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P~2T/r
Significance:
facilitates cardiac ejection increases cardiac mechanical efficiency at smaller volumes but contributes to mechanical impairment in dilated hearts
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
Cardiac Muscle Response to Stretch: F-S effect not based on increased free cytosolic Ca2+
"... 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 ()
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.
Frank-Starling
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.
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
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.
Cardiac Cellular Force-Length Relation: pre-load independent over length range studied.
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
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
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
Mechanisms
TnC C 2+ Sensitivity C Ca Se s v y
AP
Ca2+ influx
CICR
[Ca2+]
TnC-Ca2+ [Ca2+]
Contraction Relaxation
1) Stretch
2)
Contractility
2.3 m
1.9 m
pCa = 6 pCa = 5
Mechanisms
g p y Ca2+ & Crossbridge Cooperativity
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:
Lattice Spacing:
Lattice Spacing:
Lattice Spacing:
Dextran
lateral compression
Lattice Spacing:
However: 3% dextran at 1 95 m 1.95 Causes much larger lattice compression than stretch to 2.25 m
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.
Mechanisms
Other Candidates
Mechanisms
( p) (Filament Overlap) TnC Ca2+ Sensitivity Ca2+ / Crossbridge Cooperativity Lattice Spacing (Other Candidates)
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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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