© 1995 American Heart Association, Inc.
Articles |
Relationship Between Intracellular Calcium and Contractile Force in Stunned Myocardium
Direct Evidence for Decreased Myofilament Ca2+ Responsiveness and Altered Diastolic Function in Intact Ventricular Muscle
From the Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Md, and the Centre for Cardiovascular Research (P.H.B.), University of Toronto (Canada).
Correspondence to Eduardo Marban, MD, PhD, Room 844, Ross Bldg, 720 Rutland Ave, Baltimore, MD 21205.
Abstract To elucidate the abnormalities of excitation-contraction coupling in stunned myocardium, we measured [Ca2+]i and force in thin fura 2–loaded ventricular trabeculae from control or stunned (20 minutes ischemia followed by 20 minutes reflow at 37°C) rat hearts. At any given [Ca2+]o, force development was significantly lower in the stunned trabeculae than in control trabeculae. In contrast, there was no difference in the amplitude of Ca2+ transients between the two groups. The steady state force-[Ca2+]i relationship, assessed by tetanization in the presence of ryanodine, revealed both a decrease in maximal Ca2+-activated force and an increase in the [Ca2+]i required for 50% activation in stunned trabeculae. Postischemic myocardium also exhibited an accelerated rate of diastolic relaxation that was not due to changes in the rate of Ca2+ transient decay. Destabilization of attached cross-bridges in a quantitative model of cardiac myofibrils accurately reproduced the salient systolic and diastolic features of the stunned phenotype, suggesting an abnormality of the thin filaments. In response to supraphysiological increases in [Ca2+]o, diastolic [Ca2+]i and diastolic tone increased much more in stunned trabeculae than in controls, with the frequent occurrence of aftercontractions. This novel experimental model lends further support to the hypothesis that the primary lesion of excitation-contraction coupling resides at the level of the contractile proteins. The finding of enhanced susceptibility to calcium overload helps to rationalize the functional deterioration of stunned myocardium during intense inotropic stimulation and additionally suggests that stunned myocardium may represent a favorable substrate for triggered arrhythmias.
Key Words: intracellular calcium • myofilament Ca2+ sensitivity • myocardial ischemia/reperfusion • diastolic relaxation • aftercontraction
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W. D. Gao, Y. Liu, and E. Marban Selective Effects of Oxygen Free Radicals on Excitation-Contraction Coupling in Ventricular Muscle: Implications for the Mechanism of Stunned Myocardium Circulation, November 15, 1996; 94(10): 2597 - 2604. [Abstract] [Full Text]
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Y. Matsumura, E. Saeki, M. Inoue, M. Hori, T. Kamada, and H. Kusuoka Inhomogeneous Disappearance of Myofilament-Related Cytoskeletal Proteins in Stunned Myocardium of Guinea Pig Circ. Res., September 1, 1996; 79(3): 447 - 454. [Abstract] [Full Text]
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G. Heusch, J. Rose, A. Skyschally, H. Post, and R. Schulz Calcium Responsiveness in Regional Myocardial Short-term Hibernation and Stunning in the In Situ Porcine Heart : Inotropic Responses to Postextrasystolic Potentiation and Intracoronary Calcium Circulation, April 15, 1996; 93(8): 1556 - 1566. [Abstract] [Full Text]
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W. Dong Gao, Y. Liu, R. Mellgren, and E. Marban Intrinsic Myofilament Alterations Underlying the Decreased Contractility of Stunned Myocardium : A Consequence of Ca2+-Dependent Proteolysis? Circ. Res., March 1, 1996; 78(3): 455 - 465. [Abstract] [Full Text]
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M. Jane Lalli, J. Yong, V. Prasad, K. Hashimoto, D. Plank, G. J. Babu, D. Kirkpatrick, R. A. Walsh, M. Sussman, A. Yatani, et al. Sarcoplasmic Reticulum Ca2+ ATPase (SERCA) 1a Structurally Substitutes for SERCA2a in the Cardiac Sarcoplasmic Reticulum and Increases Cardiac Ca2+ Handling Capacity Circ. Res., July 20, 2001; 89(2): 160 - 167. [Abstract] [Full Text] [PDF]
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S.-J. Kim, R. K. Kudej, A. Yatani, Y.-K. Kim, G. Takagi, R. Honda, D. A. Colantonio, J. E. Van Eyk, D. E. Vatner, R. L. Rasmusson, et al. A Novel Mechanism for Myocardial Stunning Involving Impaired Ca2+ Handling Circ. Res., October 26, 2001; 89(9): 831 - 837. [Abstract] [Full Text] [PDF]
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