Transcript for:
Cardiac Electrophysiology: Week 4 Lecture Notes

hey everyone welcome to week four I know week three was a lot I mean it just is you know the heart is a really important part of patient management across you know across the board so it does take a lot of time I mean again coronary artery disease is the leading cause of morbidity IM mortality in the United States and that's just one small piece of cardiac pathophysiology or I should say cardiovascular pathophysiology that we have to discuss this quarter that's why we get two uh weeks for it and this week you'll notice that there might be less time in the slide decks might be less actual number of minutes but the content is a bit more challenging this one is about cardiac electrophysiology about the electrical events as they drive the mechanical events the next the next uh uh audio number two or you know PowerPoint section session number two this this week is actually much lighter I think it's only 33 slides and just much easier to digest this is a challenging one so we're going to jump right into it so our objectives for this section I know this is one that people struggle with I think the most because they have lesser background in it in your undergraduate um physiology courses but it really is the foundation of electromechanical Association electrical events occur in the heart to drive the mechanical contraction when we talk about you know all the time we talk about how potassium abnormalities can lead to drimia or hyperemia can lead to Broc cardia and even asy if there's too much hyperemia we know that sodium imbalances can make differences I mean we know that electrolytes have a huge impact on the function of the heart in this slid set we talk about the physiology of how that is the physiology the electro physiology exists to drive the mechanical physiology of contraction remember we talked about this in week one calcium is the contractile electrolyte of all muscle including cardiac meiocytes and so the goal is to get cardiac into the to the cardiac M myosite into the sarcomere so that the cardiac cells can contract in order to get calcium into the cells Gates have to open and for gates to open voltage has to rise and that's why sodium moves it's a whole thing we're going to talk about it in painful detail here so at the conclusion of this discussion we're going to look at the role of ion movement as it relates to cardiac function discuss the electromechanical association electromechanical dissociation is the oldfashioned term for pea pulseless electrical activity when we see electrical events happening but there's no mechanical events back in the old days we used to call that electromechanical dissociation which I really think is a better term because it speaks to the disconnect between the electrical activity and the mechanical activity ity patients can wind up in a condition where the electricity works right but the mechanical piece doesn't work right in the healthy patient in the normal world the electrical events Drive the mechanical piece and I I hope that that's clear as we finish this discussion but the real point of all of this is to understand how electrolyte anomalies really can impact cardiac function um the tasks of cardiac muscle really are to contract to move a load forward and then to relax and prepare for filling again and that's really it that's the gist of the objectives for this um actually we already talked about comparing and contrasting short and long-term regulation of blood pressure in the last section as you can see I cut and pasted some content for you in nursing 548 to try to make it a little bit more manageable and not have like these enormous chunks of complicated topic so actually I probably could have just deleted that that objective and then I wouldn't even know how to say that but since I already narrated that part I'm going to leave the fourth objective here even though we already did it at the end of week three this lecture really is about the electrical events of the heart and how they articulate with the mechanical events again from time to time I may say something especially in this lecture I may say something about other lectures this time or next week we'll do this or that I've tried to edit it out as much as I can but I will tell you that the introduction and the objective review I have recorded for nursing 548 and the fall 2023 semester here at Drexel and so what I'm telling you now is that this is week four in week three we talked about what did we talk about cardiac blood flow gosh blood pressure regulation valvular disease Venus disease I know last week was kind of heavy duty this week lesser lectures lesser amount of time but perhaps a bit more complex content this discussion here about the electrophysiology is probably the most challenging of the cardiac piece but this is grad school and now you are prescribing medications that will impact cardiac electricity you will prescribe medications that can have a real impact on electrolyte movement and it can have catastrophic consequences if you don't know what you're doing so hopefully at the end of this lecture you'll understand it and then I do believe after this I have a much shorter slide set I think it's only 33 slides or something like that so Brea a SL SL Le for slid set number two where we talk about pericarditis and endocarditis um cardiomyopathy really just to round out the discussion but the meat and potatoes here is the electricity and the electricity is is generated by electrolyte movement the whole purpose of electricity is to get calcium in the cell so that calcium can lead to Mechanical contra raction so having said that I guess we will just Jump Right In All right so first things first let's look at the path of normal electrical activity this really is critically important electricity is supposed to move through the heart in a very defined uh manner a very defined series of Pathways which ensure the smooth uniform um distribution of the electrical impulse to all of the contractile cells of the heart as I mentioned a minute ago when we were looking at uh the objectives the two primary types of cells in myocardium are rate setting SL rate limiting cells these are the cells that either generate the impulse or control its advancement these cells really don't exist to contract they exist to set or control rate um so those are your rate setting rate limiting cells also known as your slow response cells and then we have your contractile cells whose job is to generate the force that moves blood from one chamber to the other and those are sometimes referred to as fast response cells the the electricity has to move through The myocardium like I said in a very defined manner so that electricity can move through all of the cells at the same time remember that you know in the body in general all of our cells have a job to do and either they're doing it or they're not they're either working or they're at rest and if they are at rest in the heart they're in diast and then when they are stimulated um in the ventricles anyway this would be syy also keep in mind that all tissue that is all that is not already stimulated all tissue that is at rest will fire off as soon as electricity touches it it's like anything that's not electrified will respond to electricity so if we didn't have a really smooth uniform way to distribute electricity to the various chambers of the heart at just the right time then what you would wind up is with is a bunch of disorganized electrical impulses and it just wouldn't do any good remember in the first week of this course we talked about the relative refractory period and the absolute refractory period these are periods of time during which cells cannot be stimulated um in the absolute refractory period cells can't be stimulated by any amount of electricity in the relative refractory period the cells need a greater than normal stimulus to be stimulated so the this whole business of these defined Pathways of electricity in the heart ensure that electricity will be distributed to just the right place at just the right time to ensure that muscle contracts just when it's supposed to because that's how you get all the cells of a chamber Contracting at the same time and that's how you get the most smooth uniform ejection of blood into the next chamber or the next place where it's supposed to be so remember we said in week one that the cell membrane acts as a capacitor one of its jobs is to store electrical charges charge is created by the movement of charged particles across the cell membrane and as those particles move across the membrane the membrane stores a charge I know it probably seems like a long time ago now but in week one it was one of the first things we talked about with respect to functions of the cell membrane so if we accept that the cell membrane stores charges and that if electricity has to move from one cell to the other then we recognize that tight fits of cell membranes like you know all of the cells of an organ or a tissue type packed tightly together will allow smooth uniform transmission of voltage or of a charge from one cell to the next this is what's going on in myocardium in in whether it's contractile tissue of the Atria or contractile tissue of the ventricle the cells are all very tightly packed because it's the cell membrane that holds the charge and the pathway that promotes its transmission is a function of one membrane being tightly packed to the other so visualize those cell membranes really tightly packed in right like a bunch of I don't know as much as you can pack of something in a container that's how tightly those cardiac cell membranes are together the membrane stores the charge and stimulation of those pathways allows the charge to move from one cell to the other cell function and communication is often a function of its membrane voltage in other words the way one cell communicates with the other relies on the fact that it stores its voltage the membrane potential is the electrical energy difference between the inside and outside of the cell now again I know we talked about this before so hopefully this is a bit of a review but if it was the first time you ever heard it in any detail then you probably forgot half of what I said in week one so I'll say it again cuz it's really important here the membrane potential and scientific notation is as it's shown here capital E subm this is scientific notation for membrane potential membrane potential is the electrical energy difference between the inside and outside of the cell it is stored in the cell membrane and it is produced by the separation of charges so when we refer to membrane potential e subm we're talking about whatever the voltage is in the cell membrane at any point in time um the cell me the the membrane potential may be very low in a Cell that's at rest it may be comparatively high in a Cell that's active or discharging or depolarized the membrane potential is just the amount of voltage in the membrane at any point in time it is produced by the separation of intracellular and extracellular contents and as charged particles move across the cell membrane the voltage is stored in that membrane and that's where we get it so the real takeaway message from this slide is e subm is the amount of voltage stored in a membrane at any given point in time and it is produced by the separation of charged particles the intrasellar environment versus the extar environment this separation occurs when you have a membrane like a cell membrane that is separating two solutions and it's permeable to only one ion or only precise ions the conductive the conductance of the ions is different so we also talked about this in the first week of the course I believe I mentioned that you've got a cell membrane and then say in the intrasellar environment there's a lot less sodium than there is outside this cell right in the intracellular solution there's maybe 10 milliosmoles of sodium in the extracellular environment there's 140 um versus potassium but which there's a lot more of in the intell environment there's about 140 milliosmoles of pottassium in the cell and there's about four M equivalents outside the cell there's a whole lot more chloride outside the cell than in there's a whole lot more calcium outside the cell than in you know of all of the charged particles the concentrations of each in the intra versus extra Cellar environment are very different and the only thing that keeps that separation is the cell membrane so what we're talking about here in terms of you know biology and living cells the membrane we are referring to is the cell membrane and it is separating intracellular from extracellular environment and so because the charged particles just can't move through those membranes they need to have an open channel of some sort sort the separation of charge is achieved by the membranes and then if there happens to be a channel that goes through the membrane that allows an electrolyte to move through then you will see um well then you'll see then you'll see electrolytes move through I guess that was pretty repetitive hopefully we're going to look at some diagrams in a minute and hopefully this will make a lot more sense but this is another one of those Concepts that I feel like people just don't get a really good grasp on it early on and then when we try to talk about Concepts later on it becomes more difficult so okay here's an example in the resting state which again in myocardium is diast right let's just use the ventricle because the ventricle is the easiest one the left ventricle is the biggest one um most of us have encountered it clinically one way or another when something goes wrong with the left ventricle so it's a good um it's a good point of reference right it's a good foundation to have the conversation so in the resting state The ventricle is in diast at rest the conductance of potassium across the cell membranes of the cardiac meiocytes is greater than for any other ion potassium is able to just like leak through channels so since there are these open channels in cell membranes for pottassium in the resting state what is the pottassium going to do if the door is open it's going to do what any molecule will do if the door is open as a principle of diffusion it's going to move from an area of higher concentration to an area of lower concentration that is always what will happen when you try to separate two things and that thing can move across the barrier it's going to move across the barrier to try to try to achieve a steady state of equilibrium so in the resting state in diast pottassium moves more readily across the cell membranes than anything else there just Le channels open and it can just leak through and so potassium will move along its concentration gradient from the inside of the cell to the outside of the cell remember also the law of electr neutrality the body likes homeostasis the body just likes everything to be all equal the body doesn't like like when the sea salw is um really weighted in one area or the other if you think of a normal like perfect physiologic state of as as a seesaw that is level right that is parallel to the ground that's the way the body likes to be whenever anything happens to like sit on one end of the Seesaw and try to screw things up the body will try to fix it this is one of those circumstances because myocardial cell membranes are permeable to potassium more than anything else because conductance of potassium is greater than anything else in the resting state pottassium will logically Move Along its concentration gradient from the in C environment to the extra Cellar environment well potassium has a positive charge so if it moves out on its own what's going to try to happen chloride or a negatively charged ion I should say a negatively charged ion is going to follow it because the body likes electron neutrality the body likes positive and negative charges together so when potassium tries to move out a negative charge will follow it and chloride is the most common negative charge I mean potassium and chloride just bind together very well so when potassium is sort of hung out by itself being all positively charged it will have a very strong attraction for chloride so in diast when myocardium is at rest and potassium tries to or potassium does Move Along its concentration gradient outside of the cell chloride will try to follow it but there's no chloride channels open chloride can't go so what's going to happen like a magnet chloride hugs up along the inter surface of the the cell membrane it wants to go out it's like stuck it can't get out but it's got an attraction it's like when you separate these two charges when you separate the positive from the negative it's like a magnet right they want to come back together but they can't because chloride can't get through the membrane there's no chloride channels open so what happens when potassium gets to the extracellular space chloride goes as far as it can it gets hung up on the inter surface of the cell membrane that's what I tried to visualize here I know I'm not the most creative person like um what do you call it artistically but I did my best so you see CH you see potassium moving from the intracellular environment to the EXT environment that's what the red arrow is you see chloride trying to follow it but there's no chloride channels open chloride gets hung up on the inner surface of the cell membrane chloride is a negatively charged electrolyte also referred to as an anion and so all and now you're just seeing a couple of them here but a ton of these chlorides try to hang up there to get through the membrane to hook up with the pottassium it can't you get a bunch of chloride hung up on the inner surface of the cell membrane and all of those negative charges will get stored in the membrane like the capacitor that it is and this is what creates the resting voltage right in the resting state myocardium is quite negative somewhere between -60 and- 80 molts your slide says- 60 so that's fine you know good enough for the conversation and that's that's what maintains this minus 60 molts in the cell membrane of cardiomyocytes in the resting state so whenever you have a separation of charge the electrolyte or the charged particle that is hung up on the inner surface of the cell membrane is the one that is going to confer its charge in this case in the resting state because potassium channels are open and potassium can move out chloride tries to follow it it can't all the little chlorides get hung up on the under surface of the membrane those negative charges are stored in the membrane and that creates the membrane potential right the e m e subm membrane potential of minus 60 molts at the resting state so what do what do you do what's The myocardium doing when it's at rest it's diasty ventricles are relaxed they're filling up with blood right and then they're waiting for something to happen they're waiting to be stimulated they will be stimulated um these are cells like every other cell they have a nucleus and they have organel and they have receivers and they will have they have receptors and things will bind to them and some of those stimuli will be excitatory and some of those stimuli will be inhibitory and all of these stimuli will be conducted through their receptors into the cell body body where they will be processed and you'll have stimulators or exciters and then you'll have Inhibitors and when you get to the point that there's enough stimuli for excitation to make this cell fire off and do a job then you will have an action potential an action potential is when the cells are depolarized to the point of discharge remember like I said every cell has a job to do it's just waiting for a stimulus to do it in the resting state cardiac meiocytes are about minus 60 molts that's their membrane potential when we refer to cell membranes as being depolarized it means something is making the voltage go up if we say that the cells are hyperpolarized something is making the voltage go down and so when I refer to depolarization I'm talking about something raising the voltage from - 60 -50 50 - 40 something is raising the voltage to the point where the cell fires off there is a threshold there is a point at which you hit it and boom so all these cardiac myocytes are going to be stimulated by different things and some of them are a little bit excitatory and some are a little bit inhibitory so it might get a little stimulus that raises it that depolarizes it from like - 60 to - 55 and then there might be an inhibitory stimulus that would hyperpolarize it from - 60 to- 65 and so these stimuli either make the voltage go up depolarization or make the voltage go down hyperpolarization when enough excitatory stimuli cause enough depolarization to get the cell membrane to a certain point and we call that point threshold once you get to that point then there's no going back the cell will discharge then you will have an action potential and that cell will do whatever it is that it's supposed to do this is what we mean what I mean when I refer to a regenerative all or none once you hit that point once you hit threshhold boom it is it either you have a stimulus or you don't right either the cells are stimulated to the point of threshold or they're not it's all or none it's not like a little bit it's not like if you stimulate them a little bit they'll throw out a little bit of electricity that's not the way it goes It's All or Nothing so visualize this cardiac myosite that we've been talking about in The ventricle in the resting state it's relaxed The ventricle is filling up and the cell is not Contracting it's not discharging it's not doing anything it is at rest while it's at rest The myocardium is relaxed it's filling up with blood and meanwhile stimuli are occurring to these cardiac meio sites when something comes along to stimulate it to the point that the voltage goes up and you hit threshold right it depolarizes to threshold this will be the all or none this is the all the cells will fire off you are now in syy you can see why we want them to all happen at the same time right we don't want one or two cells of the ventricle just discharging on their own we want all of the cells of the left ventricle firing off at the same time to create that smooth uniform contraction that gets you a good ejection fraction so it is true the last bullet point here it says Action potentials have different F let me say that again Action potentials have different types have different functions in different cell types that's true right now we are talking about myocardium and remember I said there are there's rate setting or rate limiting tissue AKA slow response or there is contractile tissue AKA Fast Response right now we're using the example of contractile tissue just to make the point in case I didn't mention it on the last side Action potentials of different cell types have different wave shapes the wave shap shape is just the way we visualize electricity moving through um the membrane again we'll have some some we'll have several pictures to look at this and hopefully it'll make perfect sense okay let's see Okay so we've already determined that in the resting state potassium channels are open potassium moves along its concentration gradient from intrasellar to extracellular space that causes the voltage to remain low and generates a resting potential or a resting membrane potential of somewhere around minus 60 molts um with respect to cardiac meiocytes which is what we're talking about and the cells of the ventricle specifically after The ventricle has been in rest for the appropriate amount of time usually about 2/3 of a second The ventricle is full now it's time for a systolic contraction to occur so when The ventricle has been maximally stretched by diastolic filling just about this time an electrical impulse will come down along those specialized conduction Pathways that we talked about in the beginning of this discussion electricity moves along the specialized conduction Pathways electrifying all of the cells of the ventricle at the same time this electrical impulse opens sodium channels when sodium channels channels are open and sodium channels are fast by Nature they're just very fast acting channels when they open sodium will rush along its concentration gradient from the extraor space to the intra cellar space remember there's 140 M equivalence outside the cell 10 m equivalence inside the cell so when this electricity comes along and open these sodium channels sodium will rush in it's like raising the gate at the racetracks and the horses just rush out sodium rushes in but what happens now what happens is what always happens the body doesn't like separation of charge when sodium rushes into the cell a negatively charged molecule will try to follow it usually chloride so chloride will try to to follow it but it can't because chloride channels are not open so you know what happens now chloride gets like stuck along the outer surface of the membrane and like a magnet it holds sodium close by on the other side of the membrane now you have a bunch of sodium ions lining the inner surface of the cell membrane remember we said this is where a cell membrane gets its charge whatever charge is hung along the inner aspect of the membrane that charge is what stored in the membrane so now all those sodium ions all those positively charged sodium ions are stuck on the inner surface of the membrane held there by the Chlor chloride that could not follow them in suddenly the membrane voltage raises it raises rapidly it depolarizes right it goes from - 60 -50 -40 -3 -2 - 10 Z all the way up to like plus 10 or plus 20 when you think sodium channels think fast when electricity opens those sodium channels sodium rushes in chloride tries to follow it it can't it holds sodium to the inner surface of the membrane and the membrane potential the the the voltage in the membrane goes way way up it leads to Rapid depolarization and then as fast as they open sodium channels close sodium is just fast it's a fast fast moving thing now potassium channels have been open the whole time but they're just like they're overwhelmed by the sodium they're they are dominated by the sodium so even even though potassium is sort of sneaking out of the cell sodium is rushing in so for a very brief spell the membrane voltage goes up and then as soon as sodi as soon as sodium channels close sodium can no longer come in that rapid rise of membrane potential stops um and now because the potassium channels remain open the membrane voltage begins to fall and it goes down pretty much as quick as it came up like slapping the gate shut on the those sodium channels it's like boom suddenly there's no stimulus to raise the voltage the voltage just drops it repolarizes it goes back down to where it was in fact to some extent it may hyperpolarize for a fraction of a second it may go a little lower than its Baseline and then it will normalize and that is the end of your generic Garden variety action potential and here's what it looks like so this diagram is showing you um on the top half if you drew a horizontal line through the middle where basically where you see the time the thing that says time so at the top is the action potential this is showing you what's happening to voltage underneath that is showing you what the electrolytes are doing while this is happening so in the very beginning on the extreme left as sodium channels open and sodium rushes in you see the voltage go way up in fact draw some of my world famous Little Numbers here um number one sodium channels open I draw one and I Circle it sodium Channel is open when they open the voltage goes way up with the Cory one on the top part of the vid of the visual and then but as fast as they open they shut as soon as they shut sodium doesn't go in anymore um sodium closes sodium channels close and then all that's open are potassium channels and boom voltage goes down you see potassium as number two in a circle it's a bad number two but it's a two and and the corollary is up here sodium up potassium down that's pretty much the the state of your typical Garden variety action potential so this these next few slides just narrate what we just looked at at the beginning you have initiation an electrical stimulus depolarizes the membrane potential basically it opens sodium channels sodium channels open sodium rushes along its concentration gradient this makes the voltage of the membrane become less negative right - 60 -50 -40 -30 -20 everything we said this is happening because at this time this brief point in time the conductance of sodium is greater than the than the conductance of potassium sodium can move through the membrane more easily than pottassium so the conductance is greater this is what causes that upstroke that positive upstroke of the action potential and what what's happening during that upstroke is the voltage the es subm right the membrane potential is becoming more and more positive and then like I said the sodium channels stop they inactivate suddenly sodium can't move in anymore there is no further stimulus for depolarization the potassium channels they really have been going all along but now they become the dominant force and when potass I moves out of the incell space chloride tries to follow it it can't chloride gets hung up on the inner surface of the membrane all those chloride negative charges get captured by the membrane and the membrane potential hyper or repolarizes back toward a resting state and for the briefest fraction of a second there will be an undershoot this is your hyperpolarization the number of potassium channels open is more than it should be at Baseline right it's like a brief just sort of like a stone rolling downhill before it stops you know it picks up speed goes goes goes for just the briefest spell too many potassium channels are open the membrane potential is said to be hyperpolarized it might even drop down below minus 80 molts but then some of the potassium channels will close and you get back to the resting state just waiting for this to happen again now the refractory periods and there are two of them the absolute refractory period and the relative refractory period the absolute refractory period is that time during which no amount of electricity not even like lightning could stimulate that cell anymore right it is absolutely refractory to any stimulus the relative refractory period is that point in time it's when it's returning to normal it's that point of time between the peak and the hyperpolarization the membrane is returning back to normal there will be a brief spell there where you could stimulate it with a greater than typical stimulus a greater than typical amount of electricity so I know I'm starting to lose you here I'm going to let me rain you back in I promise it's going to become very pertinent in just a few minutes so let's take a few minutes to summarize here what we've just been talking about is a generic action potential I framed it in the conversation of a cardiac meos site because we are talking about cardiac here but what I've just described very generally is your typical Garden variety action potential a cell is at rest and then it is stimulated to do its job it does its job and then it returns to rest I mean it happens at every cell in the body so just by way of summary here the concentration of electrolytes on either side of a cell membrane is very different like we said there's more potassium in than out there's more sodium out than in there's more chloride Alon in there's more calcium Alon in and and the list goes on and on and on the point is the concentration of electrolytes inttra versus extrasellar environment very different this separation of charge creates the environment where the membrane the cell membrane can store a charge remember we said in the resting state when the cell is at rest whatever it is I used a I used a cardiac mosy as an example we could use a nerve cell as an example we could use smooth muscle of the gut I mean pick your poison every cell is either at rest or it's doing something in the resting state when there is no action potential only potassium channels are open when potassium channels are open potassium moves along its concentration gradient out of the cell because of the laws of electron neutrality chloride will try to follow it but chloride can't because there's no open chloride channels so chloride gets hung up on the inner surface of the cell membrane like I said picture a magnet two sides of a magnet trying to connect through a piece of plastic that's what's going on here because the chloride can't go through the membrane it's stuck on the inside and the negative charges in that chloride is what gets stored in the cell membrane this is the capacitor right the cell membrane stores the voltage this is why at rest the membrane potential of cells at rest is anywhere between -60 and -80 molts this is the resting potential we call it the resting potential because it is the m membrane potential e subm at rest then a stimulus will occur the stimulus is typically well in the heart it's electrical that stimulus will open sodium channels sodium will rush in the same process that we've described happens in Reverse sodium rushes in chloride tries to follow it it can't like two pieces of a magnet across a piece of plastic the chloride on the outside holds the sodium to the inner surface of the cell membrane all of that positive charge from sodium will get stuck in the membrane the voltage will depolarize it will go up up up up up and the voltage will stay high until the sodium channels inactivate and sodium can't move anymore and once that happens potassium again becomes the only electrolyte that can move across the cell membrane and when potassium moves across the cell membrane it will follow its concentration gradient it will go out chloride will try to follow it it can't come chloride gets stuck on the inner surface of the membrane and all that negative charge gets hung up in the membrane and you become more and more negative until it normalizes and waits for this to happen again everybody with me so far because that's like the basis of the conversation now we are going to become more specific to myocardium now we're going to talk about the cardiac action potential so as I've mentioned once or twice there are two general types of cardiac cells and cardiac Action potentials fast response and slow response the job of Fast Response cells or fast response Action potentials is to stimulate contractile tissue and that's what we're going to talk about now um in a little while well maybe on the next slide let's see yes it is um the other type are the slow response Action potentials you do not see these in contractile tissue you see these in rate setting or rate limiting tissue they're very different they're their job is to control the flow of electricity right so the thing that's unique about slow response um Action potentials is that they are calcium channel dependent number one and that hopefully will be clear in a few minutes they begin by themselves from a depolarized potential they begin from a place from a membrane voltage that's higher than the minus 60 molts we've been talking about the upstroke velocity that sharp upswing is much less overt than what we've talked about so far these are slow response cells this happens slowly these cells are most dominant in the SA node and the AV node the SA node because it's the sa node's job to set the rate it's the AV node's job to slow the electricity as it passes from Atria to ventricle the other thing that's unique about slow response cells if I didn't mention it I don't feel like I did is that they are automatic they are capable of discharging on their own initiative they don't need a stimulus from anything else almost every other cell in the body needs something to stimulate it but slow response cells don't they can depolarize on their own initiative and so um well there's a bullet point here at the bottom that says many dymas are due to sick cells meaning that the cells change their type some Fast Response cells will become slow response cells now if you remember that fast response cells job is to contract and slow response cells job is to initiate or control rate if Fast Response cells switch to slow response then you're going to have little pockets of contractile tissue suddenly impacting rate and they're not supposed to and so you'll have abnormal or ectopic folky of rate and then you wind up with dymos but that will all come later what I really want you to come away from this discussion with is the normal um electrical events of the heart so actually I think I'm going to take a moment I'm going to put you on hold you'll never know it but I want to insert I want to go back to another slide so well I'm saying hold the phone you just go on you just keep listening the next slide will pop up the way it should all right so what I wanted to do is reinsert this slide here again just to remind you about the normal wave of electrical activity so now we're going to take that generic action potentially we're talking about look at it specific to myocardium I mean the generic Garden variety action potential is the basic foundation for how this work but numerous cells of the body have action potentials that deviate a bit from that normal generic one and myocardium is among them the slow response Action potentials and the Fast Response Action potentials both have a role in the heart and in different areas of the heart they take take a slightly different shape so here I just wanted to take a minute to review with you the normal Pathways of electrical activity remember that the SA node which I'm going to label number one here is where an Impulse originates the SA node is compr it's in the right ventricle and it is comprised of slow response cells and they generate slow response Action potentials and their job is to initiate an electrical impulse those electrical impulses then are spread through specialized atrial conduction Pathways that you see here in Gray so I'm going to label them too these are specialized atrial Pathways so the electrical impulse from the SA node moves through these Pathways so that the electricity can be distributed to all the cells of the Atria at the same time now you can't really they don't show it here I don't know why but these go over to the what do you call left Atri at the same time so all of the electricity that that comes out of the SA node is spread like tentacles like like fingers reaching out through the Atria so that electricity is distributed distribut did I say distributed I made up a word distributed in a smooth simultaneous fashion so that all the cells of the Atria depolarize at the same time now these are contractile tissu so they are fast response right then the impulses all wind up back at the AV node the AV node is this gray blob here I'm going to label it number three and the atrio ventricular node is the electrical area that separates Atria from ventricle the job of the AV node is to delay the electrical impulse again it is rate setting tissue the cells of the AV node don't contract in their own rate they're not contractile tissue their job isn't to push blood their job is to control the electrical impulse cause a delay from Atri of ventricle because I mean logically electricity moves much faster than blood does so what's happened when when you depolarize the Atria is that the Atria contract and they move blood and it moves blood forward blood has to have time to get to the ventricles if the blood gets there too late if the electricity just goes as fast as it's can to the ventricles and causes the ventricles to contract there won't be anything in it yet electricity moves a lot faster than blood so the job of the AV node number three is to hold up that electrical impulse allow blood to move from Atri to ventricle and then the impulse will will continue and the impulse will go down the his bundle which our label number four I guess it's not label oh there yeah there it is number um what do you call it bundle of His I'll put the number four up here you can see it it's like the it's at the ventricular end of the uh AV node and then the electricity moves down and and through the septum and breaks apart into the left and right bundle which we will label number five I guess five there and a five there for each side and then the the pathways further break off into the pingi fibers but the job which will label six but the job of these fibers is to make sure that all of the cells are interated so that electricity can move through them in a smooth simultaneous fashion so that all the cells of the ventricle are discharged at the same time so that they all contract at the same time so that they can generate a huge Force to push blood out it's like if you were trying to put all your force behind opening a door you took both your hands and pushed on the door you'd want both those hands to push at the same time it would give it the greatest Force if you're trying to open a door and you use two hands and one hit it like even a second after the other one did you wouldn't have nearly as much force opening that door it's the same principle here the electricity moves down the AV node bundle of hit right and left bundles pingi fibers to ensure smooth uniform distribution of electricity so that all the cells of both ventricles are depolarized at the same time so that they all contract at the same time so that you get a great deal of force moving blood out of the ventricles and into their respective arteries right right ventricle moves blood into the pulmonary artery left ventricle moves blood into the aorta so those are the electrical Pathways and it's important that they that electricity moves through them just as it's supposed to at just the right amount of time that it distributes in just the right way and that the cells all respond at the same time any problem in it and you're going to wind up with drimia as a best case scenario and if the drimia is really bad then you're not going to be generating enough force and you're going to have a crappy cardiac output and then you wind up in congestive heart failure these Action potentials that we are talking about now are the way that electricity moves through these specialized Pathways from the SA node labeled number one through the atrial Pathways labeled number two stopping for a few hundreds of a millisecond at the AV node number three then down through the his bundle number four dividing into the left and right bundles number five and distributing to the pereni fibers number six fast response is in contractile cells slow response is in rate setting cells so keep that in mind and let's take a look first at Fast Response cells what's happening in Fast Response cells now remember these are this is contractile tissue and these cells are Contracting hard enough to move blood like from point A to point B so this is how we achieve the force these are the electrical events that achieve force in the resting state now and these are fast response cells right so these are the cells of contraction of the Atria and the ventricles and the resting state um actually the resting state is Phase 4 so you see a phase four on the extreme right and it's not labeled but the very start of this is also phase 4 so in Phase 4 you are at rest you are in diast we already said that in diast pottassium is the dominant ion and you can see the diagram showing you here potassium moves from the intrasellar space to the extell right you see the big Arrow going out the dominant movement of potassium is out that little tiny arrow that you see The Black Arrow under the big fat arrow is the s potassium pumps trying to push it back in but the dominant movement of potassium is out that's phase 4 and that's when your membrane voltage is very low and then remember we said what happens an electrical stimulus comes along and it opens sodium channels and when sodium channels open this is the beginning of phase zero and you can see phase zero and if you follow the red line You'll see the graphic that sodium is is your dominant electrolyte and sodium is moving in you know or so sodium is moving in yes that's what I was trying to say sodium is moving from the extracellular space to the intracellular space and that's what makes the voltage go up up up but then at point1 here sodium at 0.1 the sodium channels are no longer working remember I said sodium channels were very fast so sodium as fast as those channels open they inactivate and at the peak of this which is up here at the very top I'm circling the number one that's the place where sodium stops moving to the intracellular space now the only electrolyte that's moving is potassium again and you can see if you follow the squiggly all the way down potassium is moving it's not very exciting it's the basil state but if potassium is moving the voltage will start to come down but now in Fast Response cells we have a new twist we have a deviation from the generic action potential that we were talking about before in contractile tissue we have a phase two what's happened is that calcium channels have opened now we haven't mentioned calcium channels before because they weren't part of the just the generic discussion but calcium channels are very important in myocardium because calcium is the electrolyte of muscle contraction right all sorts of muscle strided muscle smooth muscle and cardiac muscle calcium is the electrolyte of contraction so if we want cardiac cells to contract we got to have some calcium on board the thing is that calcium is an electrolyte that needs to go through calcium channels and calcium channels won't be open until voltage Rises so calcium channels stay closed shut until membrane voltage rises above -40 molts when membrane voltage rises above -40 molts calcium channels will open calcium will start to move along its concentration gradient which is from outside to inside right you can see it if you look at number two because that's the calcium phase and then follow the arrow calcium is the dominant electrolyte calcium is moving in when calcium moves in calcium has two positive charges attached to it right it's a divalent cation calcium mov to the interest cell space what happens a negative charge tries to follow it the negative charge can't it stits like a magnet outside the cell it holds some of the calcium on the inner surface of the membrane and it keeps that voltage very high we refer to it as the plateau phase right and make a p here that didn't sound right I'll draw a p I won't make one Plateau phase you stay with a high voltage in phase two because of that calcium movement calcium channels though they will eventually close on their own calcium channels are what we refer to as voltage and time dependent they are dependent on voltage to open and they are dependent on time to close they open at a voltage of minus 400 and then calcium will move in for about 300 milliseconds and then no matter what 300 milliseconds later those calcium channels will close when they close calcium stops moving in now again the only electrolyte moving is potassium now you're in phase three and when potassium potassium is moving out of the cell and chloride tries to follow it and can't the voltage will go down and in phase three the voltage goes down down down until you get back to this resting phase phase four you're back in diast and you're waiting for this to happen again so in terms of the electrical events of the heart what's happening is that in Phase 4 the heart is at rest The ventricle is at rest it's filling with blood at the end of diast an electrical stimulus will come down that specialized electrical pathway right right or left bundle per Ki fiber and when that electricity comes down it opens sodium channels and when sodium channels open you are in Phase zero when sodium channels open sodium rushes in the voltage shoots way up and then as fast as they open the sodium channels stop sodium channels inactivate no more sodium movement no more rapid rise now you have peaked for a brief spell the only Channel that's open is potassium and so in step one here or stage one you see the voltage start to come down but then what you see is the interesting effect of calcium calcium channels are very slow to open they're like I said they are time dependent channels they opened when the voltage hit minus 40 but it took them a while to swing open they're like a slow door so a couple milliseconds later calcium finally starts moving in when calcium moves into the cell voltage goes up and it stays up that's why you have that Plateau there at Phase 2 but eventually 300 milliseconds later calcium channels will close when calcium channels close the only electrolyte moving now is potassium when potassium moves out chloride tries to follow up the voltage Falls and then you ultimately come back down to phase four and wait for the whole thing to happen again that's the electrical event the mechanical event is that we needed to open those calcium channels right because calcium is the electrolyte that's going to allow the cell to contract all of this happens to get calcium into the myosite so the cell can contract C I might be getting ahead of myself and I know I've probably lost some of you at this point so just try to hang in there stick with me I promise in another hour this should all make sense right now all I want you to appreciate moving forward is that in Fast Response cells in contractile cells there are five phases of events it begins with phase four I don't know why nobody asked me to number this but they begin with phase 4 phase four is rest it's diolate potassium channels are open ventricles are filling then an electrical stimulus comes along opens sodium channels voltage shoots up you're in Phase zero a millisecond later sodium channels close boom this is Phase One potassium channels are the only open channels potassium is moving out the voltage drops a little bit then like a couple milliseconds later finally those calcium channels swing open they were stimulated when the voltage Rose above minus 400 but it took them a millisecond or two to open once they did calcium starts shooting into the cell the voltage goes up stays up it stays up in that plateau and then 300 milliseconds later calcium has done its job you don't need it anymore the calcium channels close again potassium is the only dominant electrolyte potassium moves out the voltage drops and it drops drops drops all the way back to phase four now you're in diast just waiting for it to happen again five phases of Fast Response Action potentials that's the contractile stuff now now the slow response cells are the cells that set the rate and the cells that control the rate these are the cells primarily of the AV node the SA node and the AV node they only have three phases and these phases are labeled phase four phase zero and phase three again uh I don't know why I don't know why everybody named them that way they just did phase four is the climb remember I said that these cells depolarize on their own initiative and they are slow the the the voltage sneaks up it just sort of sneaks up there look at phase four it's just like a little Hill just slowly slowly slowly creeps up when it finally reaches some predetermined threshold finally a different type of sodium channel will open then you get to phase zero this is the discharge of electricity from the SA node and now in this node you know like you don't need this isn't contractile tissue it's not moving blood you don't need a bunch of calcium you don't need that Plateau phase all these kind of cells need to do is voltage creeps up discharge an electrical impulse and then go back to Baseline phase four phase phase zero and then repolarization back to phase three so that's the visual difference between fast response and slow response resting potential is the and we've already said this before I know I'm kind of beating up a dead horse here but it's because this is the stuff nobody ever really has a good handle on coming in resting potential is the voltage in the membrane at rest and it is determined by the ability of cell membranes to conduct various ions at rest the conductance of potassium is greatest right that's why potassium is at the top of the line here the potassium inside the cell is greater than the potassium outside the cell and so potassium will rush out at rest there's more sodium outside the cell and at rest there's more calcium outside the cell so this is the difference in concentration gradients from the intracellular environment and the extra Cellar environment in the resting state so as I might have mentioned once or twice before in the resting state most of the ion channels that are open are potassium channels potassium channels are open at rest these are referred to as inward rectifiers these are channels that actually will close when the cell membrane depolarizes so I said before that potassium channels were open all the way through and they are I mean there's a there's a series of Basil potassium channels that are always open but there's a particular special type referred to as Inward rectifiers and they will close when the cell membrane depolarizes in any event in the resting state the conductance of pottassium g a capital G is scientific notation for conductance the conductance of potassium is greater you see two greater than signs is greater than the conductance of sodium which is equal or greater to or equal to or greater than the conductance of calcium so cardiac cell membranes at rest the conductance of potassium is greatest and it's greater than the conductance of sodium which is equal to or greater than the conductance of calcium that's in the resting state and that's what it looks like and I know you've seen it before potassium comes out chloride tries to follow it this is why the membrane voltage is minus 60 then when an electrical stimulus comes along you hit phase zero this is that electrical impulse that originated in the SA node and came along those specialized conduction Pathways this electricity opens the sodium channels sodium rushes in along its concentration gradient you see sodium rushing in Chlor and you'll see a lot of you only see forb just use your imagination because there's a lot more sodium rushes in chloride tries to follow it it cannot so like a magnet it sucks some of that sodium right up against the inner surface of the cell membrane and that's what confers the positive charge and that's why the membrane voltage during depolarization can rise all the way up to plus 20 so phase zero can the sodium gate business can be just a hair um complex so take a minute and hear me out here now remember in Phase 4 which was the resting state in Phase 4 there was no sodium movement right sodium channels were closed when sodium channels are closed as they are in Phase 4 what's actually happening is that you have a sodium Channel think of it as like a tunnel and at either end of the tunnel there's a gate and one of those Gates is the m gate and the other one is the H gate and the mgate is the mgate is the one that is uding that tunnel in Phase 4 when the sodium channels or we'll say the sodium tunnels are closed sodium tunnels are closed because the mgate is blocking entrance into the tunnel now as it happened on the other side the H gate is open but it's not doing anybody any good because as long as the mgate is in the way sodium can't move so in Phase 4 which is prior to what we're talking about now we're in Phase zero now I should have said this before in Phase 4 which is the beginning of this discussion when The myocardium is in diast and the ventricles are filling and the only on the only electrolyte Channel that's open is potassium and potassium is moving sodium channels are closed when I say closed I mean that the mgate is uding the channel the H gate is not the H gate is open but it doesn't do any good because the mgate is closed in phase four sodium channels are closed the mgate udes the tunnel now when the electrical impulse comes along that triggers phase zero that electrical impulse stimulates both M Gates and H Gates both of these gates are activated over the same range okay so just visualize this at the end of phase four you've got a sodium tunnel with a gate on either end the mgate is closed the H gate is open sodium can't go through the tunnel the electricity comes along and zaps both those Gates right so stay there now when both gates got zapped the mgate responds more quickly the mgate is just a faster gate so immediately upon um receipt of that electricity the mgate opens now for just a brief millisecond both the mgate and the H gate are open this is why sodium can rush through and it does and boom sodium rushes in voltage goes way up but then just a fraction of a millisecond later finally the H gate will recover will respond to the stimulus and then that H gate will olude the tunnel from the other end when the H gate is the one blocking sodium movement I mean you still can't move sodium so the upward rise stops but now the gates are said to be inactive there's a difference between a sodium Channel That's closed and a sodium Channel That's inactive in Phase 4 at rest The ventricle is filling and nothing's going on yet the M gate is closed the H gate is open the electrical impulse comes along very quickly the mgate opens now you're in Phase zero this is what we're talking about right here here for the briefest fraction of a second the mgate is open and the H gate has not closed yet so both gates are open sodium rushes through the conductance of sodium is greater than the conductance of anything else at this point sodium rushes in and the voltage goes up and that's what we're talking about right here phase zero right but then a fraction of a second later that H gate swings into AC action this is the inactivation gate when the H gate shuts sodium can now not go through this tunnel anymore the inactivation of sodium aborts this rapid rise of voltage and then you have these little rapidly activating potassium channels that are really like really not totally relevant um this is that little phase one the your slide says this is called the transient outward current for just the briefest spell potassium dominates and you just get a little bit of a downward blip in that action potential that's what phase one is in Phase One the H Gates include the sodium channel is inactive the positive charge suddenly stops and now just for the briefest moment the only thing moving is transient potassium channels and there's your little phase one it's not very exciting doesn't last very long but it does give you that little blip but then now phase two this is an important phase right this is the phase of the calcium channel opening remember I said the calcium channels are voltage and time dependent they open when the when the voltage of the membrane rises above minus 400 and they will close about 300 milliseconds later well in Phase zero the volt the membrane of the the voltage in the membrane Rose to above -40 it just took a couple hundreds of a millisecond for the calcium channels to respond because they are slow you know in this world a millisecond is slow so finally they are responding to the rise in voltage that happened in Phase zero calcium channels open once they open calcium rushes along its concentration gradient into the cell you know now what's going on the calcium rushes in a negative charge tries to follow it it can it holds the calcium on the inner surface of the membrane and you've got a bunch of positive charge and here's the Miller interpretation of what it looks like the calcium channel rushes in or the calcium itself rushes in chloride tries to follow it it can it gets stuck on the outside it holds calcium to the inside all of this positive calcium on the inner surface of the me membrane raises the voltage so that's why the voltage stays up in that Plateau phase mechanically the electrc mechanical Association that occurs here is that now you have got calcium into the cardiac myosite this is what you need for cardiac myosite contraction right this whole series of electrical events occurs to open calcium channels so that calcium can get into the cell and cause cardiac muscle contraction so the cell is at rest electricity comes down from the SA node it stimulates sodium channels they open so that the voltage will go up when the voltage goes up calcium channels open calcium comes in contraction occurs now again calcium channels are voltage and time dependent you don't want The myocardium staying contracted too long or you wind up with a big mess so once the voltage once the voltage goes up and the calcium channels open calcium goes in they're only going to stay open for about 300 milliseconds right about a third of a second and then the calcium channels will close The myocardium can no longer contract without calcium and since calcium channels are closed calcium isn't moving in the voltage again starts to drop and of course it's phase two that we're talking about so we've got the arrow here my big red arrow showing you what we're talking about and that calcium is the dominant electrolyte moving from the outside to the inside now in phase three you might recall that there are no longer any calcium channels open there are no longer any sodium channels open all that's open now are potassium channels now contraction has already occurred myocardium is beginning to recover and get ready for the next contraction right syy has happened so now you are back in the you are in the early phase of diast right you are you are filling of The ventricle but what has to happen in phase three is that you've got to your body has to protect The myocardium from being stimulated too soon it's got to give a little break here so that it can fill up before it contracts again this is the absolute and relative refractory period well I guess I should say the absolute refractory period begins with phase zero like in Phase zero Phase 1 and phase two myocardium cannot be stimulated Again by any thing no matter how strong the electricity in the beginning of phase three you are still an absolute refraction you can't stimulate this myocardium again no matter what this is what protects you from like vac you know and viib you you stop the heart from being stimulated it you give it a chance to contract rest and fill before it can be stimulated again the transition from absolute refraction to the resting state where it can be stimulated is phase three this is final repolarization this is getting back to normal and the thing that's unique to phase three is the normalization of sodium channels so yes delayed rectifier potassium I mean they're always here probably should just take that out because it confuses things more than anything else I mean potassium channels are just always an undercurrent of that but the really important thing about phase 3 is that calcium is no longer moving you are no longer in syy you are returning now to diast but what happens is you have to go back to a state in diast where the thing can be stimulated again and this is recovery of sodium channels remember when we were talking about sodium channels a little while ago I said in phase four in diast right before they are stimulated there are two gates at each end of the tunnel there's the mgate and the H gate the mgate is the activation gate the H gate gate is the inactivation gate in Phase 4 when they can be stimulated the mgate is including the sodium channel the H gate is not so the mgate is closed the H gate is open electricity comes along and stimulates both those Gates the mgate responds really fast mgate swings open for the briefest spell both gates are open sodium rushes through but then the H gate closes the H gate inactivates or the channel when the H gate is in place that is absolute refraction that H gate cannot be open for nothing nothing will open that H gate you could hit that myocardium with a bolt of lightning and the H gate will not open and that's the way it stays phase one phase two and very early phase three but then in phase three as pottassium dominates and the voltage starts to drop again what happens is those sodium Gates switch places again and the M Gates swing closed and the H Gates will swing open and that's a cell that can be stimulated so that downhill curve in phase three as that downhill slope is forming sodium gates are recovering they're getting back into position with the m Gates being closed and the H Gates being open so like in part of that phase three some of the gates are recovered and can be stimulated and some aren't that's your relative refractory period That's the time during which a greater than normal stimulus could open some sodium channels but we don't really want that to happen we want to get all the way through phase three recover in a healthy heart you'll recover all the sodium channels and then when you get down to phase 4 now you're back to that place where all the sodium Channel are in the same position M gates are uding H gates are open open and you're waiting for your next stimulus so let's see if this this isn't the best diagram but I hope it gives you some idea here um all right let me go back to my red numbers in the resting state I'm going to label that I'm going to label it number four because it's phase four of the action potential in phase four sodium gates are closed right they're in the closed position the M gate is the one that's secluded and know they're not labeled here M and H but just bear with me here in Phase 4 one end of the channel is closed right and then you get that electrical impulse and you depolarize and you go up to phase zero and for the briefest spell both gates are open nothing is including the channel sodium can move through it and then at the end of phase zero in Phase One the H Gates olude and so here you see the difference right I'm going to circle it you see that little booger is swept over here that would be your H gate and then as you return back to a resting state for the very briefest spell both gates are closed at the same time this really just looks like it's sort of pinched off there this is the transition in phase three and then when it gets back to a resting state this little ball bubble thring here falls off and you ultimately come back to phase 4 and that's all I know about that in phase four you're back at Baseline you're waiting for the next stimulus now again we are talking about contractile tissue right the example we're using is The ventricle and here's what it looks like the top half of this screen is the action potential the bottom half is what's happening with the electrolytes in Phase 4 the conductance of potassium is greatest and then in Phase Zer the conductance of sodium I'm going to circle that zero the conductance of sodium exceeds everything else and then almost immediately the conductance of sodium drops and then the conductance of calcium is what really dominates and that's phase two and then as potass as calcium channels close you start to Peak downhill here in phase three potassium dominates again and before you know it you're back in phase four so if it takes a little while to to work through that you know go back and listen to it a little bit um I think well you're not going to get a break yet but I'm going to take a break now and then we'll come back and talk about the slow response action potential I know that this can be pretty hey stuff if you haven't spent much time with it I think just to give you a you know an end inight here something to look forward to [Music] um I think we will probably stop this slide set when we get to around slide number oh I don't know where are we now 46 well I don't know let me think about that before I come back but we'll we'll make this manageable I really think the hardest part is behind us now if you have to go back and go through this a little bit please do this is important stuff and um next up we will talk about the slow response action potential now we want to take a look at the slow response action potential so I said this is a little bit different because the job of slow response cells is to either generate electricity or control the movement electricity right so the the area of the heart that is most abundant with slow response cells is the sinoatrial node and that's because its job is to initiate the heartbeat I mean its job is to initiate the electrical events of the heart I mentioned before there were three phases of slow response spells they begin with phase four depar ation so from the resting state to the initial climb this is Phase 4 remember that these cells can depolarize on their own initiative they don't need any stimulus from anywhere else if you can remember the fast response that we were just talking about we said that in the resting state they were phas four was the resting state and then electricity comes along to open channels sodium channels and start that action potential Fast Response cells need an electrical stimulus to get started um slow response cells don't they depolarize on their own initiative from minus 50 molts phase four depolarization does occur it is very slow and steady these are a particular type of calcium channels that let that get done and it's what allows it to be slow remember calcium channels slow sodium channels fast in the slow response Action potentials of the rate setting and rate limiting tissue calcium is what gets things started and the action potential looks like this and you can see um so the extreme left of the picture where you see the line come out at about minus 70 molts there right it's coming off the last beat and then you see it return to rest that's as much of a rest as it gets is that um that little bottom out there at about- 70 molts and then you get this slow steady climb in phase four it's not acute but you can definitely see that voltage is going up in phase four SA node tissue AV node tissue any slow response cells are capable of that slow steady depolarization on their own um they will eventually reach a depolarizing threshold and in slow response cells it's about minus 50 molts it's this point that I'm circling in red and when that happens then the electrical impulse is stimulated we need this slow steady climb in phase four to put space between electrical impulses we don't want the heart beating too fast right we have to have some space between impulses that's what that slow steady calcium mediated rise in Phase 4 is so the action potential Begins by itself from a depolarized potential in Phase 4 it slowly and steady steadily depolarizes until about minus 50 molts and what allows for that slow steady depolarization is a particular type of calcium channels these are called ttype channels they're different from the calcium channels that maintain the phase 2 plateau in Fast Response cells in Fast Response cells those calcium channels are called lype calcium channels in rate setting and rate limiting tissue we have special calcium channels when you go into Farm uh far your pharmacology class you'll find that there are particular types of calcium channel blockers that Target some types over the others so in the world of calcium channels we do have specific types those that mediate slow steady rise and slow response cells are referred to as ttype so in slow response cells calcium is responsible for that depolarization to get you to threshold and then as usual pottassium is responsible for deep for repolarization so here's what it looks like in phase four in that slow steady rise you see calcium drive that right the the the phases are on the top half of the screen the electrolytes are on the bottom half of the screen so calcium is responsible for the slow steady rise of phase 4 circled and then pottassium is what allows you to come back down to the resting state now phase zero here I know that you're slide doesn't say it I'm want to complicate things just a little bit there is a theory that there's a particular type of weird sodium channel that drives phase zero it's referred to as the funny current I'm drawing it here I is Sci capital I is scientific notation for current f is the subscript for funny honest to God just like before we were talking about the conductance of electrolytes right the conductance of sodium conductance of potassium conductance of calcium and I said capital G is scientific notation for conductance well I is scientific notation for current so in this case we are talking about the funny current I subf which is an unusual type of sodium channel it's different from the sodium channels as fast response cells that's why it's called funny and there is a theory that that is what actually produces that sharp rise in this little phase zero but again these are slow response cells their job is to just discharge an electrical impulse so in phase four you have your ttype calcium channels causing a slow steady climb this is what what separates one heartbeat from another slow steady climb in ttype calcium channels of phase 4 when you get to Threshold at minus 50 then the funny sodium current allows for a relatively rapid rise that's the discharge of the electrical impulse and then once that discharge occurs the electricity is started it'll now go through atrial Pathways AV node his bundle left and right bundle branches everything we talked about this cell just has to repolarize so the potassium channels take over again and you have phase three the period of ab absolute and relative refraction and then phase four which is return to rest so that's that's rate setting tissue this is dominant in the SA node and the AV node as well but the SA node is the primary rate setting tissue of the heart and the other thing we need to look at is the effects of the autonomic nervous system on heart rate because you know that s that sympathetic stimulation will speed up the heart rate and parasympathetic stimulation will slow it down so the SA node is totally capable of depolarizing on its own initiative as long as the heart is oxygenated it will work and the SA node will discharge and it has an intrinsic rate that is you know in the healthy patient somewhere between 60 and 100 beats a minute but the autonomic nervous system can influence that most Hearts aren't beating on their own right most hearts are attached to the rest of the body and they are influenced by the autonomic nervous system so like this cells like this slide says while cardiac cells do not require nerves to beat all the heart really needs is oxygen um nerves will modulate the properties of cardiac cells in the case of the SA node it will make it discharge either faster or slower sympathetic stimulation speeds things up parasympathetic stimulation speeds or slows things down so what we've got here you've got what looks like three slow response Action potentials but it's just one it's just it's showing you normal Baseline state which is the one in the middle you can see the red arrow pointing to it and then the one to the left of Baseline is what it looks like in the setting of sympathetic stimulation and the one to the right is what it looks like in the setting of parasympathetic stimulation so let's take a look so if you have sympathetic stimulation to the heart typically epinephrine right fear flight fight response epinephrine release occurs epinephrine binds to beta 1 receptors in the heart and we know that one of the things it will do is increase the rate and increase the force of the contraction the way that it increases the rate is that it lowers depolarization threshold remember doolar threshold depolarization threshold is that place is that voltage at which the cell finally reaches an action potential it finally does what it's supposed to do which in this case in this type of cell is to release that electrical burst that will subsequently stimulate the rest of the heart so in the setting of sympathetic stimulation the threshold to reach depolarization is lower the voltage doesn't have to climb as far so it gets there faster and that's what this um picture is trying to show you so remember we said that the one in the middle was Baseline I'm going to write a b here on top of it this shows you a slow response action potential in the SA node at Baseline and you'll notice at Baseline the Threshold at which it depolarized Rises or shoots straight up into that phase zero somewhere around -50 molts it's this bend that I'm going to put a little blue um circle around right here that's threshold and when the volt you know the voltage climbs that slow steady rate you see that slow steady incline and when the voltage gets there to that place that I've circled in blue then it discharges an electrical impulse is is set out and the heart will now beat in the setting of sympathetic stimulation the threshold or the voltage let me say that again in the setting of sympathetic stimulation the voltage to which phase 4 must climb to initiate depolarization is lower than the Baseline and I'm going to circle this one in light blue so you can see the difference and the arrow is pointing to it the arrow the red arrow is pointing to that place where it depolarizes so you see they start off in the same place both of these Action potentials start off on the same curve and I'm going to use a purple line to follow it along so here's where it's coming off the next beat these are Easter colors right it's coming off the last beat hyperpolarizes a little bit and then you start that slow steady climb that slow steady climb is the same for both the Baseline beat the one that's labeled B and the one that is responding to sympathetic stimulation which I will label s where they split off is that the one that's labeled s reaches depolarization threshold sooner so it fires faster so the beat occurs sooner sooner if you didn't have if you didn't have sympathetic stimulation here it would have to go on and continue to climb about another 10 molts before it fires off to that Baseline beat I hope that makes some sense I I know it's this is when if we were in a classroom I would be watching faces to see if I had to say this again or say it differently in this setting I can't do that so if you're unsure just you know back it up and play it again but the real point of this slide is that SA node tissue will depolarize on its own it doesn't need any nervous system influence at all however it can be modulated by the nervous system in the setting of sympathetic nervous system stimulation depolarization threshold is lower so the voltage it gets there faster so the beat discharges faster and that's why there's less time between two heartbeats that's sympathetic influence now parasym syp athetic is different in the setting of parasympathetic stimulation this is you know the parasympathetic nervous system um aka the colonic nervous system when the heart is stimulated by the parasympathetic nervous system acetylcholine binds to muscarinic receptors and opens potassium channels and when those potassium channels are open the Baseline voltage then drops you can see where the red arrow is pointing to here right so in the setting of parasympathetic stimulation the beat is starting from a lower place as compared to the Baseline beat or the beat affected by sympathetic stimulation the Baseline beat and again I'm going to label everything here so we're all on the same page B is for Baseline it's a sloppy B but I'm doing this by hand s is for sympathetic we talked about that in the last slide and then the parasympathetic influenced beat is the one on the right so notice that the climb for all of these is at the same incline the rate of ascent of voltage is on the same the same plane right all of these ascents are parallel and I'm going to circle them in purple all of these ascents are parallel it's the same rate of climb the difference is that in parasympathetic stimulation because acetylcholine will open potassium channels and and drive the Baseline lower the heartbeat is starting from a lowered voltage and I'm going to circle this in dark blue this is where it's starting and you can see the red arrow pointing to that as well so even though because ttype calcium channels will open the voltage does climb and it climbs at the same rate as the other impulses because it's starting from a lower place it has further to go to get to depolarization threshold which in the parasympathetic place or in the parasympathetic realm depolarization threshold is the same as it is for the Baseline impulse and I'm circling it in blue it's got to get to the same spot but it's starting out from a lower place the red arrow that's why it takes longer to get there that's why the heartbeats are spaced further and further further apart so in sympathetic stimulation the heart beats will occur closer together because depolarization threshold is lower in parasympathetic stimulation the heartbeats are further apart because the starting point the Baseline point at which that climb of voltage starts is lower and I think that's all I have to say about that piece of this conversation right now now I think we're going to look at some of the specific properties of particular types of cardiac action potentials switching topics just a little bit in our original discussion about Fast Response Fast Response Action potentials we used the ventricular cells to illustrate the point and you might remember that there are five phases right Phase 0o 1 2 3 and four and we talked about all of the electrolytes that drive each one but what you would remember about the ventricular cell is that Phase 2 is really prominent there's this long protracted Plateau phase excuse me this long protracted Plateau phase in ventricular cells and that's necessary because the cells of the ventricle have to generate enough Force to push its volume a long way right to overcome a lot atrial muscle or atrial cells are a little bit different because the Atria only has to push blood forward into the next ventricle which is the next chamber right there so while the structure of the Fast Response Action potentials in atrial muscle is basically the same right five action or five um phases 0 1 2 3 and four the plateau phase phase two is not nearly as prominent because the muscle doesn't have to generate nearly as much force to get the blood where it needs to be that's really the only difference otherwise Fast Response cells in Atria and Fast Response cells in the ventricles are very similar similarly we talked about slow response cells and we use the SA node as the as the frame of reference for the discussion because the SA node really is the primary home of slow response cells they are most critical there because they generate the impulse on their own initiative but we do have slow response cells elsewhere too the next place that they are really important is the atrio ventricular node um like I said before the real job of the atrio ventricular node is to slow down the impulse as it passes from Atria to ventricle because you just don't want the electricity to get there too soon because electricity travels a lot faster than blood so if the electricity gets there first and there's no blood yet the Atria or the ventricles are going to be stimulated to contract and there's nothing in it and there's no cardiac output and that just defeats the purpose of the whole thing so the AV node really is its purpose is delay and its delay is driven by these slow calcium dependent action potential it just allows that electrical movement to slow down take a breath and let the blood get there first calcium channels those ttype calcium channels that we talked about before in slow response cells are very important here AKA delayed calcium rectifiers these are just cells that really slow things down they slow the movement of electricity and that's their place in the world and so by way of review ventricular conduction is very similar to atrial conduction we already have talked about it at length it is characterized by five phases 012 3 and four these are characterized by fast response cells in the ventricles the plateau phase is very prominent and like all action potentials they are characterized by refractory periods absolute and relative Again by way of review in the slow response cells we've talked mostly about about the SA node and a little bit of a lesser extent to the AV node slow response cells do not require any ination to beat as long as they have oxygen they'll work however autonomic nervous system inovation can moderate the properties the sympathetic side of the autonomic nervous system can speed up heart rate the parasympathetic easy for me to say parasym parasympathetic side of the autonomic nervous system can slow down rate I mentioned that the SA node has the greatest ability to beat autonomously it's got the fastest intrinsic rate the rate is between 60 and 100 beats a minute these cells do depolarize on their own initiative and the particular type of calcium channel that is important for that that slow steady phase 4 rise is the ttype calcium channel in case Cas it slipped your mind the effects of autonomics are described here acetylcholine slows the rate of depolarization by activating potassium channels and lowering the starting point with respect to voltage in that slow steady phase 4 climb it is actually I don't think I mentioned this before but the release of catacol amines that increases the rate of spontaneous depolarization by lowering that Threshold at which um the threshold to which the voltage must rise to get that phase zero um depolarization and this is a consequence probably the theory is the sodium Channel funny current I subf now another concept you want to keep in mind here is the concept of excitability how excitable is the membrane of myocardium and this actually refers to both slow response cells and fast response cells how excitable are they how easily can they be stimulated I mean remember the whole idea here is there is a resting potential at which they are at rest and not doing anything and then there is a depolarization threshold the voltage to which they must climb to actually discharge and do their job how readily they discharge and do their job is the property of excitability and the primary determinant of citability is that resting potential so if the resting potential or aka the resting membrane potential is very low like- 80 molts orus 70 molts The myocardium will not be as excitable because it has to rise more to get to the place where depolarization occurs on the other hand if resting potential is too high if it's depolarized then there's going to be a really narrow space between where it's starting at rest and where it has to get to to depolarize and then it may become very excitable and you'll find that myocardium discharges faster than we would expect it to now a healthy example of this is the autonomic influence in the SA node I mean this is exactly what we're talking about um how excitable are the cells of the SA node well in the setting of sympathetic stimulation they're more excitable because depolarization threshold is lower so the time from Baseline rest to depolarization the voltage is very narrow so it's more the cells are more excitable in the setting of sympathetic stimulation on the other hand in the setting of parasympathetic stimulation the starting point the resting potential is lower than usual so the voltage has to rise further to get to threshold and so it's less excitable it slows the heart rate down those are examples of healthy deviations of excitability and and sometimes it is a very healthy there's very healthy ranges sometimes when myocardium gets sick when it gets hypoxemic um when it has old damage from an MI it permanently Alters the membrane and changes the property of excitability one of the problems one of the reasons that people with chronic esea or an old Mi one of the reasons that they are more susceptible to dysrhythmia and disorganized conduction is that they injured or hypoxic cells tend to have a higher resting potential so there's a lesser amount of voltage between rest and depolarization so they are very excitable they can be triggered very easily so that's the property of excitability and resting potential is the primary determinant if resting potential is lower then cells will not be as excitable it's harder to get them to fire off if resting potential is higher then it's going to be easy to get them to fire off because it doesn't take much just like in people you know you think about your very calm Zen people it takes a whole lot to get them fired up their resting potential is very low then you think about those people that always exist on a hair trigger it's like the littlest thing will set them off their resting potential is depolarized we have AUD to refractoriness but it is an important property so I'm just want to remind you again I'm just summarizing here before we go on to the next topic the concept of refractoriness is how refractory is the Cell at any particular point in these five these three or five phases is it refractory to another stimulus one of the things about myocardium is we want it to be able to go through its normal cycle we don't want it to be able to be stimulated like any old time because then you just have a bunch of contraction is going on for no good reason or you have a bunch of cells Contracting when the cells next to it aren't and the force of the contraction is just no good so this property of refractoriness is built in to the cardiac cycle and so when cells are in the throws of depolarization when they are at the height of their action potential they are absolutely completely refractory to any other stimulus they can't be stimulated by anything but any cell that is discharging has to go through a recovery phase a phase where it finishes its job and then it has to get back to its resting state to wait for to wait for the next stimulus the longer it takes to get back to their resting state the longer the recovery phase the longer of the period of time that you're going to have some cells in the tissue recovered and others are not and that means that they are susceptible to a higher than normal stimulus and this is the relative refractory period and when it comes to myocardial cells both phase um both slow response and Fast Response phase three is pretty much that relative refractory period at the very beginning of phase three cells are just starting to recover and you're pretty much absolutely refractive at that point but as you progress through phase three more and more cells cover and then by the end of phase three virtually all of the cells have recovered and now you are not refractory at all you are ready for another stimulus in between the bulk of phase 3 the tissue or the cells are relatively refractive they can be stimulated but it takes a greater than normal stimulus cardiac conduction I mean this is another concept that goes hand inand with this conduction is the ability of that electrical impulse to move through those specialized conduction Pathways from one part of the heart to the other speed and direction of the cardiac action potential determines the sequence of contraction of the cardiac Chambers and this is what we record on an ECG at some course I think it's nursing 522 we will spend a lot of time talking about transferring these Concepts to paper and the interpretation of the EKG for right now conceptually just keep in mind that when we look at a 12 Le kg what we are looking at is the the paper version um the printed version of the speed and direction of this electrical activity you can trace every piece of this on a 12 lead you need 12 leads to do it because 12 leads are 12 different views but what we are looking at here is speed and direction remember that the electrical impulse is supposed to start in the right Atria in the essay node it moves through those oh actually the next few slides are going to go into that yep so the electrical impulse begins in the SA node it begins on its own initiative and when it fires off that electricity moves through specialized atrial Pathways from right to left so the SA node is in the right upper part of the heart and then this electricity fans through these specialized atrial Pathways specialized interatrial conduction Pathways allow the impulse to be smoothly and uniformly distributed to all the cells of the Atria so that they all are stimulated at the same time they all contract at the same time and you have a good smooth forceful movement of blood from Atria to ventricle I've already mentioned that the AV node job is to well I keep getting ahead of myself here hold that thought okay I've already said that the job of the AV node is to slow the conduction velocity of this impulse it's to slow down the impulse from Atri Tri 2 ventricle once it does get through the AV node then the bundle of His aka the his pereni system is what allows for smooth uniform rapid conduction from the top of the intraventricular septum down through the intraventricular septum and to Branch off into the left and right bundle branches and that would be your ventricular muscle all activation does proceed from endocardium to epicardium from the inside out so Electric electrical activity happens in three dimensions in the heart right because the heart is a three-dimensional organ so as electricity moves through all of these Pathways that we just discussed also keep in mind that the wave of electrical activity goes from inside out endocardium to epicardium all right so I have decided the last concept we're going to talk about in this slid set is electromechanical Association I think it's another 10 slides or so and then that'll be the end for today and we will pick up the rest of this next week which is a bit shorter of a week anyway we've up until now we have talked almost exclusively about the electrical piece all the electrical stuff all of the electrolytes moving across cell membranes and storing voltage in a in a membrane that's all the electrical piece now we have to look at how that articulates with the mechanical piece remember the whole purpose of initiating this electrical discharge from the SA node and having it move in a smooth uniform manner through the Atria through the AV node the hisper kinji system the left and right bundles like the whole reason for that is to allow this myocardium to contract right it has to contract and move the blood to the next forward chamber whatever that forward chamber is whether it's a ventricle or whether it's an artery the electrical events exist to support the action of the mechanical right the mechanical is the contraction the articulation between the two is calcium you have to get calcium into the cardiac myosite because calcium is the electrolyte of contraction so let's take a look at how the electrical articulates with the mechanical to achieve contraction so think about the structural unit of the cardiac myosite right the cardiac cell myosite cell I always say in science we have to have five words for the same thing the basic structural unit of contractile cardiac muscle is the sarom Mir the smart the sarir is the structure and the sarir is is bordered by zines zines separate muscle fibers into the functional unit of the sarir and within the sarir we have thin filaments and thick filaments and they slide across each other and that's what contraction is the thin filaments are anchored onto the Z lines on both ends which you know forms yet another term the eye bands don't worry we're going to look at a picture in a minute here we're just laying the foundation so the eye bands are formed from contractile proteins actin troponin and tropomyosin troponin and amas and probably sound familiar to you because troponin are the things that we look at when someone has myocardial damage and cardiac meiocytes are destroyed and they spill their intracellular contents into serum and we can measure those intracellular contents and troponin is an important one troponin is not supposed to be in the blood it's supposed to be inside a sarir but when the sarir die which is what happens in an MI that troponin is Spilled Out into serum and we can measure it that's why it's a good marker of cardiac injury all right so the basic structural unit is separated by zines and coming from the zines are the thin filaments which are formed from actin and they're anchored onto the thin filaments all right keep that in mind thin filaments are anchored in place by troponin which is the regulatory protein and in the resting state troponin sits on top of tropomyosin and udes binding sites so that thin filaments can't bind to thick filaments but when calcium is released into the myosite calcium is binds to troponin it's attracted to it the calcium and troponin come together that then the calcium troponin complex dissociates from tropomyosin tropomyosin no longer has a partner to keep it in place the tropomyosin just floats away from the acting B actin binding site and now you have an exposed actin binding site which will cross with the thick filament the mein and come together and this is what contraction is now the way that we get calcium into the myosite is that when an action potential occurs calcium channels open sound familiar when calcium channels are stimulated remember they are voltage and time dependent so in the cardiac myosite when the membrane potential is excited above min-40 molts calcium channels will open calcium channels open and then calcium which is stored in the sarcoplasmic reticulum is allowed to come out the sarcoplasmic reticulum is the structure that stores calcium and it's comprised of this longitudinal system of tubules that spans the sarir it's like finger-like projections that stick into the sarir and in the resting state the t- tubules hold on to this calcium and don't let it out but when the membrane voltage is stimulated above minus 4 molts calcium channels will open calcium is released from the sarcoplasmic reticulum through the T tubules into the sarir and then calcium will bind to troponin and troponin once they come together they form a different kind of complex that will dissociate from tropomyosin and then tropomyosin no longer has anything holding it down so like a helium balloon it just floats away from The Binding site and now actin and mein can come together and bind and this is what produces contraction hopefully we have pictures coming up soon here oh hooray here's one all right so visualize the whole thing right this is the the cardiac myosite everything you're looking at here is the cardiac myosite um you can see how like the sympathetic uh sympathetic nervous system stimulation will release epinephrine which binds to Beta receptors I'm I'm circling it in blue where it says dress here right so this is outside the membrane this is the cell membrane this thing that we're looking at here the amphipath amphipathic molecules right the lipid bilayer the hydrophilic heads and the hydrophobic Tails I'm circling a little chunk of those in blue right next to that beta adrenergic receptor okay so this is the outside of the cell right within the cardiac myosite you see the functional unit which is the sarir which I am going to try to find a color to outline it in the sarir is this thing that I'm going to surround in a blue a light blue rectangle that's really poorly drawn but you get the idea there's the functional unit in contractile tissue that's the sarir that's the thing that's going to make it contract now what you can't see here because the level of detail isn't here is that if you like looked much closer at the sarir you see the thin filament which are I'm going to label as a t right all these little thin ones are the thin filaments there's one two three four five under each te and they're long they go all the way to the other side right that's your thin filament and then in the middle of them you see the thicker line right you see the thick filament and let me see if I can Circle those in yellow the thick filament now I just circled it in the middle but the thick filament runs all the way through so so you see how there's there's like overlap between the thick filaments and the thin filaments that's the contractile unit in the resting state they're not Contracting they're not attached to each other they're just like lined up there you know killing time just waiting for something to happen however when an action potential occurs which in the case of contractile muscle is when you get that electrical impulse down that specialized pathway the electrical impulse which I'm going to label as e up here at the top the electrical impulse will open sodium channels right now you're in Phase zero of the action potential when sodium channels open sodium goes in which you can see by way of this Arrow when sodium goes in it raises the voltage of this membrane and when the membrane voltage goes up I'm drawing a little horizontal line here and I'll put a m under it that's the membrane when the membrane voltage goes up and climbs above minus 40 molts what happens is that calcium channels open and when calcium channels open calcium shoots from inside the t- tube out of it and I'm circling this in red too on like the left side of your screen Cal shoots out of that t tubule and calcium now can get down into the saram Follow the arrow red arrow all the way down to where it says contraction contraction occurs because calcium can now get down to those actin and myosin filaments when calcium gets down there it will complex with the troponin which is sitting on top of tropomyosin which are blocking actin and mein binding sites so when the calcium binds to the troponin they go away the tropomyosin is now exposed it goes away The Binding site is open and then the thin filament which is actin will bind to the thick filament which is myosin pull them close together and then you get a contraction so like this is what I just said I think is spelled out in the next few slides the action potential propagates over the surface of the cell membrane when that action potential occurs it spreads along the tules and opens the calcium channels contraction can only happen in the sarir when the t tubule is depolarized because that's how calcium gets out calcium gets out of the T tubule it goes down it runs into the saram miror along its concentration gradient it will bind to tronin which I just said and this is the sliding filament theory of muscle contraction the calcium binds to tronin makes the troponin dissociate from tropomyosin the tropomyosin is now exposed it dissociates from The Binding site and the actin myosin binding SES come together brings the Z lines closer together and maintains that muscle tension which is contraction and this is what I just said now this takes energy right bringing them together actually doesn't but then breaking this Bond allowing them to go back to the resting state requires ATP or energy which is why oxygen is so important to this process so this is the visual and I again I know it's not the best one there's actually several good links in the external um links section of you know this unit three or week three if you're still struggling with this I would really encourage enourage you to try to watch at least a couple of them um I did I think I indicated in the external links which ones should be the priority if you don't have time for all of it this really isn't uh it isn't an especially complex uh system but it's just there's a there's a lot of moving Parts there's a lot to it and if you've never really spent time thinking about it before then this might all be new to you but do go watch those videos I'm sure that will help as well but the whole thing exists for this to happen I just can't emphasize this enough the job of the heart is to move blood forward right to move deoxygenated blood to the lungs receive reoxygenated blood and then send that out into arterial circulation and the way that happens is by the contraction of contractile muscle and Fast Response Action potentials are what Drive contractile muscle in order to get those Fast Response cells to contract you need an electrical impulse which is produced by slow slow response action potentials so everything works together here to make this happen in the SA node those slow ttype calcium channels allow a slow steady rise in membrane potential which controls heart rate so that it doesn't go too fast or too slow when those slow ttype calcium channels actually get the voltage up to a thresold then the funny sodium current allows a very quick burst of upward voltage the SA node discharges the electricity and then it's it it goes right back to repolarization that electricity then diffuses through specialized atrial Pathways and begins the process of conduction in the Atria the atrial cells which were at rest in Phase 4 are now stimulated by electricity so sodium channels open in Phase zero when sodium channels open and sodium rushes in the voltage shoots up very quickly now remember we said as fast as those sodium sodium channels activate they will inactivate so sodium channels are only actually open for a very brief time but just long enough to make the voltage rise when the voltage rises above minus 40 molts calcium channels will open within the sarcoplasmic reticulum right calcium comes out of the T tubules calcium can get into this contractile area calcium will bind to tronin which I know you can't see here but the troponin is like sitting on top of binding sight we'll put a a capital T for troponin troponin is sitting on top of binding SES here complexing with tropomyosin which we will call a little T so in the resting state troponin Big T and tropomyosin Little T are sitting on top of actin binding SES making it impossible for mein to bind to actin but when that membrane voltage is depolarized and sodium channels or when when the membrane voltage is depolarized and sodium channels open and sodium rushes in and raises the voltage in the sarcoplasmic reticulum above minus 40 calcium channels within those T tubules will open calcium will rush in calcium will complex with tronin and it pulls it away so then you've got tronin capital t and calcium that come together and they dissociate from the myosin binding site the troponin and the calcium go away Arrow out when that happens tropomyosin is left all alone so it just doesn't know what to do it goes away and then you have these binding sites exposed and while you really can't visualize it here the the actin binding SES and myosin binding SES will come together it pulls this thing together and you can see how the Z lines come closer together right look in relaxation it's all the way over here to the left we'll do R for relaxation but in the contracted State they get pulled in and shorten the muscle and that's how it generates the force that will push the volume of blood forward this whole thing happens to open calcium channels so that calcium can come out of the sarcoplasmic reticulum via the T tubules get calcium in there into that contractile unit complex with tropomyosin to pull it away from troponin so the troponin can dissociate and expose those binding sites so the whole damn thing can come together and generate Force which will push blood into the next part of the anatomy and then it's over and when it's done because we said calcium channels are time dependent and a about 300 milliseconds they will close and when they close calcium is actively pumped back into the sarcoplasmic reticulum it just stays there waiting for the next impulse now after the calcium is actively pumped back into the sarcoplasmic reticulum there is no calcium to be connected to troponin and when calcium is no longer connected to troponin it doesn't know what to do it goes back to tropomyosin and with troponin and tropomyosin get back together they plunk right back on that mein binding site and block it up so that it can't bind with actin anymore and there can't be a contraction I know I've said to you before that on so many levels life life cycles replicate themselves over and over again whether it's at the level of the cell or it's whether it's at the level of society this is a totally other example of how this happens think about what's Happening Here the cardiac cell is at rest it's comfortable it's not very exciting it's just in diast nothing is going on right and then all of a sudden something comes along to excite it to shake it up a little electricity to throw some voltage into the equation and when the voltage happens calcium channels open and calcium is new like it doesn't belong there right it's suddenly released into the myosite and the calcium is all young and looks good and when the calcium's all down there like throwing itself around the troponin is attracted to it it's something new it's something different it's something young so the tronin leaves its complex with tropomyosin and it runs off with the calcium that little trampy calcium and now troponin and calcium just disappear doing who knows what and the troponin is like wait what happened all of a sudden I was had a union and now I'm alone I'm not sure what to do and the tropomyosin just aimlessly dissociate so now the tropomyosin is over here not knowing what to do the troponin over here mess around with the calcium and this binding site is totally exposed so then what happens a contraction and the contraction just shakes everything up Suddenly everybody's aware of what happened right and they're like oh no this we don't want this so as fast as it happened contraction stops when contraction stops finally calcium's parents come along and say you don't belong here get back in your t- tubal the calcium is pumped away it gets pumped back to where it came from suddenly the troponin is all alone again it doesn't know what to do so it goes back to what's comfortable which is the tropomyosin and when the troponin and tropomyosin get back together and they're comfortable again they sit right back on their seat on top of that binding site and they keep actin and mein from binding and everything is relaxed again and then life just goes on in a tip typical Baseline relaxed date until some other voltage of electricity comes along to shake things up I mean it really is true all joking aside in in life cycles over and over again we have the complacent State the resting state you know the daytoday not always exciting but it's stable and then something comes along to shake it up molecules become attracted to other molecules it changes everything but it never lasts and at the end of the road things just tend to want to go back to that relaxed state okay sigh end of end of lecture one for week four and like I promised lecture two is much lighter it's faster and it's just lighter content so I'll see you there