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Frank–Starling law

From Wikipedia, the free encyclopedia

Not to be confused with the Starling equation that describes transcapillary exchange.
Cardiac function curve. In diagrams illustrating the Frank–Starling law of the heart, the y-axis often describes the stroke volume, stroke work, or cardiac output. The x-axis often describes end-diastolic volume, right atrial pressure, or pulmonary capillary wedge pressure. The three curves illustrate that shifts along the same line indicate a change in preload, while shifts from one line to another indicate a change in afterload or contractility. A blood volume increase would cause a shift along the line to the right, which increases left ventricular end diastolic volume (x axis), and therefore also increases stroke volume (y axis).

The Frank–Starling law of the heart (also known as Starling's law and the Frank–Starling mechanism) represents the relationship between stroke volume and end diastolic volume.[1] The law states that the stroke volume of the heart increases in response to an increase in the volume of blood in the ventricles, before contraction (the end diastolic volume), when all other factors remain constant.[1] As a larger volume of blood flows into the ventricle, the blood stretches cardiac muscle, leading to an increase in the force of contraction. The Frank-Starling mechanism allows the cardiac output to be synchronized with the venous return, arterial blood supply and humoral length,[2] without depending upon external regulation to make alterations. The physiological importance of the mechanism lies mainly in maintaining left and right ventricular output equality.[1][3]

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  • The Frank-Starling Law of the Heart Part 1
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Transcription

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. And 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 100 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. 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-- you're going to get a curve that looks something like this. 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 "ED" comes from-- "pressure-volume relationship." "EDPVR." 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. 5 points on this curve. And you realize that, as you go up from point 1 through point 5-- let's say this is point 1, 2, 3, 4, and 5. And as you go from point 1 through point 5, your preload is going up. Remember 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? 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. Let's say this could be 1. This could be 3. And this could be 5. 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 5 points-- 1, 2, 3, 4, 5. And we're going to go kind of point by point through them each. So let's start with point 1. And here in point 1, 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. I'm drawing, let's say, about 20 or so on the bottom and on the top. This is our myosin molecule in purple. And I want you to keep an eye on how many myosin heads are actually working, 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 I don't have to 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 we have our myosin there. 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. I'll write it bigger just so you can see it very clearly. We have actin, and actin is we'll do in red. But because we have a very low preload-- or almost no preload-- I'm going to show you what that means for our molecules. You're going to have 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. You have lots of crowding problems. And of course, the myosin-- on the ends of here-- this is our Z-Disk. I'm going to write "Z-Disk." And you have another Z-Disk here. What I'm showing you is kind of a part of the sarcomere. Remember, the sarcomere is kind of the basic unit of contraction, and it usually goes from Z-Disk to Z-Disk. 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? And this is, of course, our actin. The question is-- and I guess I should-- sorry. Before the question, let me throw in titin. This little green molecule is titin. So the question is-- how would 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 you 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. The myosin is going to yank on the actin ropes-- you could 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-- and I'm going to write it very clearly-- is that the 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-- 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-Disk in 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. These two actin molecules that I've drawn arrows around are fundamentally different because there's a directionality to the way those proteins are laid out. And we call that "polarity." So actin has 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-- I'm going to draw a little 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 myosins 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 "actin 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 issue is that myosin, frankly, is just crowded. So in terms of force, would 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 just no space. Now, let's say we stretch things out. This is scenario two. So things are a little bit stretched out now. You're 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. These ones are blocked, and these ones are blocked. 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. 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's 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 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. The very first point we talked about, that's completely non-issue now because look at the titin. Watch as I draw the titin. Look at this. All those coils, all that space for the myosin to move. The Z-Disks here-- remember, these are our Z-Disks-- have a lot of room. If we really want to tank 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 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 and to yank the Z-Disks in. So that was scenario three. Scenario four is going to be really, really similar-- a lot of the same kinds of issues-- because now I'm just kind of pulling it a little bit further apart. And again, all those myosins are going to be able to work. They're going to have no problems of crowding. I've, in fact, even made more space out by the titin so the Z-Disks are even further apart. So certainly, all 20 myosins are going to be working, and I would expect no problems again. Really, no problems here either. So in scenario three and four, 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. 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, well, 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 titin is definitely going to keep my myosin attached to the Z-Disk. So that's good. They won't just float away. It'll stay attached. But in terms of actually doing work, would I expect this to be a good setup? Well, I've really stretched things out. So there's no crowding issue. That's true. But I have a new issue. Right? Really, I have actin out of reach. 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? I would say no. I would expect really no force because it's just too stretched out. This is 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 5, these 5 scenarios-- would basically be one of these two. Situation three and four are looking really good, where we got lots of force, no crowding issues, no "actin out of reach" issues, no myosin-actin-overlap issues. Nothing. Right? Three and four are really our golden situations. Just keep this in mind when you look a preload curve. It really does start affecting how well the myosin and actin are able to create force. And this idea of stretch relating to force is something that Frank and Starling thought of a long time ago.

Physiology

The Frank-Starling mechanism occurs as the result of the length-tension relationship observed in striated muscle, including for example skeletal muscles, arthropod muscle[4] and cardiac (heart) muscle.[5][6][7] As striated muscle is stretched, active tension is created by altering the overlap of thick and thin filaments. The greatest isometric active tension is developed when a muscle is at its optimal length. In most relaxed skeletal muscle fibers, passive elastic properties maintain the muscle fibers length near optimal, as determined usually by the fixed distance between the attachment points of tendons to the bones (or the exoskeleton of arthropods) at either end of the muscle. In contrast, the relaxed sarcomere length of cardiac muscle cells, in a resting ventricle, is lower than the optimal length for contraction.[1] There is no bone to fix sarcomere length in the heart (of any animal) so sarcomere length is very variable and depends directly upon blood filling and thereby expanding the heart chambers. In the human heart, maximal force is generated with an initial sarcomere length of 2.2 micrometers, a length which is rarely exceeded in a normal heart. Initial lengths larger or smaller than this optimal value will decrease the force the muscle can achieve. For longer sarcomere lengths, this is the result of there being less overlap of the thin and thick filaments;[8][9][10] for shorter sarcomere lengths, the cause is the decreased sensitivity for calcium by the myofilaments.[11][7] An increase in filling of the ventricle increases the load experienced by each cardiac muscle cells, stretching their sarcomeres toward their optimal length.[1]

The stretching sarcomeres augments cardiac muscle contraction by increasing the calcium sensitivity of the myofibrils,[12] causing a greater number of actin-myosin cross-bridges to form within the muscle. Specifically, the sensitivity of troponin for binding Ca2+ increases and there is an increased release of Ca2+ from the sarcoplasmic reticulum. In addition, stretch of cardiac myocytes increases the releasability of Ca2+ from the internal store, the sarcoplasmic reticulum, as shown by an increase in Ca2+ spark rate upon axial stretch of single cardiac myocytes.[13] Finally, there is thought to be a decrease in the spacing between thick and thin filaments, when a cardiac muscle is stretched, allowing an increased number of cross-bridges to form.[1] The force that any single cardiac muscle cell generates is related to the sarcomere length at the time of muscle cell activation by calcium. The stretch on the individual cell, caused by ventricular filling, determines the sarcomere length of the fibres. Therefore the force (pressure) generated by the cardiac muscle fibres is related to the end-diastolic volume of the left and right ventricles as determined by complexities of the force-sarcomere length relationship.[11][7][6]

Due to the intrinsic property of myocardium that is responsible for the Frank-Starling mechanism, the heart can automatically accommodate an increase in venous return, at any heart rate.[1][10] The mechanism is of functional importance because it serves to adapt left ventricular output to right ventricular output.[3] If this mechanism did not exist and the right and left cardiac outputs were not equivalent, blood would accumulate in the pulmonary circulation (were the right ventricle producing more output than the left) or the systemic circulation (were the left ventricle producing more output than the right).[1][14]

Clinical examples

Premature ventricular contraction

Premature ventricular contraction causes early emptying of the left ventricle (LV) into the aorta. Since the next ventricular contraction occurs at its regular time, the filling time for the LV increases, causing an increased LV end-diastolic volume. Due to the Frank–Starling mechanism, the next ventricular contraction is more forceful, leading to the ejection of the larger than normal volume of blood, and bringing the LV end-systolic volume back to baseline.[14]

Diastolic dysfunction – heart failure

Diastolic dysfunction is associated with a reduced compliance, or increased stiffness, of the ventricle wall. This reduced compliance results in an inadequate filling of the ventricle and a decrease in the end-diastolic volume. The decreased end-diastolic volume then leads to a reduction in stroke volume because of the Frank-Starling mechanism.[1]

History

The Frank–Starling law is named after the two physiologists, Otto Frank and Ernest Henry Starling. However, neither Frank nor Starling was the first to describe the relationship between the end-diastolic volume and the regulation of cardiac output.[5] The first formulation of the law was theorized by the Italian physiologist Dario Maestrini, who on December 13, 1914, started the first of 19 experiments that led him to formulate the "legge del cuore" .[15][16][17][18][19][20][21][22][23][24][25][26][27][excessive citations]

Otto Frank's contributions are derived from his 1895 experiments on frog hearts. In order to relate the work of the heart to skeletal muscle mechanics, Frank observed changes in diastolic pressure with varying volumes of the frog ventricle. His data was analyzed on a pressure-volume diagram, which resulted in his description of peak isovolumic pressure and its effects on ventricular volume.[5]

Starling experimented on intact mammalian hearts, such as from dogs, to understand why variations in arterial pressure, heart rate, and temperature do not affect the relatively constant cardiac output.[5] More than 30 years before the development of the sliding filament model of muscle contraction and the understanding of the relationship between active tension and sarcomere length, Starling hypothesized in 1914, "the mechanical energy set free in the passage from the resting to the active state is a function of the length of the fiber." Starling used a volume-pressure diagram to construct a length-tension diagram from his data. Starling's data and associated diagrams, provided evidence that the length of the muscle fibers, and resulting tension, altered the systolic pressure.[28]

See also

References

  1. ^ a b c d e f g h i Widmaier, E. P., Hershel, R., & Strang, K. T. (2016).Vander's Human Physiology: The Mechanisms of Body Function(14th ed.). New York, NY: McGraw-Hill Education. ISBN 978-1-259-29409-9
  2. ^ Costanzo, Linda S. (2007). Physiology. Hagerstwon, MD: Lippincott Williams & Wilkins. pp. 81. ISBN 978-0-7817-7311-9.
  3. ^ a b Jacob R., Dierberger B., Kissling G. (1992). "Functional significance of the Frank-Starling mechanism under physiological and pathophysiological conditions". European Heart Journal. 13: 7–14. doi:10.1093/eurheartj/13.suppl_E.7. PMID 1478214.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ West, J. M.; Humphris, D. C.; Stephenson, D. G. (1992). "Differences in maximal activation properties of skinned short- and long-sarcomere muscle fibres from the claw of the freshwater crustacean Cherax destructor". Journal of Muscle Research and Cell Motility. 13 (6): 668–684. doi:10.1007/BF01738256. ISSN 0142-4319. PMID 1491074. S2CID 21089844.
  5. ^ a b c d Katz Arnold M (2002). ""Ernest Henry Starling, His Predecessors, and the "Law of the Heart". Circulation. 106 (23): 2986–2992. doi:10.1161/01.CIR.0000040594.96123.55. PMID 12460884. Archived from the original on 2018-07-13. Retrieved 2017-05-03.
  6. ^ a b Stephenson, D.G.; Stewart, A.W.; Wilson, G.J. (1989). "Dissociation of force from myofibrillar MgATPase and stiffness at short sarcomere lengths in rat and toad skeletal muscle". Journal of Physiology. 410: 351–366. doi:10.1113/jphysiol.1989.sp017537. PMC 1190483. PMID 2529371.
  7. ^ a b c Stephenson, D.G.; Williams, D.A. (1982). "Effects of sarcomere length on the force-pCa relation in fast- and slow-twitch skinned muscle fibres from the rat". Journal of Physiology. 333: 637–653. doi:10.1113/jphysiol.1982.sp014473. PMC 1197268. PMID 7182478.
  8. ^ Huxley, H.; Hanson, J. (1954-05-22). "Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation". Nature. 173 (4412): 973–976. Bibcode:1954Natur.173..973H. doi:10.1038/173973a0. ISSN 0028-0836. PMID 13165698. S2CID 4180166.
  9. ^ Huxley, A. F.; Niedergerke, R. (1954-05-22). "Structural changes in muscle during contraction; interference microscopy of living muscle fibres". Nature. 173 (4412): 971–973. Bibcode:1954Natur.173..971H. doi:10.1038/173971a0. ISSN 0028-0836. PMID 13165697. S2CID 4275495.
  10. ^ a b Moss, Richard L.; Fitzsimons, Daniel P. (2002-01-11). "Frank-Starling Relationship". Circulation Research. 90 (1): 11–13. doi:10.1161/res.90.1.11. ISSN 0009-7330. PMID 11786511.
  11. ^ a b Allen, D.G.; Kentish, J.C. (1985). "The cellular basis of the length-tension relation in cardiac muscle". Journal of Molecular and Cellular Cardiology. 17 (9): 821–840. doi:10.1016/S0022-2828(85)80097-3. PMID 3900426.
  12. ^ Klabunde, Richard E. "Cardiovascular Physiology Concepts". Lippincott Williams & Wilkins, 2011, p. 74.
  13. ^ Iribe, G; Ward, CW; Camelliti, P; Bollensdorff, C; Mason, F; Burton, RAB; Garny, A; Morphew, MK; Hoenger, A; Lederer, WJ; Kohl, P (2009-03-27). "Axial stretch of rat single ventricular cardiomyocytes causes an acute and transient increase in Ca2+ spark rate". Circulation Research. 104 (6): 787–795. doi:10.1161/CIRCRESAHA.108.193334. ISSN 1524-4571. PMC 3522525. PMID 19197074.
  14. ^ a b Hall, John (2016). Guyton and Hall textbook of medical physiology (13th ed.). Philadelphia, Pa.: Saunders/Elsevier. pp. 169–178 (Ch. 14). ISBN 978-1-4160-4574-8.
  15. ^ Spadolini, Igino (1946). UTET (ed.). Trattato di Fisiologia. Vol. 2. Torino.{{cite book}}: CS1 maint: location missing publisher (link)
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  17. ^ "www.ancecardio.it" (PDF) (in Italian). pp. 29–31. Archived from the original (PDF) on 2013-11-09. Retrieved 6 August 2010.
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  19. ^ MAESTRINI, D. (July 1951). "[The importance of the altered organic exchange (fatigue), of the structure and colloidal state of the fiber, for the genesis of the so-called small, insufficient contractions of the heart in failure.]". Policlinico Prat. 58 (30): 933–45. PMID 14864102.
  20. ^ MAESTRINI, D. (November 1951). "[The law of the heart in biology and clinical medicine.]". Minerva Med. 42 (80): 857–64. PMID 14919226.
  21. ^ MAESTRINI, D. (June 1952). "[A new theory of cardiac decompensation.]". Policlinico Prat. 59 (24): 797–814. PMID 14957592.
  22. ^ MAESTRINI, D. (1947). "[Not Available.]". Gazz Sanit. 18 (5): 162–4. PMID 18859625.
  23. ^ PENNACCHIO, L.; D. MAESTRINI (September 1952). "[Comment on a new theory of cardiac insufficiency.]". Policlinico Prat. 59 (37): 1223–4. PMID 13026471.
  24. ^ MAESTRINI, D. (January 1958). "[The law of the heart from its discovery to the present time.]". Minerva Med. 49 (3–4): Varia, 28–36. PMID 13516733.
  25. ^ MAESTRINI, D. (December 1958). "[Variations of cardiac volume dynamics in clinical practice, examined in the light of the law of the heart.]". Minerva Cardioangiol. 6 (12): 657–67. PMID 13643787.
  26. ^ MAESTRINI, D. (February 1959). "[S. Baglioni and the law of the heart.]". Policlinico Prat. 66 (7): 224–30. PMID 13645276.
  27. ^ MAESTRINI, D. (October 1959). "[On cardiac dynamics in the phase preceding right hypertrophy and on its electrocardiographic aspect in man.]". Policlinico Prat. 66: 1409–13. PMID 13853750.
  28. ^ Boron, Walter F.; Boulpaep, Emile L. (2012-01-13). Medical Physiology, 2e Updated Edition E-Book: with STUDENT CONSULT Online Access. Elsevier Health Sciences. ISBN 978-1455711819.
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