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(Circulation. 1995;92:1169-1178.)
© 1995 American Heart Association, Inc.


Articles

Alterations in Intracellular Calcium Handling Associated With the Inverse Force-Frequency Relation in Human Dilated Cardiomyopathy

Burkert Pieske, MD; Bodo Kretschmann, MS; Markus Meyer, MD; Christian Holubarsch, MD; Jörg Weirich, MD; Herbert Posival, MD; Kazatomo Minami, MD; Hanjörg Just, MD; Gerd Hasenfuss, MD

From the Medizinische Klinik III (B.P., B.K., M.M., C.H., H.J., G.H.) and Physiologisches Institut (J.W.), Universität Freiburg, and Klinik für Thorax- und Kardiovaskularchirurgie (H.P., K.M.), Herzzentrum Nordrhein-Westfalen, Bad Oeynhausen, Germany.

Correspondence to Burkert Pieske, MD, Medizinische Klinik III, Universität Freiburg, Hugstetter Str 55, 79106 Freiburg, Germany.

Background The present study was performed to test the hypothesis that the altered force-frequency relation in human failing dilated cardiomyopathy may be attributed to alterations in intracellular calcium handling.

Methods and Results The force-frequency relation was investigated in isometrically contracting ventricular muscle strip preparations from 5 nonfailing human hearts and 7 hearts with end-stage failing dilated cardiomyopathy. Intracellular calcium cycling was measured simultaneously by use of the bioluminescent photoprotein aequorin. Stimulation frequency was increased stepwise from 15 to 180 beats per minute (37°C). In nonfailing myocardium, twitch tension and aequorin light emission rose with increasing rates of stimulation. Maximum average twitch tension was reached at 150 min-1 and was increased to 212±34% (P<.05) of the value at 15 min-1. Aequorin light emission was lowest at 15 min-1 and was maximally increased at 180 min-1 to 218±39% (P<.01). In the failing myocardium, average isometric tension was maximum at 60 min-1 (106±7% of the basal value at 15 min-1, P=NS) and then decreased continuously to 62±9% of the basal value at 180 min-1 (P<.002). In the failing myocardium, aequorin light emission was highest at 15 min-1. At 180 min-1, it was decreased to 71±7% of the basal value (P<.01). Including both failing and nonfailing myocardium, there was a close correlation between the frequencies at which aequorin light emission and isometric tension were maximum (r=.92; n=19; P<.001). Action potential duration decreased similarly with increasing stimulation frequencies in nonfailing and end-stage failing myocardium. Sarcoplasmic reticulum 45Ca2+ uptake, measured in homogenates from the same hearts, was significantly reduced in failing myocardium (3.60±0.51 versus 1.94±0.18 (nmol/L) · min-1 · mg protein-1, P<.005).

Conclusions These data indicate that the altered force-frequency relation of the failing human myocardium results from disturbed excitation-contraction coupling with decreased calcium cycling at higher rates of stimulation.


Key Words: aequorin • excitation • contraction • sarcoplasmic reticulum • heart failure




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Eur J Heart Fail, June 1, 1999; 1(2): 177 - 186.
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Am. J. Physiol. Heart Circ. Physiol.Home page
Y. Murakami, J. Zhang, M. H. J. Eijgelshoven, W. Chen, W. C. Carlyle, Y. Zhang, G. Gong, and R. J. Bache
Myocardial creatine kinase kinetics in hearts with postinfarction left ventricular remodeling
Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H892 - H900.
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CirculationHome page
S. R. Houser and E. G. Lakatta
Function of the Cardiac Myocyte in the Conundrum of End-Stage, Dilated Human Heart Failure
Circulation, February 9, 1999; 99(5): 600 - 604.
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CirculationHome page
G. Hasenfuss, W. Schillinger, S. E. Lehnart, M. Preuss, B. Pieske, L. S. Maier, J. Prestle, K. Minami, and H. Just
Relationship Between Na+-Ca2+–Exchanger Protein Levels and Diastolic Function of Failing Human Myocardium
Circulation, February 9, 1999; 99(5): 641 - 648.
[Abstract] [Full Text] [PDF]


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CirculationHome page
M. Anger, A.-M. Lompre, O. Vallot, F. Marotte, L. Rappaport, and J.-L. S. MD
Cellular Distribution of Ca2+ Pumps and Ca2+ Release Channels in Rat Cardiac Hypertrophy Induced by Aortic Stenosis
Circulation, December 1, 1998; 98(22): 2477 - 2486.
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Cardiovasc ResHome page
S. D. Prabhu
Ryanodine and the left ventricular force-interval and relaxation-interval relations in closed-chest dogs: insights on calcium handling
Cardiovasc Res, December 1, 1998; 40(3): 483 - 491.
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CirculationHome page
G. Hasenfuss, B. Pieske, M. Castell, B. Kretschmann, L. S. Maier, and H. Just
Influence of the Novel Inotropic Agent Levosimendan on Isometric Tension and Calcium Cycling in Failing Human Myocardium
Circulation, November 17, 1998; 98(20): 2141 - 2147.
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Circ. Res.Home page
G. Hasenfuss
Calcium Pump Overexpression and Myocardial Function : Implications for Gene Therapy of Myocardial Failure
Circ. Res., November 2, 1998; 83(9): 966 - 968.
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Cardiovasc ResHome page
C Mittmann, T Eschenhagen, and H Scholz
Cellular and molecular aspects of contractile dysfunction in heart failure
Cardiovasc Res, August 1, 1998; 39(2): 267 - 275.
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Cardiovasc ResHome page
G. Hasenfuss
Animal models of human cardiovascular disease, heart failure and hypertrophy
Cardiovasc Res, July 1, 1998; 39(1): 60 - 76.
[Abstract] [Full Text] [PDF]


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CirculationHome page
K. Dipla, J. A. Mattiello, V. Jeevanandam, S. R. Houser, and K. B. Margulies
Myocyte Recovery After Mechanical Circulatory Support in Humans With End-Stage Heart Failure
Circulation, June 16, 1998; 97(23): 2316 - 2322.
[Abstract] [Full Text] [PDF]


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CirculationHome page
L. R. C. Dekker, H. Rademaker, J. T. Vermeulen, T. Opthof, R. Coronel, J. A. E. Spaan, and M. J. Janse
Cellular Uncoupling During Ischemia in Hypertrophied and Failing Rabbit Ventricular Myocardium : Effects of Preconditioning
Circulation, May 5, 1998; 97(17): 1724 - 1730.
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Am. J. Physiol. Heart Circ. Physiol.Home page
L. S. Maier, R. Brandes, B. Pieske, and D. M. Bers
Effects of left ventricular hypertrophy on force and Ca2+ handling in isolated rat myocardium
Am J Physiol Heart Circ Physiol, April 1, 1998; 274(4): H1361 - H1370.
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Cardiovasc ResHome page
G. Hasenfuss
Alterations of calcium-regulatory proteins in heart failure
Cardiovasc Res, February 1, 1998; 37(2): 279 - 289.
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Cardiovasc ResHome page
C.W. Balke and S. R. Shorofsky
Alterations in calcium handling in cardiac hypertrophy and heart failure
Cardiovasc Res, February 1, 1998; 37(2): 290 - 299.
[Abstract] [Full Text] [PDF]


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Cardiovasc ResHome page
S. Richard, F. Leclercq, S. Lemaire, C. Piot, and J. Nargeot
Ca2+ currents in compensated hypertrophy and heart failure
Cardiovasc Res, February 1, 1998; 37(2): 300 - 311.
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Cardiovasc ResHome page
A. D Wickenden, R. Kaprielian, Z. Kassiri, J. N Tsoporis, R. Tsushima, G. I Fishman, and P. H Backx
The role of action potential prolongation and altered intracellular calcium handling in the pathogenesis of heart failure
Cardiovasc Res, February 1, 1998; 37(2): 312 - 323.
[Abstract] [Full Text] [PDF]


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Cardiovasc ResHome page
R. M Phillips, P. Narayan, A. M Gomez, K. Dilly, L. R Jones, W.J. Lederer, and R. A Altschuld
Sarcoplasmic reticulum in heart failure: central player or bystander?
Cardiovasc Res, February 1, 1998; 37(2): 346 - 351.
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Cardiovasc ResHome page
M. A Movsesian and R. H.G Schwinger
Calcium sequestration by the sarcoplasmic reticulum in heart failure
Cardiovasc Res, February 1, 1998; 37(2): 352 - 359.
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M. Meyer and W. H Dillmann
Sarcoplasmic reticulum Ca2+-ATPase overexpression by adenovirus mediated gene transfer and in transgenic mice
Cardiovasc Res, February 1, 1998; 37(2): 360 - 366.
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Cardiovasc ResHome page
P. P de Tombe
Altered contractile function in heart failure
Cardiovasc Res, February 1, 1998; 37(2): 367 - 380.
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Cardiovasc ResHome page
M. C. Schaub, M. A. Hefti, R. A. Zuellig, and I. Morano
Modulation of contractility in human cardiac hypertrophy by myosin essential light chain isoforms
Cardiovasc Res, February 1, 1998; 37(2): 381 - 404.
[Abstract] [Full Text] [PDF]


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Cardiovasc ResHome page
T. Neumann, U. Ravens, and G. Heusch
Characterization of excitation-contraction coupling in conscious dogs with pacing-induced heart failure
Cardiovasc Res, February 1, 1998; 37(2): 456 - 466.
[Abstract] [Full Text] [PDF]


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Cardiovasc ResHome page
K. R Sipido, T. Stankovicova, W. Flameng, J. Vanhaecke, and F. Verdonck
Frequency dependence of Ca2+ release from the sarcoplasmic reticulum in human ventricular myocytes from end-stage heart failure
Cardiovasc Res, February 1, 1998; 37(2): 478 - 488.
[Abstract] [Full Text] [PDF]


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Cardiovasc ResHome page
C. Holubarsch, J Ludemann, S Wiessner, T. Ruf, H Schulte-Baukloh, S Schmidt-Schweda, B Pieske, H Posival, and H Just
Shortening versus isometric contractions in isolated human failing and non-failing left ventricular myocardium: dependency of external work and force on muscle length, heart rate and inotropic stimulation
Cardiovasc Res, January 1, 1998; 37(1): 46 - 57.
[Abstract] [Full Text] [PDF]


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Cardiovasc ResHome page
M. Pauschinger, A. Doerner, A. Remppis, R. Tannhauser, U. Kuhl, and H.-P. Schultheiss
Differential myocardial abundance of collagen type I and type III mRNA in dilated cardiomyopathy: effects of myocardial inflammation
Cardiovasc Res, January 1, 1998; 37(1): 123 - 129.
[Abstract] [Full Text] [PDF]


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CirculationHome page
F. G. Spinale, R. Mukherjee, J. P. Iannini, S. Whitebread, L. Hebbar, M. J. Clair, D. M. Melton, M. H. Cox, P. B. Thomas, and P. B. Marc de Gasparo
Modulation of the Renin-Angiotensin Pathway Through Enzyme Inhibition and Specific Receptor Blockade in Pacing-Induced Heart Failure : II. Effects on Myocyte Contractile Processes
Circulation, October 7, 1997; 96(7): 2397 - 2406.
[Abstract] [Full Text]


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J. Pharmacol. Exp. Ther.Home page
R. H. G. Schwinger, K. Brixius, U. Bavendiek, S. Hoischen, J. Müller-Ehmsen, B. Bölck, and E. Erdmann
Effect of Cyclopiazonic Acid on the Force-Frequency Relationship in Human Nonfailing  Myocardium
J. Pharmacol. Exp. Ther., October 1, 1997; 283(1): 286 - 292.
[Abstract] [Full Text]


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J. Appl. Physiol.Home page
K. Brixius, M. Pietsch, S. Hoischen, J. Muller-Ehmsen, and R. H. G. Schwinger
Effect of inotropic interventions on contraction and Ca2+ transients in the human heart
J Appl Physiol, August 1, 1997; 83(2): 652 - 660.
[Abstract] [Full Text] [PDF]


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Cardiovasc ResHome page
K Davia, C.H Davies, and S.E Harding
Effects of inhibition of sarcoplasmic reticulum calcium uptake on contraction in myocytes isolated from failing human ventricle
Cardiovasc Res, January 1, 1997; 33(1): 88 - 97.
[Abstract] [Full Text] [PDF]


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CirculationHome page
G. Hasenfuss, L. A. Mulieri, P. D. Allen, H. Just, and N.R. Alpert
Influence of Isoproterenol and Ouabain on Excitation-Contraction Coupling, Cross-Bridge Function, and Energetics in Failing Human Myocardium
Circulation, December 15, 1996; 94(12): 3155 - 3160.
[Abstract] [Full Text]


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Circ. Res.Home page
S. M. Pogwizd, K. Schlotthauer, L. Li, W. Yuan, and D. M. Bers
Arrhythmogenesis and Contractile Dysfunction in Heart Failure : Roles of Sodium-Calcium Exchange, Inward Rectifier Potassium Current, and Residual {beta}-Adrenergic Responsiveness
Circ. Res., June 8, 2001; 88(11): 1159 - 1167.
[Abstract] [Full Text] [PDF]


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M. Vogel, M. R. Schmidt, S. B. Kristiansen, M. Cheung, P. A. White, K. Sorensen, and A. N. Redington
Validation of Myocardial Acceleration During Isovolumic Contraction as a Novel Noninvasive Index of Right Ventricular Contractility: Comparison With Ventricular Pressure-Volume Relations in an Animal Model
Circulation, April 9, 2002; 105(14): 1693 - 1699.
[Abstract] [Full Text] [PDF]