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Current time:0:00Total duration:14:18

Video transcript

so a long time ago there were two gentlemen one by the name of Frank and the other his last name was Starling so Frank and Starling coming from two different countries Frank was from Germany and Starling was from England came up with a set of ideas that we still use today not just use but actually are pretty relevant to how we think about how the heart works and so these two guys I just want to give a little shout out to both of them because they were leaders in their field a hundred plus years ago and their ideas are still very very relevant to how we think about things today so what they came up with and this is kind of the content of the video is related to pressure and volume so let's start there let's talk about both pressure on this axis and volume on this axis and you understand that P and V are pressure and volume so if you increase pressure and volume over time and let's say the heart is completely relaxed right you're going to get a curve that looks something like this right it's going to kind of go up near the end as you start really packing in the fluid and we call this the end diastolic that's where the IDI comes from pressure volume relationship EDP VR so this is kind of what the curve looks like and I could take different points on this curve I'm just going to kind of choose some points arbitrarily let's say 3/4 let's choose one up here five points on this curve and you realize that as you go up from 0.1 3.5 let's say this is point one two three four and five as you go from point one three point five your preload is going up remember that that preload is related to pressure and preload is really a sense for what is the stress on the walls and of course within the walls you've got these little heart cells so what's the stress on these heart cells and we know that as the stress goes up the heart cells themselves begin to really stretch out and so I'm going to just kind of show that to you in this little diagram you've got let's say this could be one this could be three and this could be five right so this is kind of what's happening with heart cells as you go up up up in terms of the preload they stretch out so thinking about heart cells stretching out and of course this is before they contract what does this mean for contraction and this is something that Frank and Starling thought about and that's what I want to kind of jump into next so just think about these five points one two three four five and we're going to go kind of point by points through them each so let's start with point one and here in point one you've got very little preload right very very little preload and maybe it'll be useful to kind of just draw some myosin so this will be our myosin and I'll draw the myosin heads drawing let's say about twenty or so on the bottom and on the top so this is our myosin molecule in purple and I want you to keep an eye on how many myosin heads are actually working kind of almost as if you're the taskmaster and you've got to make sure that the myosin heads are all working make sure you keep an eye on exactly how many are doing what we want them to do which is contract or pull in the actin so let me actually just take a little shortcut here so now after keep redrawing this I'm going to move this down here and I'll do it again and I'll move it even lower so if our myosin they're now around the myosin in fact let me label it while I still can this is our myosin right around our myosin we have of course actin right a bigger just so you can see it very clearly we have actin and actin is going to be will do in red but because we have a very at this point almost a very low preload or almost no preload I'm going to show you what what that means for our molecules you're going to something like this where you have everything kind of crowded together and that's kind of the core issue I want to point out to you is that you have lots of crowding problems and of course the myosin on the ends here we've got you know this is our z disk and right z disk and you have another z disk here and what I'm showing you is kind of a part a part of the sarcomere remember the sarcomere is kind of the the basic unit of contraction and it usually goes from zeda status so this is just a part of it because you'd have many many more actins and myosins stacked up and below it but this is just to kind of give you a sense for what we're looking at right this is of course our actin so the question is and I guess I should start it before the question let me throw in Titan this little green molecule is Titan so the question is how or how would a contraction occur if you were to look at this scenario and you're kind of an inspector you're just kind of assessing for problems would you expect that there would be any problems would you expect any problems here and afterwards I also want to think about force what kind of force do you expect to get out of this sort of arrangement a lot of force or a little force what do you think well immediately I can see some problems right I mean you know that the whole goal is to pull the Z disks in closer to each other that's the whole point or the myosin is going to yank on the actin rope so you can think of it as a rope and yank the Z disks in and if there's really almost no space here see this right here there's almost no space here it's all crowded and this myosin is basically almost touching the Z disk right this guy right here is almost touching the Z disk already so close well then what do I really expect to happen there's going to be almost no force because the problem I'm going to write it very clearly is that the myosin is crowded myosin is crowded myosin is crowded meaning it's right up against the z disk right from the beginning and that's a problem right because that means that you know what can you really hope to achieve if you've already gotten the myosin already against the z disk there's really no space for you to yank the actin in to bring the z to skin closer there's no space there it's crowded so I would say that's the biggest problem and secondly there's actually another problem here and that's around actin right because the actin has polarity and this is an important issue that these two actin Moll skills that I've kind of drawn arrows around are fundamentally different right because there's a directionality directionality to the way those proteins are laid out and we call that polarity so actin has polarity polarity and what that means is that then myosin can't simply reach up and grab the nearest actin it has to grab the correct actin so for example these four right here you can draw them a circle around them in yellow these four really want this actin on this side and these four down here they really want the actin on this side but both of those groups of Acton's or myosins rather are blocked by the other actin so for example these four at the top are blocked by this segment right here and these bottom four are being blocked by I could actually change it I could say these or this segment right there so there's actually some actin blocking going on so I call that actin overlap or act in blocking overlap let's call it overlap because I think that makes a little bit more sense so you've got some actin overlap but that's kind of a secondary point here because the main issues that myosin is just frankly it's just crowded so in terms of force what I expect any I would say no I wouldn't really expect any because there's really nothing for the myosin to really get done there's there's just no space now let's say we stretch things out this is scenario two so things are a little bit stretched out now looking at our graph up above now things are stretched out meaning that here instead of the way it was drawn before let me actually kind of correct it and draw it like this you still have to consider the polarity issue but things are a little bit more spaced out now right you've got something like that and going on the other side you've got something like let's say that so look at this and now tell me what you think you've got a couple of myosins that are still blocked right you still have a little bit of blockage here right these ones are blocked and these ones are blocked and the main reason again for the blockage is that there's a polarity issue here and here meaning that those myosins cannot simply bind whatever is closer and they're really not able to get over to the side where the actin is where they need to bind so those 4 out of 20 myosin heads are not going to be able to work but the rest of it is actually looking a lot better than before right we have some improvement so here you've got some actin overlap issues so in terms of problems I would say actin overlap is still kind of an issue right and so in terms of force I wouldn't say no anymore because now at least the myosin is crowded problem has gone away it's not as crowded and there is room to move so I would say I would expect some force so when there is contraction I would expect some force here so things are definitely getting better right the stretching is helping things out because it's basically moving the actin so that it's not congesting the area and the myosin is similarly moving away from the z disk let me make a few more of these I'll make one more and we'll keep going so now let's go to the third picture well here let's keep it up let's see what what we can do if we keep the stretch going now I can say well gosh I've got lots and lots of space for the myosin to work so the very first point we talked about that's a non-issue completely non-issue now because look at the Titan watch watch as I draw the Titan look at this all those all those coils all that space for that for the myosin to move right so the Z disks here remember these are Z disks have a lot of room if we really want to yank them in we could we could really yank them in because the myosin is not right up against them anymore and we've actually solved the other problem the actin overlap problem because there is no overlap at this point now you've really got nice spacing and the actin isn't blocking the myosin from binding to another actin molecule so in terms of problems I would say no problems no problems here and in terms of force I would say lots of force because really I've got 20 myosin heads all ready to go right they're all pumped up and ready to do their thing to bind the actin in to yank the Z disks in so that was scenario 3 now scenario 4 is going to be really really similar right a lot of the same kinds of issues because now I'm just kind of pulling a little bit further apart and again all those myosins are going to be able to work they're they're going to have no problems of crowding I've in fact even made more spaced out by the Titan so the Z disks or even further apart so certainly all xx myosins are going to be working and I would expect no problems again really no problems here either so in Scenario 3 & 4 things are looking really good and so of course I would expect lots of force I would expect lots of force on this one as well so it seems like well the more we stretch things out the better things get so let's just keep stretching let's just see how it goes and let me just really stretch things out to the point where it looks almost like that so you're thinking we'll wait a second wait a second Rishi I got a little too carried away here and now how the heck is this even going to stay put well remember the Titan is definitely going to keep my myosin attached to the z disk so that's good so it won't just float away it'll stay attached but in terms of actually doing work what I expect this to be a good setup well I've really stretched things out so you know there's no crowding issue that's true but I have a new issue right really I have actin out of reach actin is out of reach and if actin is out of reach of my myosin then how the heck am I supposed to get work done if they can't even attach themselves to the actin then would I expect any force out I would say no I would expect really no force because it's just too stretched out so this is kind of the overall look and feel of what happens as the preload goes up as you get more and more stretched out things seem to be getting better initially but then they get a little bit too stretched out at the very end in the optimal situation this is pretty important the optimal situation is really out of these five these five scenarios would basically be one of these two so situation three and four are looking really good right where we get lots of force lots of force no crowding issues no you know acting out of reach issues no myosin actin overlap issues nothing right it's just three and four really are golden situations and so just keep this in mind when you look at a preload curve that it really does start affecting how well the myosin and acting actin are able to create force and this idea of stretch relating to force is something that Frank and Starlin thought of a long time ago