The Frank Starling Law

8/3/2019 The Frank Starling Law

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The Frank Starling Law

Peter Kohl, MD, PhD

The Cardiac Mechano-Electric Feedback Lab, ULP Oxford

Mammalian Circulatory System:

LVLA

RV RA

- Drive flow (i.e. create pressure difference) - Direct flow

- Match input and output (each side) - Match outputs of both sides

- Cope with volume loading effects on pressure generation (Laplace)

Biophysic s of pressure generation in

P ~ 2 T / r

Significance: facilitates cardiac

increases cardiac

but contributes to

Cardiac Muscle Response to Stretch:

Stretch instantaneous inc followed by slow i


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Cardiac Muscle Response to Stretch: F-S effect not based on increased free cytosolic Ca2+

3 () & 4 () 4 () & 5 ()

Kentish JC, Wrzosek A. J Physiol 1998/506:431-444.

Frank-Starling

Starling (dog, 1914)Frank (frog, 1895)

Experiments carried out in this laboratory have shown that in an

isolated heart [] (within physiological limits)

the larger the diastolic volume []

the greater is the energy of its contraction.

EH Starling & MB Visscher. The regulation of the energy output of the heart. J Physiol 1926/62:243-261.

The Frank-Starling Law?

"... a strong heart that is filled

completely, in other words, [filli

extent of c

Carl F.W. Ludwig CFW. Lehrbuch der Physiol

18

The Frank-Starling Relationsh

century

AM Katz. Ernest Henry Starling, His Pre

2002

Curve is read from right to left. Effect of step-wise red(H) pressures and force of contraction. Recording by H

Otto Franks Set-up:

Otto Frank: Die Grundform


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Ernest Starlings Set-up:

AfterEH Starling & MB Visscher. The regulation of the energy output of the heart. J Physiol 1926/62:243-261.

IMPORTANCE

Phases of the Cardiac Cycle:

P

80

120

v50 120

Cardiac Length-Tension Relation (afte

Maxima of

afterloaded

contractions

Sagawa K, Lie RK & Schaefer J. Trans

arteriellen Pulses. J Mol Cell Cardiol1


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Cardiac Length-Tension Relation:

2 < 12 1

Cardiac Length-Tension Relation: load-dependent or not?

e.g. Frog Most Mammals

Cardiac Cellular Force-Length Relation: p

2

4

6

8

10

2

4

6

8

10

-2

0

87 89 9

SL = 1.9-2

0

64 66 68 70 72 74

SL = 1.903 m 1.970 m

Cardiac Cellular Force-Length Relation: M

force

ES

length


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Mechanisms

Filament Overla ?

Myofilament overlap IS NOT THE principal determinant of maximum cross-bridge formation.

Active tension is proportional to number of active cross-bridges.

In Cardiac Muscle:

Heart Skeletal Muscle

Passive Tension

Bers DM. Kluwer Academic Publishers 2002: p.27.

In Cardiac Muscle:

Passive tension determined by ext

Passive tension in phy

In Cardiac Muscle:

Large differences b

Modulated by p


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Titin Structural Arrangement:

Granzier HL & Labeit S. Circ Res 2004/94:284-95.

Titin = Stretch AND Compression Spring:

Helmes M, Trombits K, Granzier H.

Circ Res 1996/79:619-626.

Reviewed in Granzier HL & Labeit S.

Circ Res 2004/94:284-95.

Mec

TnC Ca

Regulation of Cardiac Contraction: No

AP Ca2+ influx CICRCa2+ extrusion (N

1) Stretch


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SL Affects Ca2+ affinity: rat skinned trabaeculum

Hibberd MG & Jewell BR. J Physiol 1982/329:527-40.

Length-Dependent TnC-Ca2+ Binding: rat skinned trabaeculum

Allen DG & Kurihara S. Journal of Physiology 1982/327:79-94.

quick length reduction (10%) increased free [Ca2+]I (aequorin fluorescence)

SL Affects TnC-Ca2+ affinity:

[Ca2+] 1 M = 10-6M pCa = 6[Ca2+] 10 M = 10-5M pCa = 5

Mec

Ca2+ & Crossb


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Cooperativity:

Ca2+ binding and formation of crossbridge shift of tropomyosinincreases probability of downstream crossbridge formation

Helmes M & Kohl P. Lecture Notes on Human Physiology (5th ed). Ed Ole Petersen; Blackwell Publishing 2007, p.364.

Cooperativity: rat skinned trabaeculum

Note sigmoidal shape of curv es and stretch-induced increase in peak force.

Kentish JC et al. Circulation Research 1986/58:755768.

Mec

Latti

Lattice Spacing:


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Lattice Spacing:

Dextran lateral compressionmimics stretch effectsrat skinned trabaeculum

SL:

1.95 m2.10 m

2.25 m 3% dextran at 1.95 mcauses similar

Ca2+ sensitisation

as stretch t o 2.25 m

Konhilas JP, Irving TC & de Tombe PP. Circ Res 2002/90:59-65.

Lattice Spacing:

However:

rat skinned trabaeculum

. Causes much larger

lattice compression

than stretch to 2.25 m

Konhilas JP, Irving TC & de Tombe PP.Circ Res 2002/90:59-65.

Lattice Spacing:

Fukuda N, Sasa

Stretch and dextran induce match

Lattice Spacing: Role for Titin?

Fukuda N, Sasa

Partial digestion of


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Lattice Spacing: Role for Titin mouse skinned cardiomyocytes

Cazorla O et al. Circ Res 2001/88:1028-1035.

Mechanisms

Other Candidates

Other Candidates:

1) Stretch-induced increase in tota

Stretch activation of iCa,LNa+ influx via SAC with kn

Ca2+preservation via incre

2) Stretch-induced increase in SR C

3) Slow stretch-effects on Ca2+(pa

Believed to be largely t

Stretch-sensitivity of SR Ca2+ relea

termination of [Ca2+] transient as sh

Mec

Filame

TnC Ca

Ca2+/ Crossbr

Latti

(Other


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Frank Starling Reading List

Reviews:

Sagawa K, Lie RK & Schaefer J. Translation of Otto Frank's paper "Die Grundform des arteriellen Pulses"Zeitschrift fr Biologie 37: 483-526 (1899). Journal of Molecular and Cellular Cardiology 1990/22, 253-277.

Katz AM. Ernest Henry Starling, His Predecessors, and the "Law of the Heart. Circulation 2002/106:2986-2992.

Zimmer H-G. Who discovered the Frank-Starling Mechanism? News in Physiological Sciences 2002/17:181-184.

Moss RL & Fitzsimons DP. Frank-Starling relationship: long on importance, short on mechanism. Circ Res2002/90:11-13.

Shiels HA, White E. The Frank-Starling mechanism in vertebrate cardiac myocytes. J Exp Biol 2008/211:2005-2013.

Sarcomere length: Gordon AM, Huxley AF, Julian FJ. The variation in isometric tension with sarcomere length in vertebrate

muscle fibres. J Physiol 1966/184:170-192.

Moss RL & Buck HS. Regulation of cardiac contraction by Ca2+. In: Handbook of Physiology. Page E,Fozzard HA, Solaro RJ (eds.). Oxford University Press 2001.

Stelzer JE, Moss RL. Contributions of stretch activation to length-dependent contraction in murine myocardium.J Gen Physiol 2006/128:461-471.

TnC sensitivity:

Hibberd MG & Jewell BR. Calcium- and length-dependent force production in rat ventricular muscle. J Physiol.1982/329:527-40.

Allen DG & Kurihara S. The effect of muscle length on intracellular calcium transients in mammalian cardiacmuscle. Journal of Physiology 1982/327, 79-94. Allen DG & Kentish JC. The cellular basis for length-tension relation in cardiac muscle. J Mol Cell Cardiol

1985/17: 821840

Kentish JC, ter Keurs HEDJ, Ricciardi L, Bucx JJJ & Noble MIM. Comparison between the sarcomere length-force relations of intact and skinned trabeculae from right ventricle: influence of calcium concentrations onthese relations. Circ Res 1986/58:755768.

Babu A, Scordilis SP, Sonnenblick EH & Gulati J. The control of myocardial contraction with skeletal fastmuscle troponin C. J Biol Chem. 1987/262:5815-22

Terui T, Sodnomtseren M, Matsuba D, Udaka J, Ishiwata S, Ohtsuki I, Kurihara S, Fukuda N. Troponin andtitin coordinately regulate length-dependent activation in skinned porcine ventricular muscle. J Gen Physiol

2008/131:275-283.

Cooperativity:

Geeves MA & Lehrer SS. Dynamics of the muscle thin filament regulatory switch: the size of the cooperativeunit. Biophys J 1994/67:273-82.

Fitzsimons DP & Moss RL. Strong Binding of Myosin Modulates Length-Dependent Ca2+ Activation of RatVentricular Myocytes. Circ Res1998/83:602 - 607.

Dobesh DP, Konhilas JP & de Tombe PP. Cooperative activation in cardiac muscle: impact of sarcomerelength.Am J Physiol Heart Circ Physiol 2002/282: H1055-H1062.

Bers DM. Excitationcontraction coupling and cardiac force. Kluwer Academic Publishers 2002: p.25.


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Lattice Spacing and Titin:

Fuchs F & Wang YP. Sarcomere length versus interfilament spacing as determinants of cardiac myocilamentCa sensitivity and Ca binding. J Mol Cell Cardiol 1996/28:1375-1383.

Cazorla O, Vassort G, Garnier D & LeGuennec J-Y. Length modulation of active force in rat cardiac myocytes:is titin the sensor? J Mol Cell Cardiol 1999/31:1215-1227.

Cazorla O, Freiburg A, Helmes M, Centner T, McNabb M, Wu Y, Trombitas K, Labeit S & Granzier H.Differential expression of cardiac titin isoforms and modulation of cellular stiffness. Circ Res 2000/86:5967.

Bang ML, Centner T, Fornoff F, Geach AJ, Gotthardt M, McNabb M, Witt CC, Labeit D, Gregorio CC, GranzierH, Labeit S. The complete gene sequence of titin, expression of an unusual approximately 700-kDa titinisoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. Circ Res2001/89:10651072.

Fukuda N, Sasaki D, Ishiwata S & Kurihara S. Length dependence of tension generation in rat skinned cardiacmuscle: role of titin in the Frank-Starling mechanism of the heart. Circulation 2001/104:16391645.

Muhle-Goll C, Habeck M, Cazorla O, Nilges M, Labeit S & Granzier H. Structural and functional studies oftitin's fn3 modules reveal conserved surface patterns and binding to myosin S1--a possible role in the Frank-Starling mechanism of the heart. J Mol Biol 2001/313:431-47.

Bers DM. Cardiac excitationcontraction coupling. Nature 2002/415:198-205. Konhilas JP, Irving TC & de Tombe PP. Myofilament calcium sensitivity in skinned rat cardiac trabeculae: role

of interfilament spacing. Circ Res 2002/90:59-65.

Helmes M, Lim CC, Liao R, Bharti A, Cui L, Sawyer DB. Titin determines the Frank-Starling relation in earlydiastole. J Gen Physiol 2003/121:97-110.

Fukuda N, Wu Y, Farman G, Irving TC & Granzier H. Titin-based modulation of active tension and interfilamentlattice spacing in skinned rat cardiac muscle. Pflgers 2005/449: 449-457

Yagi N, Okuyama H, Toyota H, Araki J, Shimizu J, Iribe G, Nakamura K, Mohri S, Tsujioka K, Suga H & KajiyaF. Sarcomere-length dependence of lattice volume and radial mass transfer of myosin cross-bridges in rat

papillary muscle. Pflgers 2004/448: 153-160 Fukuda N, Granzier HL. Titin/connectin-based modulation of the Frank-Starling mechanism of the heart. J

Muscle Res Cell Motil 2005/26(6-8):319-323.

Pearson JT, Shirai M, Tsuchimochi H, Schwenke DO, Ishida T, Kangawa K, Suga H, Yagi N. Effects ofsustained length-dependent activation on in situ cross-bridge dynamics in rat hearts. Biophys J 2007/93:4319-4329.

Fukuda N, Granzier HL, Ishiwata S, Kurihara S. Physiological functions of the giant elastic protein titin inMammalian striated muscle. J Physiol Sci 2008/58(3):151-159.

Other Potential Mechanisms:

Lakatta EG & Jewell BR. Length-dependent activation: its effect on the length-tension relation in cat ventricularmuscle. Circ Res 1977/40:251-257.

Fabiato A. Sarcomere length dependence of calcium release from the sarcoplasmic reticulum of skinnedcardiac cells demonstrated by differential microspectrophotometry with arsenazo III. J Gen Physiol 1980/76:15.

Allen DG & Kurihara S. The effects of muscle length on intracellular calcium transients in mammalian cardiacmuscle. J Physiol 1982/327:79-94.

Gannier F, White E, Garnier D & Le Guennec J-Y. A possible mechanism for large stretch-induced increase in[Ca2+]i in isolated guinea-pig ventricular myocytes. Cardiovascular Research 1996/32, 158-167.

Kentish JC & Wrzosek A. Changes in force and cytosolic Ca2+ concentration after length changes in isolatedrat ventricular trabeculae. Journal of Physiology 1998/506, 431-444.

Vila-Petroff, M. G., Kim, S. H., Pepe, S., Dessy, C., Marbn, E., Balligand, J.-L. and Sollott, S. J. Endogenousnitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes. Nature Cell

Biology 2001/3, 867-873.


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Calaghan S & White E. Activation of Na+-H+ exchange and stretch-activated channels underlies the slowinotropic response to stretch in myocytes and muscles from the rat heart. J Physiol 2004/559:205-214.

Massion PB, Pelat M, Belge C & Balligand J-L. Regulation of mammalian heart function by nitric oxide.Comparative Biochemistry and Physiology (A) 2005/142:144-150.

Herron TJ, Rostkova E, Kunst G, Chaturvedi R, Gautel M, Kentish JC. Activation of myocardial contraction bythe N-terminal domains of myosin binding protein-C. Circ Res 2006/98(10):1290-1298.

Hidalgo C, Wu Y, Peng J, Siems WF, Campbell KB, Granzier H. Effect of diastolic pressure on MLC2vphosphorylation in the rat left ventricle. Arch Biochem Biophys 2006/456:216-223.

Iribe G & Kohl P. Axial stretch enhances sarcoplasmic reticulum Ca2+ leak and cellular Ca2+ reuptake inGuinea pig ventricular myocytes: experiments and models. Progress in Biophysics and Molecular Biology2008/97:298311.

Iribe G, Ward CW, Camelliti P, Bollensdorff C, Mason F, Burton RAB, Garny A, Morphew M, Hoenger A,Lederer WJ & Kohl P. Axial stretch of rat single ventricular cardiomyocytes causes an acute and transientincrease in Ca2+ spark rate. Circulation Research 2009/104:787-795.

Cannell MB. Pulling on the Heart Strings: A New Mechanism Within Starlings Law of the Heart? CirculationResearch 2009/104:715.

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