNet6 to adoxaban versus placebo. NOAAFNet6 did not show a benefit to anticoagulation. Artesia did, but I think subsequent analysis has shown, it's mainly a sample size issue, that both showed about a 0.5 to 0.8 percent reduction in stroke or systemic embolism with systemic anticoagulation at the expense of an increase in bleeding, about 0.75 to 1 percent. In Artesia, the sample size was high enough that the stroke reduction was significant, but that has a ratio of 0.63. In NOAAFNet6, there was a reduction, but an overlap of one, so not significant. But I think we can say that both studies, if you put them together, do show about a half to 0.8 percent reduction in stroke risk, but at some expense of increased bleeding, and so it ends up being a shared decision-making, looking at the patient's bleeding risk, stroke risk, and having that discussion. Again, I think subsequent analyses of these data have been helpful. This is from Artesia, which showed that the CHA2DS2-VASc greater than four patients, they're really the ones at highest risk of stroke, and they benefited most from DOACs compared to not anticoagulation patients. The CHA2DS2-VASc less than four really didn't have much benefit, and the equal four was sort of borderline. So if you are counseling patients with, again, less than 24 hours of device-detected AF, it's the CHA2DS2-VASc greater than four patients that benefit most from anticoagulation, where the stroke risk outweighs the increase in bleeding. Okay, let's move now to catheter ablation, which has become a very common treatment approach to atrial fibrillation for all of us. Again, as mentioned, we know that the pulmonary veins, you know, these muscle sleeves, not just in the pulmonary veins, but also the posterior antrum and the left atrium can be triggers that start AFib. We know that reentry can also anchor on the pulmonary vein left atrial junction, and we know there's also autonomic ganglionid plexi often that are at the same regions, and that's why this proximal isolation pulmonary veins is the treatment mainstay for interventional treatment for atrial fibrillation. More proximal isolation also prevents narrowing of the pulmonary veins that could happen if you're ablating inside the pulmonary veins. You know, with the classic isolation of the pulmonary veins, circular mapping catheters were used to measure electrical activity, and here you see overlapping left atrial electrical activity, and what we would see with ablation is progressive delay of the pulmonary vein activity, and then eventually loss of the pulmonary vein signal. This remaining signal is far from the left atrial signal, and this is defined when you're ablating around the pulmonary vein as entry blocks. You've lost entry of electrical activity into the pulmonary vein, and that's kind of the minimal acute outcome that we look for when we're performing a pulmonary vein isolation procedure. This is just an example of a voltage map of the left atrium from the PA view at baseline showing purple, which is voltage over 0.5, so healthy muscle sleeves in the pulmonary veins, and then after ablation around the pulmonary veins, in this case with radiofrequency energy, isolation of the pulmonary veins shown by lack of any electrical activity in red. Here's the RF connected dot lesion approach to isolation of the pulmonary veins. In addition to entry block, we also like to show exit block with RF isolation, and here you can see we're pacing in the pulmonary vein. You can see capture of the electrical signal of the pulmonary vein sleeve on the circular mapping catheter in the vein, but that does not exit to the rest of the atrium, so that's exit block, and that's important because we don't want triggers to start AF. So typically, we like to look at both entry and exit block. Another maneuver that's been described is use of adenosine after isolation to see if the pulmonary veins reconnect. In this case, we're giving six milligrams of adenosine on the circular mapping catheter. We see actually the isolated pulmonary veins reconnect, and that can be a sign that you need to do more ablation. I would say this is used less commonly, but it still looks like a board question because mechanistically, it's important to understand, so you may see this. So when you see preablation arresting cell membrane potential, and then postablation, some cells can be injured, but not sufficiently. You know, the cells aren't destroyed, and they can recover over time, but what happens is they're injured enough that their cells partially depolarize, and then in response to stimuli, it won't create an action potential, and so it looks like they're blocked. What adenosine does is it hyperpolarizes the cell membrane by blocking IKACH, and that can restore conduction that then goes away when the adenosine is washed out. So it's a mechanism of adenosine leading to PV reconnection. It's due to hyperpolarization of the cell membrane. This can also be used to look for early reconnection of atrial flutter, so that concept, I think, is important to understand. In terms of anticoagulation around ablation, there have been studies with each of the drugs, apixaban, pradaxa, and rivaroxaban, showing that uninterrupted anticoagulation actually is safer than—with a DOAC is safer than warfarin, and also safer than interrupted anticoagulation. So most ablation procedures, according to the guidelines, should be done on uninterrupted anticoagulation, basic continuing anticoagulation, the morning of the procedure even, and then resume it the night after or the next day, depending on the drug. You know, again, we'll talk about the newer approach with pulse field ablation, but since RF ablation has been around for a while, there may be some—it's important to understand, because you may still need to use it in some cases, but also maybe questions on the boards. Looking to differentiate complex potentials in the pulmonary veins after ablation, because there are other structures, like the appendage, the left atrial muscle, and how do you know for sure when a pulmonary vein is isolated? And one trick is to pace from adjacent structures, pull in that activity early, and then you can see if this pulmonary vein activity late. So, for example, this is electrical activity on a circular mapping catheter. After ablation, is this vein isolated, or is this, you know, is this far field of atrial activity, or is this residual pulmonary vein activity? And what we can do is pace from the left atrial appendage, and you can see that it pulls in those electrical signals quite early, nothing late, and so that means that pulmonary vein is isolated, and these signals are just far-field noctational appendage signals, shown here with the red arrow. In this case, again, pacing from the appendage after isolation, you see late signals, they're sort of mid-P wave, and so these are actually pulmonary vein signals that still require additional ablation. Cryoballoon came around as another improved method for pulmonary vein isolation, sort of an all-in-one balloon approach with a latex and latex balloon with nitrous oxide that's perfused into the balloon and leads to freezing and pulmonary vein isolation. One thing to be wary of is that the phrenic nerve does run along the SVC just adjacent to the right pulmonary veins, and that there is a higher incidence with cryoablation because the balloon is pushed up against the phrenic nerve. A phrenic nerve injury, probably a half to 1% in many studies. So you can always see an x-ray like this in real life or on the boards where patients short of breath after cryoablation. Here we see elevation of the right hemidiaphragm, and that is diaphragmatic paralysis due to cryoablation. It is sometimes reversible, but sometimes not, and is a potential complication of cryoablation. It can also happen with RF, though less commonly, something to be aware of. It's a possible risk of ablation. But in studies looking at outcome, comparing cryoabalone to RF, and this is the fire and ice study by Carl Heinz Cook, both are equally effective. Proceeded duration is a bit shorter with cryoabalone. And so, you know, given the ease of cryoabalone, several studies now have looked at primary ablation, so as opposed to trying drugs first and then going on to ablation if patients failed or broke through a drug, which was a standard approach, just going straight to ablation as the first treatment and showing that ablation was clearly much more effective, even as a first-line agent, than drug therapy. On the left, with the early AS study by Jason Andrade showing, again, about a 25% improvement in outcome. The outcome was with implantable loop monitors. That's why the numbers are a little lower than on the right, where they were by intermittent monitoring in Osama Wazni's Stop AF First study. But both studies showed benefit of ablation over drug therapy, and this has led to the latest guidelines that recommend ablation as first-line therapy for atrial fibrillation. You can see it's a class one indication in generally younger patients with few comorbidities, but also an acceptable 2A indication in patients other than younger with few comorbidities. It's certainly an option for any patient, although, again, if a patient prefers drug therapies, that's reasonable too. With a longer-term follow-up, it's also been shown that progression from paroxysmal to persistent AF is lower with ablation compared to drug therapy. Let's move on to pulse-field ablation, kind of a newer approach that's been FDA-approved for, you know, since early 2004. We'll talk more about this in the biophysics section, but pulse-field ablation is a non-thermal ablation modality that leads to electroporation. So it creates holes in cell membranes, the cell contents spill out, and then the cells die through a non-thermal approach. Important to realize that there's a zone of non-thermal injury. If you use high enough pulse field, you will get heat, and low enough, you can get injury, but recovery, so reversible electroporation. The benefits of electroporation, in addition to being faster, are relative tissue sensitivity, so the myocardial cells are more sensitive to pulse-field ablation compared to smooth muscle cells and nerve, and this is important because it's much less likely to injure the esophagus or phrenic nerve using pulse-field ablation. Two recent studies have been done, the Pulse AF study using a circular mapping catheter, delivering pulse-field energy, and that showed 66% efficacy in paroxysmal AF at a year and 55% in persistent AF with very low complication rate. Also, the ADVENT study, which is a randomized study between pulse-field ablation and thermal ablation, showed non-inferiority in terms of outcome with a 73% freedom of math at a year and significantly shorter procedure times, at about a 1.5% to 2% complication rate. So based on these two studies, pulse-field ablation was approved by the FDA and is now, as you know, available commercially. Again, the advantage in terms of safety is, in now over 100,000 cases, there have been zero left atrial esophageal fistulas, zero pulmonary vein stenosis, and no permanent phrenic nerve injury, so definitely safety advantages. There are some newer complications to be aware of, I won't get too into just for the time allowed, but coronary artery spasm, if you're ablating over a coronary artery, and hemolysis and dysrenal failure, as you can see, both fairly rare. The complications obviously can still occur, you know, in addition to stroke and mechanical complications. And, you know, there are many new catheter designs that are being studied and should be available in the future. What about persistent AF? So we know, you know, in terms of pulmonary vein isolation, the outcome is, you know, as we said, in the 70% range for paroxysmal AF, but often lower for persistent AF, and that's because of the remodeled atrium. And there have been many approaches looked at to try and improve the outcome in patients with persistent AF. That includes ablation of non-pulmonary vein triggers with high-dose isoprel, complex fractionated H-electrograms. That was shown early on, but basically has been debunked as a method of ablation, linear ablation, ablation of other thoracic veins, such as the SVC, posterior wall isolation, appendage isolation, vein of martial alcohol ablation, low-voltage regions, and hybrid ablation. We'll touch on all of these. So STAR-AF2 was a study by Atul Verma in 2015, compared PVI alone and persistent AF to PVI plus CAFE, or PVI plus linear ablation, and to everyone's surprise, shown here that adding either CAFE or linear ablation did not improve outcome to just PVI alone. It kind of put to rest these other approaches in terms of ablating AF. The CONVERGE trial was a trial that compared catheter ablation to surgical ablation, so a surgical ablation followed serially by an endocardial catheter ablation. These are the two strategies. I always think the study's a little unfair because surgical ablation included PVI and posterior wall isolation, whereas catheter ablation was just PVI plus a roof line, which we know often can reconnect, but nevertheless, with this comparison, hybrid converging ablation had better freedom from AF compared to endocardial catheter ablation, and so that can be a strategy for more persistent cases of atrial fibrillation. While early studies showed some benefit to electrical isolation of the appendage, the AMAZE trial was a large randomized trial using valeriates, so an endocardial appendage occlusion device added to PV antral isolation versus PV antral isolation alone, only, again, surprising because early studies showed this benefit that the appendage could be a trigger for AF. This study showed really no difference in freedom from AF, so appendage isolation, which shouldn't be considered a standard part of ablation, also leads to higher stroke risk, which may then necessitate appendage closure. Miguel Valderrabano ran his VENUS trial. This was looking at alcohol infusion in the vein of marshal for persistent AF compared to AF ablation alone, including other structures when needed. This was a prospective randomized trial and did show in persistent AF about a 10% improvement in outcome when alcohol ablation of the vein of marshal was utilized, so this is one potential strategy to improve outcome in persistent AF. Several studies, including this TAPLIS study by Peter Kistler, have looked at adding isolation of the posterior wall based on surgical data compared to pulmonary vein isolation alone. In three randomized trials, including this one, there was no added benefit in persistent AF to posterior wall isolation, so there's no data that that should be a routine approach to first-line ablation in patients with persistent AF. And several studies have looked at ablation of low-voltage scarred regions of the atrium in addition to standard ablation. Some of those were negative, but this is one study that did show some benefit of adding low-voltage ablation to pulmonary vein isolation with a 15% improvement in outcome, but I think, you know, based on this one study, I don't think there's enough data to advocate this being done routinely, but certainly should be considered, especially if it's within your planned ablation region. So, the main approaches to ablation of persistent AF beyond pulmonary vein isolation include alcohol ablation of the vein of marshal and hybrid surgical catheter ablation of AF at this point in time. The Gabana trial should be mentioned, obviously, in the boards. People love asking questions about randomized trials. This is run by Doug Packer. It's thought to be a modern-day approach to affirm where patients were randomized, not just to sinus rhythm or not, but either to catheter ablation versus drug therapy. Again, a large international study in over 2,000 patients. Unfortunately, the primary endpoint, including death, disabling stroke, or bleeding in an intention-to-treat analysis showed no clear benefit to ablation, although, you know, compared to affirm, at least ablation is trending in the right direction. But, and again, in terms of all-cause mortality, ablation did not improve outcome compared to drugs. Again, there's subsequent on-treatment analysis that showed that if you actually received ablation, your outcome was better, but it did not meet that in the intention-to-treat analysis. But obviously, there was a reduction in nature for ablation with ablation compared to drug therapy. So, if someone asks about Gabana conclusions, AF ablation does reduce AF burden significantly more than medical therapy. It certainly reduces hospitalization more than medical therapy, but has not been shown, at least in an intention-to-treat analysis, to reduce mortality for the composite endpoint. Everyone should be aware of potential complications after AF ablation. Obviously, the one we worry about the most, LA esophageal fistula, mechanical complications like perforation, tamponade, stroke, pulmonary stenosis, front of nerve injury, vascular complications, and reports of death, you know, running around 1 in 1,000 or so have also been described. In terms of atrial fibrillation and heart failure, we know atrial fibrillation is very common. About a third of patients with heart failure will develop atrial fibrillation over the next 10 years. Several studies have looked at AF ablation in patients with heart failure. In this study by Peter Kistler, the CAMRA MRI study, they looked at just medical rate control versus catheter ablation to restore sinus rhythm in patients with a reduced ejection fraction, less than 45%. And what they found was catheter ablation was associated with a dramatic 18% improvement in ejection fraction, compared to only 4% with rate control. In the CASLA-F study, patients were randomized to either medical therapy, these are patients with an EF less than 35%, NYHA greater than 2, heart failure, and an ICD. They're randomized to catheter ablation or just pharmacological treatment. And not only was there a reduction in AFib with atrial fibrillation, but also a significant reduction in mortality with ablation compared to medical therapy. And then finally, in this study in end-stage heart failure with AF, patients were randomized, about 200 patients to medical therapy or ablation, and it was noted that there was a significant reduction in the primary composite endpoint, but also significant reduction in mortality with catheter ablation. So all of these have led to a class one recommendation in patients with recent onset of HF and AF. Even once you're on guideline-directed medical therapy with a reasonable expectation of benefit, catheter ablation is beneficial for improving outcomes, including mortality. It's also a two-way indication in patients with HF-PEF, and the next CABANA study, CABANA-HF-PEF, will further assess this group. Finally, despite all these interventional approaches, we also should mention risk factor modification in terms of all our patients with AF. It shouldn't be ignored, and several studies have shown that the intervention of weight loss leads to not elimination of AF, but a reduction both in the number of episodes of AF patients have and also the duration of AF. In this study that looked at risk factor modification in patients with hypertension, diabetes, smoking or alcohol, and obesity, risk factor modification mainly was weight loss, but also treatment of sleep apnea. You can see that either after a single procedure or multiple procedures, patients who pursued risk factor modification had a much better outcome in terms of freedom from AF. I show this to patients in clinic. If you want to be in this group or this group, even after multiple procedures, you'll see 87% freedom from AF in patients who are able to lose weight and treat sleep apnea, versus only 50% in control. We can't just ablate patients and leave them alone. We really have to continue to get them to work on risk factors, including alcohol, obesity, and sleep apnea treatment. These are now class one recommendations, and anyone with a BMI over 27, weight loss is recommended. People often ask about exercise, but exercise, moderate to vigorous exercise, is actually associated with less AF, not more. Again, elite athletes are a different situation. What about alcohol and AF? My partner, Greg Marcus, has looked at this quite extensively. When people have a drink, their likelihood of AF in the next four hours is doubled, so alcohol is a clear trigger for atrial fibrillation. In this study by Alex Voskoboynik, in patients who are able to abstain from alcohol, they had a significant reduction in recurrence of AF after cardioversion. Abstinence or reduction in alcohol is an important part of AF management. That's also class one in the guidelines. Smoking, again, less of an issue in the U.S. these days, but also has been associated with an increased incidence of AF occurrence. Smoking cessation should be part of risk factor management. Then preliminary studies, other drugs, including cocaine, opiates, and even cannabis, has been shown with an increase in AF. Cessation of these should also be recommended. The one good news is caffeine. Multiple studies now have shown no increase in AF in patients who drink coffee. In fact, there may be some protective effects. There's no benefit to caffeine cessation. At least you can tell your patients they need to stop smoking, they need to stop drinking, but coffee is okay. To summarize all this information we've gone through, and a lot of information in the past hour, AF is typically triggered by pulmonary vein firing. That's enhanced by sympathetic activity, activation of the nervous system, and maintained by both a combination of pulmonary vein firing and reentry, which is enhanced by parasympathetic stimulation, often at night. AFib tends to promote more AF, or AF begets AF, through both structural and electrical remodeling. Antidepressant drug risks and benefits should be carefully considered, used primarily to improve symptoms and also minimize adverse effects. The direct anticoagulants should be used. In general, anyone with a chance of AS greater than zero, or maybe one in some select cases. The cornerstone for interventional AF treatment, whether paroxysmal or persistent, remains pulmonary vein isolation. Again, I think this is becoming less of an issue with pulse field ablation, but still important to understand how to distinguish near from far field signals when analyzing the pulmonary veins to see if they're effectively isolated or not. In heart failure, several studies have documented lower mortality with ablation in AF and recent onset heart failure, so ablation should be considered first line in that group. For recent onset AF, less than a year, data also supports maintenance of sinus rhythm, and then don't forget risk factor modification is an important part of overall AF management. Hope these thoughts are helpful. Thank you again for tuning in to Core Concepts and Electrophysiology, and look forward to seeing you for other lectures. Thank you.

atrial fibrillation

Ed Gerstenfeld

treatment options

antiarrhythmic drugs

catheter ablation

pulse field ablation

risk factor modification

sinus rhythm

CHADS-VASC score

UCSF

treatment strategies

pulse-field ablation

clinical outcomes