Thanks a lot, and thanks for the invitation. Well, good evening everybody. Let's jump right into it. Yeah, this is a title of my talk is Cellular Electrophysiology Made Ridiculously Clinical. It's a loosely homage after one of my favorite med school textbooks, Clinical Microbiology Made Ridiculously Simple, where they tried to do kind of the same thing, you know, antibiotics and things like that, but going back to the basic science of it and putting everything into perspective. So hopefully you guys will find it pretty useful. So here the goal is pretty simple. First part, we're going to try to understand the action potential will take us back to the first two years of medical school, understand the basics of membrane currents and what gives rise to the rhythmic excitation of the heart. Number two is to use the action potential to understand some excitable tissue behavior. It will be some mechanisms that we, like Nishant was saying, invoke often, but don't always go through the time to understand what's happening on the cellular level. Finally, a bunch of mechanisms of arrhythmia formation and therapy, all related to the basic mechanisms that underpin it. You know, another set of goals here though is, you know, I want you guys to be able to answer questions when you get put on the spot by your attending. You know, sometimes you'll be asked to answer what is phase four block, which was the teaser question if any of you guys saw it, and maybe you'll get a little bit more catheter time if you get that question right. The other important thing is, you know, on the boards every once in a while there are questions about heritable arrhythmia syndromes and cellular electrophysiology that are important if you want to get those extra points. But most importantly, you know, and I think we're all pretty guilty of this at times in late nights in electrophysiology lab when we're kind of on autopilot and doing things according to protocol, whether it's isolating the veins or doing something pretty routine, where we miss some of the subtleties of EP. And I think that's kind of a shame. And so hopefully by going back to the roots of EP, we can understand some of these mechanisms and point them out when they happen and it makes EP a lot more interesting. So I previewed the answer to this question. Let's see if you guys saw it quickly. Here's a first poll question. You can see it sort of on the screen. We have the action potential, fairly typical ventricular action potential. Starts out at about minus 90 millivolts, peaks at positive 20 millivolts, typical plateau. And, you know, this membrane potential evolution is the result of multiple membrane currents that rise and fall throughout the course of the action potential. So show of votes. We have five options here and we want to go from top to bottom and say, what is the summed, appropriate summed species? So if it's sodium at the top, is it potassium at the top? Pick the best answer. How do we do it, Nishant? Do we wait for everyone to respond here? I've been usually giving them a minute or so. Okay. I think we have everyone, right? Yeah, there's the results. I think they can see it. Great, great. So we got a little bit of a spread, but most are absolutely correct. So the top row is the sodium current, middle row is the summed calcium current, and the bottom row is the potassium current. I am really happy to note that everyone got the top row correct, because that is indeed the most important. So keep in mind the action potential starts out of minus 90 millivolts, as I was mentioning, and the first thing that kicks off the entire process is that fast sodium current, right? So that fast sodium current gives that rapid uptake, all the channels open and then they shut as we'll get into in the coming slides. What that does for us is it leads to a rapid depolarization of the action potential, and it raises the membrane potential to a level where the potassium and calcium currents can get activated. Now by convention, I should mention that inward current, outward current, so the inward current for a positive ion will serve to depolarize the membrane, and the outward current for a positive ion will basically remove charge from the interior of the cell and hyperpolarize the membrane. So that's somewhat of a convention, but outward usually means repolarizing, and inward positive currents are typically denoted with negative currents, but inward currents typically depolarize the cell. All right, off to a great start. So this is basically more of the same. The cartoon to the right points out that there is such diversity of the membrane currents in the cardiac cell, and really it is this diversity and the cascade of each of those membrane currents that determines what the shape of the action potential will be. And so for different tissue types, actually the density and the kinetics of these membrane currents may look a little bit different, and because of that the action potential duration, as well as the plateau potential where it's, you know, in phase two over here may look a little different, as well as sort of the time course of each of these membrane currents will be different from tissue to tissue with important implications. So I'll be brief with the micro-EP study, as I call it, which is a sort of an experimental technique known as patch clamping, which is how we know about all these membrane currents, their kinetics, and their density. So basically these experiments are kind of fun to do. Basically they're done by taking these glass pipettes and forging the tip of the pipette under fire to really sharpen it, melt it down, and sharpen it. And then we're able to look under a microscope and look at the cell itself. And there's a complex rig, basically, where the entire table is shielded with kind of an air flotation device to minimize vibrations. And then you can minutely move the position of the pipette down left and right, up and down, until it's able to touch the surface of the cell. It actually requires a lot of manual dexterity, much like an EP study might actually. And then when that pipette touches the tip of the cell, it's able to just sort of kiss the surface of it and make a seal. And with that seal, actually, we call it a gigaseal, you're able to capture just several of these ion channels that are spanning the cell membrane inside the interface with the glass pipette and the cell. And so with that in the middle tracing, you'll see that you see these little step potentials here. They're actually step currents. And these are the activation of individual ion channels, which are enclosed by the pipette. So it's really, you know, a very micro manipulation kind of experiment. In a different configuration, once you so-called kiss the cell, you can actually rupture the cell membrane and allow the interior of the cell to equilibrate with a pipette solution. And so basically, you can control the inside and outside solution of your cell and apply voltages across the membrane. And by doing that, basically, you can elicit different size currents, which may have different time courses, as you see on the right panel. These are whole cell currents. And by carefully selecting the drugs that you expose the cell to, as well as the different ions that are in the bath, you can basically get rid of all the potassium in your bath, and then you know that all of the currents are going to be sodium and so forth. So you can do tricks in that way and characterize the membrane currents that pass through the cell. So this has a rich history going back to the 1940s, actually, of doing these experiments. And with the advent of further experimentation, we know that these channels have different behaviors that they can do. And so these membrane currents flow through ion channels that are sitting in the membrane. And basically, they represent conduits. These are proteins that can undergo conformational changes. And one of the conformations that it can adopt is to allow for a central pore to emerge. And through that central pore, the different ions can pass. And those conformational changes are known as gating. And within electrophysiology, usually, the way that these channels gate are through voltage. So voltage will lead to all of the charges within the channel itself may be exposed to a voltage across the membrane. And because of the electrotonic influences on those portions of the gate, they will actually move and change configuration. So in this sodium channel, for example, we see that it has four activation gates and these little hairpin looking things in these four domains. And when it's exposed to positive potentials, those hairpins will end up moving out of the way of the pore and allow the channel to conduct current. Now, it's always confusing about the relation between current flow. We know as electrophysiologists, we know that potential is equal to current times resistance. And basically, the amount of current that flows through those ion channels is related to something called the electrochemical gradient. And so this is, again, review from medical school that currents flow through an open channel down the gradient. So for potassium, for example, there are quite a few ATP-consuming machinery that basically ensure homeostasis of potassium to a certain balance. So inside the cell, usually, potassium averages about 140, 150 millimolar. And outside, it's about four or five millimolar. And so that balance sets up a significant gradient for potassium to be favored to go out of the cell. Because of that electrochemical gradient, when the potential across the cell membrane is about minus 90 millivolts, there won't be any current flow through the open channel. But going back to that faucet analogy from a moment ago, you can turn up the faucet but increase the gradient across by changing the membrane potential. And so as you veer from that minus 90 potential for potassium, you're going to have lots of current flow through open channels. Now, the confusing part is that channels don't always stay closed, and they don't always stay open, and they actually gate. And so that's the part of this that's a little tricky, that voltage determines the driving force for current flow through open channels, but it also drives the opening and closing of channels. And we'll go through that in the coming slides. Similarly, for the sodium here, before the cell fires, there's relatively little sodium inside the cell, but all of the channels are closed. And so when the channels start to open, it's kind of like a tinderbox or something. As soon as a few channels open, there's going to be an influx of these sodium ions that are rushing in to depolarize the cell. A common finding is that it's commonly held that sodium channels open in an all-or-none fashion, and that is mainly true in that there's a cooperativity in the opening of these channels. But this curve in the middle here shows the response of gating of sodium channels to membrane potential. So you can see in the blue here, in the x-axis, if the cell is hovering about minus 90, you know, the open fraction of these channels is hovering about zero. But as I show over here, for these channels that are staying closed, if the channel is exposed to a potential of minus 80, there may be a 1% chance that the channel will open and conduct current, and even if it does, it may close right back because it's so energetically favorable for that channel to be in a closed configuration. But if you expose that same channel to a potential of minus 50 millivolts, then there's about a 20% chance that these channels will open. And so in that case, the sodium is rushing into the cell. It is opening up the potential further. It's climbing up to minus 40, minus 30. It's opening up some of the neighbor channels. And so it is sort of an all-or-none fashion where there's rapid depolarization of the cell. There's a catch here somewhat, and that is that as soon as the sodium channel opens and conducts large amounts of current into it to depolarize the cell, immediately it slams shut with an inactivation gate. So in this cartoon, you can kind of see this little ball and chain configuration here. And basically, as the membrane depolarizes and the channel opens, now the interior of the cell is relatively positive. And because this moiety on the channel is positively charged, it basically sort of electrically shuts the pore or occludes the pore in a process called inactivation. So these charged amino acids in that ball, this motif, basically are key for that process of inactivation. So basically, that gives rise to that characteristic membrane current that all of you got correct in that sodium current. So what does this inactivation mean? I mean, it's totally critical for activation of the heart because whenever we talk about refractoriness in the EP lab, it's totally because these sodium channels are inactive. The pore is occluded with this moiety. And that pore needs to recover from inactivation in order for refractoriness to be released. And so how do they un-inactivate or release that refractoriness? Well, it's really with hyperpolarization. So you can see in this curve, which is called an availability curve, that if you leave the potential at minus 60, that inactivation gate is going to be occluding the pore forever. But if you hyperpolarize the cell and the action potential goes down to resting, then slowly there's going to be relief of that inactivation, and you're going to get more of those sodium channels raring to go again. So it's relieving that refractoriness. So that leads us to our next question. And here I have an example of an action potential, pretty normal looking ventricular action potential. And then I want us to do a thought experiment where in a different cell, we actually force the resting membrane potential to be a little bit higher. So in your second cell, which is closer to the activation threshold where some of these sodium channels open, what should you see? Should you see slowed conduction? Should you see faster conduction because there's going to be a higher amplitude of the action potential? Are you going to see faster conduction because you're going to get to the threshold quicker and open those channels? Or are you going to get faster conduction because there are going to be other currents that help sodium along? So let's vote. All right, guys. So I think everyone is seeing the poll results there. So it's about 50 50 between slower and faster and Let's go through it. So the correct answer here is that it will be slower conduction, actually. And that's because The resting membrane potential depolarization actually reduces the availability of these channels. So again, going back to that curve where we bought the availability of the Of the sodium channels. What we're doing basically in this thought experiment is we're bringing it from more negative to less negative and that's reducing the availability of these channels where all of them are raring to go. To, you know, if it's going down to minus 70 or something, maybe only 30% of them are even available to be activated. And so because of that, when you finally do activate the cells, the aggregate sodium current is much lower and the conduction velocity is slowed. So they're going to be a couple of examples of this that are relevant in the EP lab that we can kind of trace through the bottom line is that the conduction velocity really correlates With the conduction from cell to cell. So that conduction velocity that we see in the lab when we're mapping a complex arrhythmia. It is related to this conduction velocity And it depends on a few factors. Number one is tissue type which determines how many sodium channels in the membrane and how big that current density is so Famously, the Purkinje system has a very large sodium current. And so that conduction velocity through that his Purkinje specialized conduction system is very, very fast compared to atrial tissue or even ventricular tissue. It also depends on the connections between cells. So this is where in the lab where we see fibrosis or what have you. Scar VT that those connections might be compromised by deposition of fibrosis or scar. And so those connections are intracellular resistance might be higher, but the third thing is about the availability of the sodium channels. And that's what this example is showing So in the lab. One of the ways and this paper, by the way, by stand that tells group and circulation is definitely worth a read How we use a denizen to unmask dormant conduction. And one of the ways that a denizen might unmask this dormant conduction is illustrated in this sort of In this sort of experiment. So taking a cell. If you have the membrane potential minus 75 and then you perform some ablation and then you give a denizen you can see that the denizen does hyperpolarize the cell a little bit Now when you have dormant conduction post ablation. This is the situation and then you hyperpolarize it, you're likely Increasing the availability of the sodium channel. So if there are 20 or 30% sodium channels, you know, it's all all of them are being used as opposed to just a 10% of them or what have you. And so you can unmask it by hyperpolarizing membrane and making full avail of all the sodium channels in that preparation. Another example that is often sort of hand waved is is the so called super normal conduction. So for purposes of illustration. I've put here a neuronal action potential which lasts about two milliseconds, as opposed to the 300 400 milliseconds that we're used to in the human heart. But in the neuronal action potential actually after it repolarizes. There's a brief period where it actually goes to below the resting membrane potential In the early phases of EP, we used to think that when there were situations with unexpected conduction that perhaps the stimulus was falling in this privileged zone where it was hyperpolarized and the channels were more available and the cell could actually fire, but then if you Extended it another 10 or 20 milliseconds. There wasn't conduction anymore. So it would used to be invoked as sort of an explanation for that. So, I don't know if we have a poll for this Nishanth, but Here's three possible My personal opinion is that a lot of times when super normal conduction is invoked that it's actually other more conventional mechanisms at play. Go ahead and Vote A, B, or C. All right, great. So I think everyone is pretty much right. I think I was thinking gap phenomenon, but I suppose summation could be another phenomenon. So this is kind of, you know, you're right if you chose either one of those. But anything where you would see unexpected conduction. So gap phenomenon is one of these classic things, right? So just to review, I'll go to the next slide. So this was the first demonstration of gap conduction where we're looking at retrograde VA conduction here, right? So we're doing V1, V2s here. We're looking at the April depolarization here. I know it's kind of small. So here we're doing a basic drive train of 500, bringing in the V2. Here's V1, V2 at 380. Now we're bringing it into 360. V1, V2 is 360. The H1, H2 is also 360. Now we're bringing in the V2 a little bit more, and we're starting to see a little bit more of the VH prolongation with respect to the VB prolongation. So it's V1, V2 is 320, and VH is a little bit longer. And then it hits a critical amount where you actually get recovery of conduction, unexpected conduction here to the A. There's retrograde conduction here. If you look closely, it's actually because the VH interval has pushed out to 445, which was a critical interval for it to recover and conduct. So basically this is an example of unexpected conduction. So before the demonstration of gap phenomenon, you might invoke that maybe, hey, the cells are finally hitting that zone as you bring it in shorter where it's hyperpolarized enough that it's able to conduct once again. But I think in practice, a lot of times we do more hand-waving when we invoke supernormal conduction. Most of the time it's things like gap phenomenon. So this was a teaser question, but it's another example of where... I'm not sure if we have this one. I don't know if I sent it to you, Nishant, but basically here's the teaser question where we were talking about phase 4 block. So great, great, thanks a lot. So hopefully most of you saw the strips before. In the top strip we have sinus rhythm, right bundle branch block, got a PVC, and then sort of uninterrupted compensatory pause, sinus rhythm, right bundle block. And then we have another PVC, a long run of AV block. D, we've got something similar. Some explanation on this slide. Hopefully most of us will get it. Great, great, great. I think I should have made the poll question more, how many people have heard phase four block in an EP conference in the last month? Because I think it gets mentioned so many times and we're always trying to end ring and kind of come up with explanations. So this is a good time to kind of go through it. Most people are right. It is attributed to the sodium channel inactivation, which is the topic of these last few slides. I'm glad some people did say activation of the vagus nerve. A lot of times you'll see paroxysmal AV block in a hospitalized setting. And typically the hallmark of that though, is you will see sinus rate slowing concomitant with AV block. Because the influence of the vagal nerve stimulation and it's a slow sinus rate, slow AV nodal conduction. So that kind of AV block we see all the time in sleeping patients in the hospital, for example. But this is something different, right? So this is a PVC with retrograde conduction. And in that bottom slide, in that bottom tracing, that PVC actually produces a long sinus pause. And so what we're seeing is that, if you look in the second sort of panel here, you can see that in diseased his Purkinje system, right? So we have a right bundle branch block. You know, the remaining conduction system is not the healthiest. You can see that that long pause might be expected to lead to a very prolonged phase four of the action potential, right? So that's that slow diastolic depolarization phase of the action potential. And so the thinking is that in this slow depolarization, much like the previous example where we artificially raised our action potential resting membrane potential to a higher level, that not the channels are not available for activation anymore. So the channels go straight from being closed to completely inactive. And because of that, the stimulus just won't get through when it's stimulated from above and usually gets to a phase four block, which is typically associated with the bradycardia, which is the clinical hallmark of this. But if you understand that this is a sodium channel problem, you'll kind of remember, I think, what leads to this. Another more everyday occurrence that we see, this is from the Murgatory text, is if we're doing V1, V2s in the lab, and we start to see with the S2, S2 is what we program, and then you measure when the V actually starts. For a long time, you start 600, 560, 600, 540, that S1, S2 is gonna be the same as the V1, V2 for the most part. But then as you start to bring in that S2, you'll start to see a little bit of latency, right? So you'll see there's a little bit of distance time between the stim and your extra systole and the actual ventricular depolarization. And this is probably a very similar concept where the sodium channels are not available because you're encroaching on that recovery of inactivation. You're getting fewer sodium channels available to go, and you're getting some latency, some slowed conduction before it's captured. Usually, it immediately precedes loss of capture, as you see in that very lowest tracing there when you encounter a complete refractoriness. All right, I'm gonna keep going. If there are any questions or anything, I suppose Nishant could probably field some in the text box and certainly feel free to interrupt and try to weave it into the slides. Shifting gears a little bit to repolarization. So we've spent a lot of time talking about sodium. So the flip side of this is that during the action potential, after the action potential gets to a certain and depolarized potential of 20 millivolts, you're starting to activate those calcium potassium channels. And that is during that plateau phase, opposing forces of inward depolarizing calcium current and outwards repolarizing potassium currents. And eventually the potassium currents do end up activating more and more and bring that membrane potential down to repolarization. We'll spend some time talking about IKR and IKS, which are the major determinants of repolarization in the ventricular cell, and also have implications for both heritable and acquired channelopathies. And then we'll talk a little bit about repolarization reserve in that setting. In the atrial tissue repolarization, a special current called the ultra-rapid delayed rectifier, IKUR, is gaining increased attention recently because of its role in potentially the pathogenesis of atrial fibrillation. So as you know, in the atrial tissue, while we try to limit the prolongation of QT and prolongation of refractories in the ventricular tissue, in the atrial tissue, it's actually our friend, right? So we wanna reduce excitability on average and prevent atrial fibrillation. But disturbances in the ultra-rapid potassium current are invoked as potentially and both in familiar forms of atrial fibrillation and potentially in future therapeutics, an important target. And there is some relation to beta stimulation as we'll get into in some of the examples. So you probably heard this concept of repolarization reserve. And that is the fact that in a cell, if you rob that cell of some of its repolarization ability, so classic example is that you administer an antibiotic to a patient and they have a QT that's totally normal, but with that antibiotic, they get a subtle QT prolongation, right? The reason that that QT prolongation is not necessarily worse than it is, is sometimes cells will have this repolarization reserve, which is more of a descriptive term in which when one of the membrane currents is depressed, it leads to a prolonged plateau phase such that other membrane currents can activate to take its place. So for example, if you did a computational model of a ventricular cell and a Purkinje cell, and you simulated what might happen in a potassium channel deficit, you might see that the action potential is long lengthened by 20 or 30 milliseconds. But since we have two components of ventilated rectifier, the IKR and the IKS, if you basically rob the cell of one of those components, the other component over time will start to activate further the density of that current will start to increase and it'll drive that membrane potential eventually back towards repolarization. So this is a concept that often it takes more than one hit to kind of prolong the action potential. And in many instances, some of the patients that you're giving these antibiotics to may have a snip or something like that that leads to impaired repolarization in one of their delayed rectifier currents. And so when you expose them to one drug or maybe even two drugs, then you're giving them a second and a third hit that really compromises their repolarization reserve, prolongs the action potential duration on the surface ECG leads to QT prolongation. Now, this is probably a tissue specific thing. So what happens in one tissue type may not happen in a different tissue type illustrated here for the Purkinje tissue, but also importantly, between the atrium and the ventricle, right? So we use class three antirhythmics all the time and they do suppress delayed rectifier occurrence. And we're just hoping that the amount that it suppresses in the ventricle is that it's more atrial specific in that way. And we'll get into this a little further. Repolarization is not all driven by potassium currents. So just to give you a word about sodium current, and it seems like a few years ago, everyone started talking about late sodium current with the sort of identification of ranolazine as a specific late sodium current inhibitor and an antirhythmic. We started to pay a lot more attention to this, but inheritable channelopathies, late or persistent sodium current is an important sort of phenomenon. So we went through the typical waveform for a fast sodium current, where it goes from zero to probably 100 amps per picofarad. So that's 100 times any other current in the cell very quickly. And then it goes from that 100 all the way back down to zero very quickly. But in reality, not all of those channels are completely inactivated. And even normal sodium channels, maybe like 0.1% or 0.2% of them don't completely inactivate. And because of where they are in the action potential, they're still conducting current. And so during the course of the action potential, you'll get a little bit of influx of sodium. But 0.1% is a small number, but when it's multiplied by this huge density of sodium channels in a cell, it can be appreciable for prolonging the action potential. But in disease states, it's particularly important because if that 0.1% goes to 1%, then that cell is in a little bit of trouble. So here in this slide, we're looking at a mouse model of Long QT syndrome and transfecting the cells with the GFP tagged detective channel leads to increased persistent sodium current. And so you can kind of see in these slides in the second half of things, these mouse action potentials, which were narrower to begin with than human cells. And when you give them a little bit more of that persistent current, you start to see really prolonged looking action potentials and some action potentials that don't repolarize at all. You can envision the same thing happening to human heart and the Long QT syndrome leading to disturbed repolarization. We're not gonna talk a ton about calcium just because it would take a full hour to talk about it anyway, but calcium can be an important driver of repolarization as well. And classically in heart failure is one of these situations where calcium cycling within the cell is definitively disturbed. There is a process known as calcium induced calcium release where once the calcium is released into this cell, it actually turns off the initial trigger L-type calcium channel that comes into the cell. And so in heart failure where there's just deficient intracellular calcium, sometimes you get these prolonged action potentials that may partially explain the irritability within heart failure in terms of ventricular arrhythmias. So this isn't a poll question, I don't think, but this is a very commonly encountered thing that we'll see in the lab. So we're queuing up the bloom stimulator, your favorite stimulator to a drive train at 600 and you get a ventricular ERP of 260. But when you do the same thing at a basic drive train of 400, you find that the VERP is 240 and it's not the same. So the main take home of this is that the action potential duration and therefore the effective refractory period in almost any tissue is gonna be a function of the preceding diastolic interval. So when you're bringing in that extra stimulus, you're gonna encroach upon that refractory period and eventually that stimulus is not gonna conduct. But if you're driving at a faster basic cycle length, the diastolic interval between your extra stimulus and the last beat of your drive train is gonna be shorter. And because the action potential is direction, the duration is directly proportional to the preceding duration of the diastolic interval, you're gonna see that when the drive train is shorter, that diastolic interval is shorter and that extra stimulus is shorter. And so effectively your ERP is gonna be shorter when you pace a tissue faster, but it also works with prematures as well. Anytime you introduce a premature at any basic cycling, that premature on average is going to have in itself, it's gonna have a shorter APD. So if you put a second premature, you may encroach on its ERP a little bit earlier than you would at the basic drive train. So here's some curves that kind of explain this. If you choose a drive train on your Bloom or your favorite stimulator of 2000, you'll see that the baseline action potential is about 400. And then as you bring in your S1, S2, this time it's going to the left, you'll see that slowly for a long time that ERPs, the action potential duration is going to be pretty stable. But as you encroach, you're starting to encroach into that diastolic interval, the repolarizing currents are not the same for these extra stimuli. And you start to see that there are changes in the action potential duration of your extra stimulus. And then when you do the same thing at 1000, you get a different curve because the ERP is different at those drive trains. It's probably outside the scope of this, but every tissue type is a little bit different in terms of why this happens. So in a ventricular cell, it seems to really depend on the calcium current not being as ready to go. A lot of those cells are still not available. All those channels are not available. And so you get a lower inward current there. And because of that, the action potential duration might be shorter. Interestingly, not all channels inactivate. So for example, with this IKS current, you might see that this IKS current has a pedestal here because the previous action potential has it already activated. And then you fire it again. So it's starting off from an incomplete state. And so that is a repolarizing current. It's getting a headstart and it's shortening the action potential by a bit. So there are a number of mechanisms that might explain this finding, but it's useful to remember just as a take-home that the action potential and the ERP is a function of the preceding diastolic interval. Now we use this all the time, right? We use this all the time in the EP lab to induce arrhythmias because we're trying to often dissociate, for example, in AVNRT, where we think conceptually of a fast pathway and a slow pathway, and we're trying to dissociate the function of these pathways. Often we will muck with the drive train to try to get an ERP of the fast pathway that allows it to block, allow us to conduct down the slow pathway and jump, and then kind of circle back around and initiate the tachycardia. So that's what we're really doing. And when we're giving beta stimulation with isoprenol, your favorite beta stimulator, basically we're adjusting the ERPs and differentially affecting these pathways. And so using those pacing maneuvers is often really helpful to bring this down. When I was a fellow, I remember vividly a case when we couldn't get any PVCs going at all. We were giving isoprol, we were giving everything. But we did induce some different pacing maneuvers to try to sort of muck with the calcium cycling of the cell by using a phenomenon called post-exorcistolic potentiation. And so every once in a while, if you keep these in mind and you're having trouble inducing arrhythmia, or you're having trouble getting something to get going, try to use different pacing maneuvers. And I always recommend, especially with inducing SVTs to try that second drive train because you might be able to use this to your advantage. Same thing with VT. This is a classic Josephson slide where we're looking at the excitable gap of prematures and successive prematures. And basically by reducing your effective refractory period with successive prematures, you're able to engage some critical isthmus tissue in ways and kind of allow it to block in one direction and circle back around. So that's what's happening behind the scenes is that you're really mucking with it with those extra stimuli. So when you're doing those must protocol, S1, S2, S3, S4s, it is useful to try to bring it out. Successively with prematures, you're gonna have a higher yield in bringing out your VT. So this is a poll question, I think, Nishant. So this is a continuous rhythm strip, patient in the hospital. See this happening in front of your very eyes. It's obviously wider on the left, narrow on the right. So what's going on? Is it that VT is inducing SVT? Change refractoriness. Is there evidence of a left-sided accessory pathway here? And adenosine is unlikely to terminate the tachycardia. All right, everyone got it. So we're talking about refractory, so it's good. Yes, it is definitely a change in refractoriness here. So I'm glad we didn't, no one said that, you know, obviously a left-sided accessory pathway, whenever you see a bundle branch block, all of us should get excited, right, during an SVT because we're looking for a change in a cycle length concomitant with the disappearance of that bundle or the appearance of that bundle, because, you know, the epitome of the Kumail sign, right? You wanna see if there's an ipsilateral bundle branch block and there's a change in the cycle length. That might be instructive for kind of making your diagnosis then and there. In this case, it's a right bundle branch configuration, so it's not gonna be too helpful. This is a situation where the right bundle is refractory, right, for the first 10, 15 beats with the tachycardia that I'm showing you here, and then it narrows down. And there is a phenomenon called accommodation. So it's as you abruptly change the rate of a tissue and you encroach on its refractoriness, you might encroach on the refractoriness of the right bundle in the example previously shown. And then with successive stimulation at that same drivetrain, you'll start to see that there are changes in the action potential at the cellular level. And you might see that the action potential duration actually shortens with successive beats at that same drivetrain. Another example that you might see in this is sometimes when you're trying to get, say you're trying to get atrial flutter or atrial fibrillation going, and sometimes you burst pace at 210 milliseconds from the coronary sinus. You may see that you get two-to-one capture at times, and then you're pacing at 420 effectively for a few beats. But then as it warms up, we kind of hand wave and say, hey, it's warming up. Then it starts to capture one-to-one on the coronary sinus. It's probably a similar concept here that that atrial tissue is refractory at that drivetrain of 210, but after you've paced it at 420 for a while, then those action potentials are shortening, shortening, shortening. And now it's bringing it into a range that the refractory period is shorter. And now you're pacing at 210 and it's conducting one-to-one. Same thing happens with the conduction system tissue where we see it all the time in SVT, and thankfully we can use it to our advantage to make some quick diagnoses. I want to transition into some categories of arrhythmia formation mechanism and a few examples of that. So we know classically, if you look it up in a textbook, there are three major categories of arrhythmia formation. Number one is abnormal automaticity. We'll go through all of these. Second thing is triggered activity, which is a lot of what we deal with in the EP lab, and reentry, which is probably the other half of what we deal with in the EP lab. I want to spend some time on abnormal automaticity because I think we see it more often than we invoke it. The clinical hallmark of these arrhythmias is often there's some disturbance in the potassium levels in this tissue preparation. Maybe you don't know about it. Maybe it isn't like a whole body potassium elevation, but usually there's an increase in extracellular potassium in the vicinity of where the arrhythmia is going on with a lot of these conditions. And the hallmark is that usually you can't terminate these arrhythmias with burst pacing. It's not like suppressing the sinus node, for example, where you get overdrive suppression and pace it faster, and then you see that that automaticity drives down. But the abnormal automaticity, it's kind of a different animal entirely. A lot of times we'll encounter this in ischemia. So if you have ischemic ventricular tissue, part of the hallmark is that that tissue is partially depolarized. And it may be because the local potassium is deranged, but basically it's been known that those cells carry a higher resting membrane potential on average compared to healthy tissue. And so by driving that resting membrane potential up, say from minus 90 to the minus 70 or 60 range, you might start to activate other channels other than sodium channels that will start to get its own automaticity. And usually it's relatives of these funny currents or these pacemaker currents, which all cells have, but these channels coupled with that elevated potassium leads them to conduct current in the opposite direction at times. And so often bring in potassium influx into the cell, depolarize the cell and lead to automaticity. So these idioventricular rhythms, I mean, this is hand-waving for me as well, but we suspect that a lot of times these ischemic idioventricular rhythms are from abnormal automaticity. It happens in the hysperkinesis system a lot as well, either in the border zone of infarcted tissue where you get partial ischemia and damage to that tissue or in some rare heritable arrhythmia syndromes such as Anderson-Tewhill syndrome, also known as long QT7. So in these situations, you might encounter it. I bring it up because it's kind of related to another topic that gets thrown around a lot, or it's called use dependence, right? So we know that some drugs have use dependence and how that's defined is that the more depolarized the tissue is, the more that drug will have an effect. So the times that you encounter use dependence, situations with depolarization predominance. What does that mean? Well, ischemia is one of those that we mentioned. Another area is that if you're in an arrhythmia, a tachyarrhythmia, where the average activation rate is fast, then as a function of time, in one second, you're gonna have more, the cell's gonna be more depolarized and it's gonna be hyperpolarized. So that's a classic situation where you have depolarization predominance. And the second thing that you need is you need a special drug where that special drug is dependent on what conformation those ion channels are in. So there are drugs out there that preferentially have an affinity to bind to the channel. When the channel is either wide open or when several of those voltage sensors, those activation gates have opened, then it facilitates binding of that agent to the channel. And so if that drug does have use dependence, meaning it has a higher affinity to the open or partially activated states, then you might expect that drug to have a greater effect during situations with depolarization predominance. One of those might be this abnormal automaticity. Another one that's a little bit maybe closer to home is during atrial fibrillation, right? So classically, you would want to use a drug with use dependence if you're trying to terminate atrial fibrillation to sinus rhythm for pharmacologic cardioversion, for example. And classically, you would want maybe something with reverse use dependence if you have a patient in sinus rhythm and you wanna keep them in sinus rhythm because then their activation rate is nice and slow in the atrium and that drug is binding to it so that it has more of an effect at those slow rates. So it can go both ways where a drug can be more prone to bind into the closed states. Unfortunately, sometimes that reverse use dependence in a lot of the drugs we use, and classically, I'm gonna throw out there that Sotalol is one of these that has reverse use dependence. A lot of times that ends up shooting ourselves in the foot, right? So it has reverse use dependence. It's not great. Actually, it's contraindicated to try to convert an arrhythmia with Sotalol. Unlike ibutylide, it just doesn't seem to work as well. But it does have that reverse use dependence, right? So when you convert them back to sinus rhythm, a lot of times you'll see that because Sotalol isn't purely affecting the atrium, it's affecting our ventricular tissue too, you might see that it has a disproportionate impact on the repolarization of the ventricular cells, and then you can get QT prolongation. So that's one of the reasons why we like to keep the heart rate somewhat more elevated when we're giving someone Sotalol. A lot of us feel a lot more comfortable prescribing Sotalol to a patient with a pacemaker, where we have backup pacing, we can avoid that bradycardia. Sometimes we'll even atrially pace a little bit faster so we can reduce the impact on the ventricle if that's a situationally appropriate. So there's normal automaticity in the sinus node. I just want to quickly go through the fact that you can overdrive suppress automaticity. And the way that that happens is when you have enhanced automaticity that's normal, that's going through the regular sort of funny current mechanism that's a node. You're giving it your favorite chronotrope, whether it's isopraternal or something else. Usually you'll see that phase four depolarization here if you're in control of the sinus. Phase four depolarization here, if you're in control in red, it's a nice slow depolarization. This probably marches out to a nice sinus cycle length of probably a thousand milliseconds. But if you give it a chronotrope, the slope of that phase four depolarization, funny current as we're calling it, it's dramatically increased until it starts to require an action potential and then it repeats itself. But if you have a patient with sinus tachycardia, most of the times you'll be able to overdrive suppress that sinus tachycardia. And you might see that when you're testing the sinus node recovery time, for example, if you're kind of looking at the comeback rates and so forth, then you'll see some overdrive suppression of that tissue. And really it's because you're increasing. So say this is your cell that you're interested in, you're pacing it. So you're driving it by its next door neighbor and you're increasing the time average entry of sodium into that cell. So what does that do? Well, we all have these homeostatic mechanisms, right? That keep our ion concentrations at bay. Once that time average increase in sodium occurs, well, now the cell is chock full of sodium and this pump is getting rid of the sodium and bringing in potassium, which is a hyperpolarizing current. So the net net of this is in order to get rid of all that sodium, the cell is gonna be hyperpolarized. And so then you're getting into a situation where this red curve is downward shifted. It's gonna take longer for that cell to reach the threshold. So you can overdrive suppress classically situations where you have enhanced normal automaticity. So that might be something like inappropriate sinus tachycardia. Totally different is triggered activity though. Triggered activity is usually comes in two flavors. And we often talk about EADs, early after depolarization and DADs or delayed after depolarization. And this cartoon shows us on this, Tony Fauci is cited here. I always like to cite him these days, but these EADs occur early in the action potential. So that tail end of phase three, phase four, where you get a little bit of a bump in the membrane potential. And if that bump is big enough, it can trigger another action potential. That's why we call it triggered activity. Same thing with the DAD, but the mechanism is totally different. The mechanism here in a DAD is often due to intracellular calcium overload, where you get these spontaneous outpourings of calcium into the interior of the cell from the sarcoplasmic reticulum. And in order for the heart to get, when the heart cell to get rid of that calcium, it actually leads to depolarizing current, which I think we'll see in a slide or two. The magnitude of these depolarizing currents, if it's big enough, can trigger another action potential. So a lot of the PACs that we see, PVCs, a lot of this is triggered activity, and a lot of this is calcium overload. So I mentioned a moment ago an anecdote about getting PVCs going. Beta adrenergic stimulation is a great way to get calcium into the cells, different pacing protocols, but this is a time where you really wanna facilitate this abnormal calcium cycling, but that's really what's going on. So EADs, DADs, EADs think about QT prolongation, long QT syndrome, DADs think about calcium overload. So thinking about the EADs, if you ever wanted to bring out something that is QT related as an arrhythmia, often you'll want to maximize your action potential duration. And the way to do this is really with long short mechanisms, right? So in the wild, when we see torsades de point in our hospital wards, usually we'll see it associated with a relative period of bradycardia, and usually with the short, long, short kind of sequence. And what I mean by that is you'll have someone trucking along, baseline QT might be normal or a little bit prolonged, and then you'll see a PVC, and then the post-PVC beat will have an abnormally long QT interval. And that's like a hallmark. If you wanna make sure that something is torsade, you wanna make sure that the QT is baseline prolonged maybe, but really that beat before the torsade is kicked off, you'll wanna see that that preceding pause in the long short, that classic initiation is present, and that there's significant QT prolongation before your episode of torsade. So keep in mind that the action potential duration is a function of the preceding diastolic interval. So when you have these long short intervals, you'll see that in beat number, letter C here, you have an extremely long preceding diastolic interval. So you would think that the action potential of this guy is gonna be really long. And so I think that this action potential is, these are the right conditions for EAD formation, right? So you have the QT prolongation. It's not hard to envision that's some cell. Usually in the His-Purkinje system, we're learning more and more as a site of initiation of some of these phenomenon. But some cell in there might fire off an EAD that's large enough to trigger an action potential. And so often this is a precipitant to torsade de pointe. And the other area that we kind of intentionally do something like this is in the EP lab, right? When we're trying to bring out bundle branch reentry, right? That's a situation where we're trying to induce block in the right bundle, or at least in the integrated direction. And so these long, short, and especially short, long, short, because that's maximizing the action potential duration on that triggering beat. Those are either from the atrium or the ventricle. If you can do that in the EP lab, you'll often be successful in blocking in the right bundle, getting it to go up retrograde and initiate a bundle branch reentry in the clockwise direction. So here's a couple of, you know, if you're in ICU and you're seeing torsade, most of this is basic, but it's important to keep in mind. I think a lot of times things get called torsade de pointe when it's not really TDP. It's something like polymorphic VT or it's even VF. And so it's important to look at the initiation because how you treat torsade de pointe is very different than how you treat polymorphic VT. For example, in torsade de pointe, we want to increase the amount of TDP For example, in torsade de pointe, we want to increase the ventricular rate to shorten that action potential duration, shorten the refractory period. Sometimes you might even, if you don't want, if the patient doesn't have a pacing wire and you don't want to put in a pacing wire, you might even try to increase the ventricular rate. Sometimes we do that if for sure there's not ischemia at play or something like that. We want to prevent pauses, which are the precipitant, as we discussed, maybe put in a temporary pacemaker. And by the way, you want to give magnesium, even if the serum magnesium is not too low. So those are your tools and your toolbox for torsade de pointe. But you want to make sure it's that first. So definitely look at the QT interval, look at the mode of initiation and make sure that it's torsade de pointe before reaching for any of these tools. The flip side of things, DADs are totally different, right? So those lead to calcium overload when things are going smoothly, get smooth excitation-contraction coupling. But classically, when you have pathologic calcium overload, you can see that from the sarcoplasmic reticulum, you get the spontaneous depolarization, spontaneous release events of calcium. And because we, again, have these homeostatic mechanisms for the ion species, that calcium gets extruded, brings in sodium. So that's called a transient inward current, which leads to the depolarization or the delayed after depolarization. The other classic area that we see this with calcium overload is in digoxin toxicity. Thankfully, we don't use that nearly as much as we used to, but certainly digoxin, by poisoning the sodium potassium ATPase, again, it leads to a compensatory mechanism by the sodium calcium exchanger, where you bring in tons and tons of calcium into the cell. And so that's loading up the sarcoplasmic reticulum. If you're really toxic, you might lead to these spontaneous release events. Now, I do wanna say two things. Number one is that often with DADs and EADs and any arrhythmia formation, there's always a component of reentry, which we'll talk about really briefly. And so sometimes the precipitating event is the triggered activity from DADs or EADs, but then you set up different repolarization states across your tissue preparation and you can get reentry in that way and that perpetuates the arrhythmia. So that's one important observation. And then the second thing is more of like a clinical pearl. If you ever encounter someone who's digitoxic and older patients taking dig forever and then it's, you know, it takes too much of it. And they're coming in with that classic hallmark, right? Of atrial arrhythmias with bradycardia and you wanna get the heart rate going. I wouldn't be too tempted to give a positive inotrope in that situation or a positive chronotrope with inotrope properties because you may actually exacerbate that calcium overload, bring more calcium into the cell. And it's actually a great way to induce ventricular arrhythmias. So hopefully all of you guys will avoid that as a clinical pearl and sometime it might come in handy. Got a few more minutes in which to kind of talk about re-entry. We kind of talked about it a little bit and I think there have been other lectures that have covered this probably more in depth. So I will kind of gloss through it other than to say that there are three fundamental criteria, right? For re-entry to occur. Need unit directional block, right? You have two pathways set up in the previous slide with the accessory pathway or a fast and a slow pathway in the AV node. And it's really interesting in EP, right? Even though the AVNRT is contained within a couple of millimeters and AVRT has this giant loop where you have an accessory pathway clear across the ventricle, that re-entry can occur in both of those settings. And really distance and time are so fundamentally related through that conduction velocity that that can happen. And so the second requirement for re-entry is that the conduction velocity is slow enough that it can chase its tail and have enough slowing of conduction velocity where that initial takeoff point has recovered from its refractoriness and is able to conduct and chase its tail. And basically that path, that distance is also important. So that path length has to be long enough that the conduction velocity times your local refractoriness, that that's exceeded by your path length. So you need a large enough path, but if you have enough conduction velocity slowing, like in a slow pathway, for example, you can circumvent that. And so when you're inducing SVTs or even inducing VT, you can keep in mind that this is exactly what you're doing. You're trying to maximize the conditions of slowing conduction velocity. The path length is something that you can't always control, but maybe you can understand. And then you wanna make sure that you get that unidirectional block, right? So that's where you introduce the PVCs and make it block in one direction. And we're leveraging that constantly in the EP lab. I think this is our last poll question, right, Nishant? Maybe. So, yeah, yeah. So let's match the subtype of long QT syndrome with the trigger, the clinical trigger that we commonly see and the channel product. I think I may have given away the answer previously. Hope not. So in A, we're saying that long QT1 is gene KCNH2 swimming. I won't read all of them. You guys can go ahead and vote. All right. So, we got a two-way tie between the second and the last two options. So, it turns out that LongQT3 is associated with SCN5A. That's a sodium channel. And the major trigger is sleep or bradycardia. Those are the major triggers. LongQT1, the second to last one is almost right. LongQT1 is typically, it's triggered actually by swimming. And the gene product is actually KCNQ1. So, there are a couple of differences there. With the HERG channel, which is KCNH2, or the delayed rectifier rapid component, that one is LongQT2, and it's typically brought out by straddle or exercise. So, we'll go through that really quickly. But do we have this one, Nishant? Probably not. Oh, yeah, we do. Quick one on this because we're running out of time. Yep, the answer is CPVT. So I think these might be two board questions that you might get. Hopefully we'll get them right. CPVT is a calcium overload heritable arrhythmias. So you might see fatal arrhythmias during swimming. Just to go through the Long QT syndrome, because this is the most likely that you'll see in your board exam. These are heritable gene mutations. Long QT1, it's repolarizing current. The condition is due to loss of function of that repolarizing current. So you get longer action potential durations and longer QT. The diving reflex, right? This is why swimming is such a trigger that if you dive, typically you will get a sort of a variation in your heart rate. And it's increasingly recognized with these Long QT subtypes, that that change in heart rate, that the action potential doesn't do a great job of accommodating to those changes in heart rates. So you're going through these constant cycles of heart rate going high, heart rate going low, and those action potentials can get really long in those cascades, leading to these EADs and the downstream effects. So inability to shorten APD with those changes in heart rate. Long QT2 is KCNH2, and startle and exercise are the key triggers. There may be a catecholamine sensitivity to this. And basically that abrupt increase in the neurohormonal input can sort of not allow enough time for the action potential to repolarize, prolong it and lead to QT prolongation. Long QT3 is interesting. It's again, that sodium current, it's a gain of function. So now we're depolarizing the action potential more. It's a persistent sodium current problem. So the advent of ranolazine and recognition that amylorone also blocks this late or persistent sodium current. So ranolazine and sodium channel blockers are obviously very useful in Long QT3. Beta blockers actually are thought to partially potentially block sodium channels. So even though these are precipitated by bradycardia, often you'll see that beta blockers are effective. And I just wanted to mark that the reason why bradycardia is associated with Long QT related arrhythmias is because in a lot of these Long QT3 mutations, the channel can actually enter into a persistently open state that comes off of the resting most state. And so in situations where the channels tend to populate this resting state, aka bradycardia, it can enter into these bursting states where it carries lots of persistent late current and prolonged action potential duration. So Long QT3, slow, tends to be very prolonged action potential durations in QT intervals and episodes of sun depth. We're running a little long, right, Nishant? Yeah, just kind of skip to the end. Yeah. That was great. So this is just a summary. I don't know if there are any questions from folks, but basically just to keep in mind, membrane currents and calcium cycling, that's the basis of the action potential. And hopefully, I don't know, a lot of times we're doing things, like I said, in autopilot in the EP lab, but we really want to be thinking about the mechanisms underlying it. And occasionally, these mechanisms will be helpful, both in the ICU setting to figure out what's going on with an ischemia-related mechanism or dish toxicity, or even in the EP lab when you're trying to get arrhythmias going, you can leverage some of these fundamental EP mechanisms, reach for the right pharmacologic agent, reach for the right pacing protocol.

cellular electrophysiology

clinical implications

arrhythmia formation

abnormal automaticity

triggered activity

reentry

ischemia

early afterdepolarizations

long QT syndrome

catecholaminergic polymorphic ventricular tachycardia