we're going to begin a consideration of the cardiovascular system by returning to cardiac muscle now we've already talked about how cardiac muscle compares to skeletal muscle in terms of its excitation contraction coupling but our return now um with a focus on cardiac muscle is going to focus on a particular property and that is the fatigue resistance of cardiac muscle your heart beats about 100 000 times a day which amounts to 35 million contractions in a year and billions of contractions in a lifetime and it never stops your heart has to continue beating or you'll die essentially chemical diffusion is not sufficient to transport nutrients to the cells that need it and dissolve gases as well and when your circulation ceases then your cells like your brain cells for example with their very high metabolism start to die uh almost instantly so you cannot afford for the cardiac muscle that your heart is largely composed of to fatigue and so the question for this many mini lecture is how does the heart avoid exhaustion now we're going to talk about three levels of security essentially in the design of your heart that help prevent exhaustion and the first focuses on the pacemaker cells of the heart so let's focus schematically on the two types of cells that we're going to talk about the pacemaker cells are known as autorhythmic cells or autorhythmic myocardial cells and they are responsible for creating the heart's beat and it can be modulated through the autonomic nervous system which we'll talk about in a bit but the autorhythmic cells themselves just one cell is capable of creating that heart beat and the action potentials generated by the algorithmic cells then propagate through the contractile cells which in addition to propagating the action potential through other contractile cells generate force so when we talk about cardiac muscle we're referring to these contractile cells or myocardial contractile cells we're going to start with the autorhythmic cells so we're going to perform one of our virtual experiments where we monitor the membrane potential in this case of an autorhythmic cell and we look at how that membrane changes over time and without exposing it to any kind of a stimulus these cells will on their own and this is what we mean by an autonomous activation will depolarize you have this gradual increase in membrane potential which is known as the pacemaker potential now when the potential the membrane potential reaches a threshold of minus in this case 40 millivolts then an action potential begins this is sort of like an action potential in a neuron but in slow motion note the time scale there it's over a half a second spanning the entire x-axis now like the action potential of a neuron once it has been tripped it cannot be reactivated it has a refractory period and it's fixed in its duration so what that means is that the autorhythmic cell is incapable of generating action potentials any more frequently than what would happen if you had a zero pacemaker potential if you just were to stack up action potentials right after each other then that still is not terribly frequent and the pacemaker potential is modulated in its duration and again we'll talk about that later but the action potential is fixed now the means of change changing the membrane potential plays similar games that we've become familiar with from a consideration of other excitable tissues although the particular channels that are involved are new to us so during the rise of the pacemaker potential the ion flux that generates that is a combination of sodium and potassium so this channel called the if channel it's f for funny because at the time the behavior was kind of unusual it has a threshold of minus 60 millivolts so we begin right there when and by the way this is showing us just one pacemaker and one action potential so the next beat would begin with another pacemaker potential that starts at that point so once the cell has repolarized from the prior action potential that will trigger the iaf channels to open and like the nicotinic receptors in the motor end plate of skeletal muscle this channel allows for flux of both sodium and potassium but more sodium than potassium and as a consequence you get a depolarization not a hyperpolarization now once the membrane has reached that threshold of minus 40 millivolts then voltage-gated calcium channels become activated calcium has a similar behavior as sodium in that it has a positive equilibrium potential and a higher concentration on the exterior of the cell so when that channel opens calcium will tend to move into the cell the repolarization as you might expect is driven by potassium now it's a relatively slow potassium channel but again it's voltage-gated it has a threshold of a high positive membrane potential and so when it is triggered then potassium floods out of the cell and that serves to repolarize the membrane so the fixed duration of this action potential serves as a safety measure to help avoid exhaustion of the contractile cells that the autorhythmic cells are connected to that long action potential limits the b frequency essentially provides a ceiling for the beat frequency and it's caused by the calcium and potassium channels that i just explained okay so the autorhythmic cells provide a means or a safety measure from avoiding exhaustion by virtue of serving as an upper limit to the beat frequency that is possible the contractile cells themselves have safety measures as well and for that we're going to compare the behavior of a myocardial contractile cell to skeletal muscle fibers so we've already talked about this physiological experiment where we take a single muscle fiber we bathe it in physiological saline and we run electrical current through that saline to generate force and in this case monitor the membrane potential of that contractile cell so this is a recording electrode not a stimulating electrode so when we play a stimulus into the physiological saline we can now monitor the membrane potential that results from that and for skeletal muscle we didn't do this before when we were presenting skeletal muscle because it's kind of trivial the skeletal muscle just reflects the changes or the depolarizations that are driven by our stimulus and then we have the tension that we're familiar with from an earlier lecture where we have a single twitch then we're illustrating summation through a succession of action potentials let's compare that to a myocardial contractile cell we're going to measure both the tension and also the membrane potential that results from the same series of action potentials that we're going to use to stimulate the cell now the first thing that you see that is different is what the membrane potential looks like it maintains a depolarization and that serves or reflects a refractory period so for this really long duration note the time scale here that's a quarter of a second or 250 milliseconds for that duration of the refractory period the tension is generated over that time scale all right that's the twitch for a myocardial contractile cell note that it's longer in duration from the skeletal muscle fiber we're spanning almost three twitches for the skeletal muscle fiber for with that duration and this refractory period is triggered by that first action potential then when the subsequent second and third action potentials arrive they have no effect on the membrane the membrane is insensitive okay that's what it means to be within a refractory period so this tension would be the same if there were just one action potential three action potentials 15 action potentials it doesn't matter because the contractile cell is insensitive to the action potentials that follow that first action potential and that is true for the entire duration the whole one-quarter second period of the refractory period once the cell has reset that is beyond the refractory period then it can be activated again and so when we send a high frequency of action potentials we see again that depolarization is driven by that initial action potential and then once the cell has repolarized then it can be activated again but it cannot be activated at the times in between these action potentials have no effect on the contractile cell and as a consequence when you look at tension it follows that fixed duration of a quarter of a second so even if the autorhythmic cells fail and somehow feed a super high train of action potentials which we know they shouldn't because they have their own refractory period but if if somehow they could then the contractile cells are resistant to those extra excitations high frequency of action potentials cannot result in contraction because of the refractory period that we see here so the refractory period guards against fatigue now i'm not going to show you a schematic of the voltage channels that generate the refractory period but i will just tell you that they're generated again by calcium channels much like the autorhythmic cells and low potassium permeability so you essentially have a depolarization that's being driven by calcium and a depressed potassium permeability okay so both the autorhythmic and the contractile cells have these measures to help avoid exhaustion there's a third measure that is more at the organ level so let's return our attention to skeletal muscles so this is supposed to be a schematic of a biceps muscle so on the left we have the contracted state and then on the right we have it fully extended and just think about you can sort of do it on your own you can play along and just think about contractions of your biceps muscle okay they contract your your hand elevates and it relaxes maybe your triceps muscle drives the extension of your arm so that your your hand lowers all throughout the length changes of the muscle whether activated or being extended are constrained by the elbow joint they're also constrained by where the muscle inserts on the bones and as a consequence what you have is the anatomy of the arm affecting the lengths that the muscles can achieve so in other words the elbow joint restricts the range of muscle lengths that are achieved so when you look at the length tension relationship for muscle as might be measured in an isometric experiment like we've considered with the kind of experimental preparation we see on the left we got a relationship that looks like this and what we can say is that the elbow joint allows almost this full range of changes in length by the muscle fibers within the biceps muscle we're going to call that the anatomical range because it's a function of in vivo the range of length changes that your anatomy allows so for skeletal muscle if you look at the anatomy of your skeleton and where the muscles are attached it turns out that the geometry of the skeleton allows for length changes that almost span the full length tension relationship all right so this is the story for skeletal muscle an anatomical range that allows for almost a full length tension relationship the length changes of the myocardial contractile cells or the cardiac muscle cells are restricted in a different way they are not actually connected to any skeletal joint now the length tension relationship of these cells is similar after all these cells have sarcomeres and they generate tension in a similar way to the skeletal muscle so when you extract a single cell like this one that we see here on the left and you measure its length tension relationship then you get a curve that looks something like that okay the slopes are different the slope is actually meaningful in terms of its function you see that for any increase in length you get a greater increase in tension because the slope continuously increases so for any lengthening or expansion in the chambers of the heart you're going to get more tension back out of it all right so that does matter but in general you see that there's a rise and then a decline just like the length tension relationship in skeletal muscle but these length differences are not driven by the same kind of muscle antagonism that you see in the skeletal muscle and set instead the heart as it's changing the volume of the chambers as they fill up with blood drive the extensions and length so we're going to get into all the details of the heart anatomy later on but what you need to know is that most of what you see here is is cardiac muscle tissue there's also a lot of connective tissue and just imagine being a cardiac muscle cell in the wall of this ventricle right here at this point in the cardiac cycle the the period of time that the heart beats and relaxes the chamber has just contracted and is now has now begun filling up with blood okay so that means that for this geometry we would be on the left hand side of this length tension relationship now as that chamber fills up with blood we can see those walls expand and the muscle tissue that comprise largely comprise the wall of that chamber have now expanded like filling up a water balloon that means that we've gone from a short length now to a long length and then when the muscle is activated then it will go back or run back down this curve and go to the shorter length okay so blood filling the chambers extend the length of the muscle another factor is all the connective tissue that surrounds the contractile cells constrain the extent to which the muscles can be elongated so in this respect we have an anatomical range that's not created by the geometry of a joint in your skeleton but instead by the connective tissue that could that surrounds the contractile cells so as a consequence of all that connective tissue the anatomical range of the contractile cells is much more narrow than we see in the case of skeletal muscle cells now why is this relevant well imagine the alternative what would happen as the ventricle expanded if it drove the contractile cells to this part of the length tension relationship when the ventricles fill the more that they fill up with blood the more that the walls need to generate pressure and therefore force in order to expel that blood so essentially the more that it fills up the more force that you're going to need to clear the blood that has entered that chamber that's a real problem if the length tension relationship is such as it is where it increases up to a an optimal length but then declines because if we had a drop off in tension the ventricles would be filled up and we'd be generating less and less pressure to clear out those chambers so we don't want that we we essentially want a measure to avoid the physiological length tension relationship that we see in green here and that's provided by the anatomical range by restricting the range of lengths that can be achieved then we're only in a region of positive slopes in the length tension relationship in other words the more you extend the muscle the more force that you get out of it and for any increase you get more of a change in tension so the heart anatomy limits the anatomical range and that prevents a drop off in tension at the high muscle lengths it's another measure to avoid fatigue because the muscles would be fatigued by this inability to clear out the chambers there's an additional benefit to the anatomical range that has to do with how the cardiac muscle functions in vivo during real heartbeats and that was classically demonstrated by experiments on the heart of a dog and this experiment is rather simple on the y-axis we have the stroke volume that's the volume of blood that emerges from the heart that is through the aorta during a heartbeat so that's how much you get out of the heart the x-axis is the amount of blood right before the contraction begins so it's the volume in the ventricle at the end of diastole so the ventricular and diastolic volume it's a bit of a mouthful but it just means how much blood the vent is filled up in the ventricle before contraction so in the length tension relationship on the left the end diastolic volume would correspond to when the muscles are lengthened the most they're the most the ventricles are the most inflated and therefore the muscles are the greatest extended at that point in the cardiac cycle the stroke volume can be less than or should be less than that volume because not all blood leaves the heart there's always some residual volume of blood at the end of the contraction left behind now the way this experiment was performed was to inflate this heart which had been extracted from a dead animal and to inflate the ventricle to varying degrees and then stimulate it to contract and measure how much blood emerged from the heart and the relationship initially is linear and that's the case up to the resting value by resting i mean the the values for both the stroke volume and the ventricular and dystog volume uh when the dog is not exercising so those values appear there so it's a linear relationship and that linear relationship largely continues at higher volumes which are achieved when the activity of the animal increases so it looks like that eventually you get diminishing returns such that there's a leveling off of that slope and so you're getting less and less stroke volume less and less blood out of the system for more and more um blood being pumped into the ventricle so it still remains a positive slope but it levels off you're basically getting diminishing returns in the effort now what this implies is a couple of things first of all in order for more blood to emerge from the heart there has to be greater pressure generated in the ventricle so greater pressures are achieved only through generating more force so as you inflate the ventricle further you're pushing on the length tension relationship the position before contraction further to the right if if not for the anatomical range what would happen is that there would actually be a drop off in force as you continue to the right but because of all the elastic tissue that prevents a movement into the right part of the leg tension relationship that doesn't happen so instead with more pulling on the muscles greater end diastolic volume you get more force more tension out of the system and in fact because the length tension relationship has an increasing positive slope for as you pull it further you get a disproportionate increase in the tension that's generated when the muscle is activated now this also demonstrates the ability of cardiac contractile cells to increase their twitch tension we'll get into that uh later when we consider the control of the cardiovascular system but twitch tension can increase in cardiac muscle cells it's not something you see in skeletal muscle cells so the length tension relationship on the left is what you can measure on single cells and on the right you see one large functional benefit to that length tension relationship and the anatomical range and this is known as the frank starling law okay so let's get back to the initial question that we set out to address how does the heart avoid exhaustion given that it contracts so many times in a lifetime we've seen three measures that help avoid exhaustion first of all in the autorhythmic cells we have the fixed duration of the action potentials that's prevents the heart rate from driving the contractile cells at too high a frequency within the contractile cells themselves we have that prevented also through the refractory period we can't activate the muscle fibers at a greater frequency than is what than what is permitted by that refractory period and finally we have at the organ level this anatomical range which prevents the hyperextension of muscle which would cause a catastrophic drop in tension