Biophysics of pressure generation in a hollow sphere: the Law of Laplace:

P~2T/r

The Frank Starling Law

Peter Kohl, MD, PhD

The Cardiac Mechano-Electric Feedback Lab, ULP Oxford

Significance:

facilitates cardiac ejection increases cardiac mechanical efficiency at smaller volumes but contributes to mechanical impairment in dilated hearts

Mammalian Circulatory System:

Cardiac Muscle Response to Stretch:

LA

LV

RV
Challenges:

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)

Stretch

instantaneous increase in contractility (F-S) followed by slow increase

Calaghan S Physiology News 2002.

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

The Frank-Starling Law?

"... a strong heart that is filled with blood empties itself more or less completely, in other words, [filling of the heart with blood] changes the extent of contractile power."
Carl F.W. Ludwig CFW. Lehrbuch der Physiologie des Menschen. Vol 2. Lepzig, Germany: CF Winter; g y g p g y 18521856:p.73.

The Frank-Starling Relationship was widely appreciated by late 19th century physiologists."
AM Katz. Ernest Henry Starling, His Predecessors, and the "Law of the Heart. Circulation 2002/106:2986-2992

3 () & 4 ()

4 () & 5 ()

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

Curve is read from right to left. Effect of step-wise reduction in reservoir height (h) on diastolic (H) pressures and force of contraction. Recording by H.P. Bowditch, Carl Ludwig Lab.

Coats (frog, 1869)

Frank-Starling

Otto Franks Set-up:

Frank (frog, 1895)

Starling (dog, 1914)

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.
Otto Frank: Die Grundform des arteriellen Pulses. Zeitschrift fr Biologie 1899/37:483-526.

Ernest Starlings Set-up:

Phases of the Cardiac Cycle:

P
120 80

50

120

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

IMPORTANCE

Maxima of afterloaded contractions t ti

Sagawa K, Lie RK & Schaefer J. Translation of Otto Frank's paper "Die Grundform des arteriellen Pulses. J Mol Cell Cardiol 1990/22, 253-277.

S Schmidt & Thews: Human Phy ysiology (Springer Verlag).

Cardiac Length-Tension Relation (after Otto Frank):

Boron & Boulpaep

Cardiac Length-Tension Relation:

Cardiac Cellular Force-Length Relation: pre-load independent over length range studied.

guinea pig INTACT cardiomyocytes

12

10

10

10

2 < 1

0 64 66 68 70 72 74

0 87 89 91 93 95 97

0 64 -2 66 68 70 72 74 76

-2

SL = 1.903 m

1.970 m

-2

SL = 1.933 m 1.951 m 1.973 m

1.970 m SL = 1.903 m 1.925 m 2.005 m

Iribe, Helmes & Kohl Am J Physiol 2007/292:1487-1497.

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

Cardiac Cellular Force-Length Relation: Myocyte = magic spring.

Systole = Total Force

ES

Magic spring !
force

ED length

e.g. Frog

Most Mammals

In Cardiac Muscle:

Mechanisms
Filament Overlap? e Ove p?

Passive tension determined by extra-cellular collagen and intra-cellular titin. Passive tension in physiological range: 80% titin; 20% collagen.

Bovine LV

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

In Cardiac Muscle:

In Cardiac Muscle:

Active tension is proportional to number of active cross-bridges. Myofilament overlap IS NOT THE principal determinant of maximum cross-bridge formation.

Large differences by species and titin isoform. Modulated by phosphorylation and Ca2+.

Heart

Skeletal Muscle

Passive Tension

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

Shiels HA, White E. J Exp Biol 2008/211:2005-2013.

Titin Structural Arrangement:

Mechanisms
TnC C 2+ Sensitivity C Ca Se s v y

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

Titin = Stretch AND Compression Spring:

Regulation of Cardiac Contraction:

No overlap mechanism! No recruitment! No spatial potentiation! No temporal potentiation!

AP

Ca2+ influx

CICR

[Ca2+]

TnC-Ca2+ [Ca2+]

Contraction Relaxation

Ca2+ extrusion (NCX, SR)

1) Stretch

2)

Contractility

use skinned cells

Helmes M, Trombits K, Granzier H. Circ Res 1996/79:619-626. Reviewed in Granzier HL & Labeit S. Circ Res 2004/94:284-95.

Bers DM. Nature 2002/415:198-205.

SL Affects Ca2+ affinity:

rat skinned trabaeculum

SL Affects TnC-Ca2+ affinity:

Rat skinned cardiac myocyte

2.3 m

1.9 m

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

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

pCa = 6 pCa = 5

Cazorla et al. JMCC 1999/31:1215-1227.

Length-Dependent TnC-Ca2+ Binding:

rat skinned trabaeculum

Mechanisms
g p y Ca2+ & Crossbridge Cooperativity

quick length reduction (10%)

increased free [Ca2+]I (aequorin fluorescence)

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

Cooperativity:

Ca2+ binding and formation of crossbridge shift of tropomyosin increases probability of downstream crossbridge formation

Mechanisms
Lattice Spacing ce Sp c g

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

Cooperativity:

rat skinned trabaeculum

Lattice Spacing:

rat skinned trabaeculum

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

contractile apparatus: constant volume stretch reduction in lateral dimensions (mimicked by dextran application)

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

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

Lattice Spacing:

rat skinned trabaeculum

Lattice Spacing:

rat skinned trabaeculum

Dextran

lateral compression

mimics stretch effects

SL: 1.95 m 2.10 m 2.25 m

3% dextran at 1.95 m causes similar Ca2+ sensitisation m as stretch to 2.25

Stretch and dextran induce matching effects (normalised to lattice spacing).

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

Fukuda N, Sasaki D, Ishiwata S & Kurihara S. Circulation 2001/104:16391645.

Lattice Spacing:

rat skinned trabaeculum

Lattice Spacing: Role for Titin?

rat skinned trabaeculum

However: 3% dextran at 1 95 m 1.95 Causes much larger lattice compression than stretch to 2.25 m

Partial digestion of titin reduces stretch response.

Konhilas JP, Irving TC & de Tombe PP. Circ Res 2002/90:59-65. Fukuda N, Sasaki D, Ishiwata S & Kurihara S. Circulation 2001/104:16391645.

Lattice Spacing: Role for Titin

mouse skinned cardiomyocytes

Other Candidates:

1) Stretch-induced increase in total intracellular [Ca2+] balance Stretch activation of iCa,L Na+ influx via SAC with knock-on effects on iNCX Ca2+ preservation via increased SR re-uptake 2) Stretch-induced increase in SR Ca2+ release 3) Slow stretch-effects on Ca2+ (partially) mediated via NO

MechanoElectric Feedback

Fabiato 1980; Allen & Kurihara 1982. Iribe et al. 2009. Vila-Petroff 2001; Massion 2005.

Believed to be largely too slow, or too small, to matter! However:

Stretch-sensitivity of SR Ca2+ release may be relevant for termination of [Ca2+] transient as shortening proceeds
Cazorla O et al. Circ Res 2001/88:1028-1035.

Iribe et al. 2009. Cannell 2009.

Mechanisms
Other Candidates

Mechanisms
( p) (Filament Overlap) TnC Ca2+ Sensitivity Ca2+ / Crossbridge Cooperativity Lattice Spacing (Other Candidates)

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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 2002/106:29862992. Zimmer H-G. Who discovered the Frank-Starling Mechanism? News in Physiological Sciences 2002/17:181184. Moss RL & Fitzsimons DP. Frank-Starling relationship: long on importance, short on mechanism. Circ Res 2002/90:11-13. Shiels HA, White E. The Frank-Starling mechanism in vertebrate cardiac myocytes. J Exp Biol 2008/211:20052013. 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 cardiac muscle. 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 lengthforce relations of intact and skinned trabeculae from right ventricle: influence of calcium concentrations on these relations. Circ Res 1986/58:755768. Babu A, Scordilis SP, Sonnenblick EH & Gulati J. The control of myocardial contraction with skeletal fast muscle 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 and titin 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 cooperative unit. Biophys J 1994/67:273-82. Fitzsimons DP & Moss RL. Strong Binding of Myosin Modulates Length-Dependent Ca2+ Activation of Rat Ventricular Myocytes. Circ Res1998/83:602 - 607. Dobesh DP, Konhilas JP & de Tombe PP. Cooperative activation in cardiac muscle: impact of sarcomere length. 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 myocilament Ca 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, Granzier H, Labeit S. The complete gene sequence of titin, expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. Circ Res 2001/89:10651072. Fukuda N, Sasaki D, Ishiwata S & Kurihara S. Length dependence of tension generation in rat skinned cardiac muscle: 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 of titin's fn3 modules reveal conserved surface patterns and binding to myosin S1--a possible role in the FrankStarling 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 early diastole. J Gen Physiol 2003/121:97-110. Fukuda N, Wu Y, Farman G, Irving TC & Granzier H. Titin-based modulation of active tension and interfilament lattice 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 & Kajiya F. 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 of sustained length-dependent activation on in situ cross-bridge dynamics in rat hearts. Biophys J 2007/93:43194329. Fukuda N, Granzier HL, Ishiwata S, Kurihara S. Physiological functions of the giant elastic protein titin in Mammalian 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 ventricular muscle. Circ Res 1977/40:251-257. Fabiato A. Sarcomere length dependence of calcium release from the sarcoplasmic reticulum of skinned cardiac 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 cardiac muscle. 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 isolated rat 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. Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes. Nature Cell Biology 2001/3, 867-873. 15

Calaghan S & White E. Activation of Na+-H+ exchange and stretch-activated channels underlies the slow inotropic 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 by the 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 MLC2v phosphorylation 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 in Guinea pig ventricular myocytes: experiments and models. Progress in Biophysics and Molecular Biology 2008/97:298311. 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 transient increase 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? Circulation Research 2009/104:715.

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