Abstract
The syndrome of congestive heart failure (CHF) is an entity of ever increasing clinical significance. CHF is characterized by a steady decrease in cardiac pump function, which is eventually lethal. The mechanisms that underlie the decline in cardiac function are incompletely understood. A central theme in solving the mystery of heart failure is the identification of mechanisms by which the myofilament contractile machine of the myocardium is altered in CHF and how these alterations act in concert with pathways that signal cell growth and death. The cardiac myofilaments are a point of confluence of signals that promote the hypertrophic/failure process. Our hypothesis is that a prevailing hemodynamic stress leads to an increased strain on the myocardium. The increased strain in turn leads to miscues of the normal physiological pathway by which heart cells are signaled to match and adapt the intensity and dynamics of their mechanical activity to prevailing hemodynamic demands. These miscues result in a maladaptation to the stressor and failure of the heart to respond to hemodynamic loads at optimal end diastolic volumes. The result is a vicious cycle exacerbating the failure. Cardiac myofilament activity, the ultimate determinant of cellular dynamics and force, is a central player in the integration and regulation of pathways that signal hypertrophy and failure. © 2000 Biomedical Engineering Society.
PAC00: 8719Hh, 8719Ff, 8719Xx, 8719Rr, 8717-d
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REFERENCES
Alpert, N. R. Myocardial Hypertrophy and Failure. New York: Raven, 1983.
Alpert, N. R., and M. S. Gordon. Myofibrillar adenosine triphosphatase activity in congestive heart failure. Am. J. Physiol. 202:940-946, 1962.
Alvarez, B. V., N. G. Perez, I. L. Ennis, M. C. Camilion de Hurtado, and H. E. Cingolani. Mechanisms underlying the increase in force and Ca(2+) transient that follow stretch of cardiac muscle: a possible explanation of the Anrep effect. Circ. Res. 85:716-22, 1999.
Anderson, P. A. W., A. Greig, T. M. Mark, N. N. Malouf, A. E. Oakeley, R. M. Ungerleider, P. D. Allen, and B. K. Kay. Molecular basis of human cardiac troponin T isoforms expressed in the developing, adult, and failing heart. Circ. Res. 76:681-686, 1995.
Anderson, P. A. W., N. N. Malouf, A. E. Oakeley, E. D. Pagani, and P. D. Allen. Troponin-T isoform expression in humans. A comparison among normal and failing adult heart, fetal heart, and adult and fetal skeletal muscle. Circ. Res. 69:1226-1233, 1991.
Ball, K. L., M. D. Johnson, and R. J. Solaro. Isoform specific interactions of troponin I and troponin C determine pH sensitivity of myofibrillar Ca2+ activation. Biochemistry 33:8464-8471, 1994.
Barinaga, M. Tracking down mutations that can stop the heart. Science 281:32-34, 1998.
Bartel, S., B. Stein, T. Eschenhagen, U. Mende, J. Neumann, W. Schmitz, E. G. Krause, P. Karczewski, and H. Scholz. Protein phosphorylation in isolated trabeculae from nonfailing and failing human hearts.Mol. Cell. Biochem. 157:171-179, 1996.
Blaufarb, I. S., and E. H. Sonnenblick. The reninangiotensin system in left ventricular remodeling. Am. J. Cardiol. 77:8C-16C, 1996.
Bodor, G. S., A. E. Oakeley, P. D. Allen, D. L. Crimmins, J. H. Ladenson, and P. A. Anderson. Troponin I phosphorylation in the normal and failing adult human heart. Circulation. 96:1495-1500, 1997.
Bowman, J. C., S. F. Steinberg, T. Jiang, D. L. Geenen, G. I. Fishman, and P. M. Buttrick. Expression of protein kinase C beta in the heart causes hypertrophy in adult mice and sudden death in neonates. J. Clin. Invest. 100:2189-2195, 1997.
Brady, A. J. Mechanical properties of isolated cardiac myocytes. Physiol. Rev. 71:413-428, 1991.
Cingolani, H. E., B. V. Alvarez, I. L. Ennis, and M. C. Camilion de Hurtado. Stretch-induced alkalinization of feline papillary muscle: an autocrine-paracrine system. Circ. Res. 83:775-778, 1998.
CONSENSUS. Effects enalapril on mortality in severe congestive heart failure. N. Engl. J. Med. 316:1429-1435, 1987.
D'Agnolo, A., G. B. Luciani, A. Mazzucco, V. Gallucci, and G. Salviati. Contractile properties and Ca2+ release activity of the sarcoplasmic reticulum in dilated cardiomyopathy. Circulation 85:518-525, 1992.
D'Angelo, D. D., Y. Sakata, J. N. Lorenz, G. P. Boivin, R. A. Walsh, S. B. Liggett, and G. W. Dorn, 2nd. Transgenic Galphaq overexpression induces cardiac contractile failure in mice. Proc. Natl. Acad. Sci. U.S.A. 94:8121-8126, 1997.
de Tombe, P. P., and G. J. M. Stienen. Protein kinase A does not alter economy of force maintenance in skinned rat cardiac trabeculae. Circ. Res. 76:734-741, 1995.
de Tombe, P. P., and H. E. D. J. ter Keurs. Lack of effect of isoproterenol on unloaded velocity of sarcomere shortening in rat cardiac trabeculae. Circ. Res. 68:382-391, 1991.
de Tombe, P. P., T. Wannenburg, D. Fan, and W. C. Little. Right ventricular contractile protein function in rats with left ventricular myocardial infarction. Am. J. Physiol. 271:H73-H79, 1996.
Dolmetsch, R. E., R. S. Lewis, C. C. Goodnow, and J. I. Healy. Differential activation of transcription factors induced by Ca 2+ response amplitude and duration. Nature (London) 386:855-858, 1997.
Dolmetsch, R. E., K. Xu, and R. S. Lewis. Calcium oscillations increase the efficiency and specificity of gene expression. Nature (London) 392:933-936, 1998.
Eichhorn, E. J., and M. R. Brostow. Medical therapy can improve the biological properties of the chronically failing heart: a new era in the treatment of heart failure. Circulation 94:2285-2296, 1996.
Fan, D. S., T. Wannenburg, and P. P. de Tombe. Decreased myocyte tension development and calcium responsiviness in rat right ventricular pressure overload. Circulation 95:2312-2317, 1997.
Feldman, M. D., L. Copelas, J. K. Gwathmey, P. Phillips, S. E. Warren, F. J. Schoen, W. Grossman, and J. P. Morgan. Deficient production of cyclic AMP: pharmacologic evidence of and important cause of contractile dysfunction in patients with end-stage heart failure. Circulation 75:331-339, 1987.
Francis, G. S., and J. N. Cohn. Heart failure: Mechanisms of cardiac and vascular dysfunction and the rationale for pharmacologic intervention. FASEB J. 4:3068-3075, 1990.
Geenen, D. L., A. Malhotra, and J. Scheuer. Regional variation in rat cardiac myosin isoenzymes and ATPase activity after infarction. Am. J. Phys. 256:H745-H750, 1989.
Gruver, C. L., F. DeMayo, M. A. Goldstein, and A. R. Means. Targeted developmental overexpression of calmodulin induces proliferative and hypertrophic growth of cardiomyocytes in transgenic mice. Endocrinology 133:376-388, 1993.
Gu, X., and S. P. Bishop. Increased protein kinase C and isozyme redistribution in pressure-overload cardiac hypertrophy in the rat. Circ. Res. 75:926-931, 1994.
Gulati, J., A. B. Akella, S. D. Nikolic, V. Starc, and F. Siri. Shifts in contractile regulatory protein subunits troponin T and troponin I in cardiac hypertrophy. Biochem. Biophys. Res. Commun. 202:384-390, 1994.
Gwathmey, J. K., and R. J. Hajjar. Relation between steady-state force and intracellular [Ca2+] in intact human myocardium. Index of myofibrillar responsiveness to Ca2+. Circulation 82:1266-1278, 1990.
Hajjar, R. J., and J. K. Gwathmey. Cross-bridge dynamics in human ventricular myocardium: Regulation of contractility in the failing heart. Circulation 86:1819-1826, 1992.
Hajjar, R. J., J. X. Kang, J. K. Gwathmey, and A. Rosenzweig. Physiological effects of adenoviral gene transfer of sarcoplasmic reticulum ATPase in isolated rat myocytes. Circulation 95:423-429, 1997.
Hajjar, R. J., U. Schmidt, P. Helm, and J. K. Gwathmey. Ca++ sensitizers impair cardiac relaxation in human myocardium. J. Pharm. Exp. Ther. 280:247-254, 1997.
Hill, A. V. The heat of shortening and the dynamic constants of muscle. Proc. R. Soc. London., Ser. B. 126:1366-1195, 1938.
Hofmann, P. A., and J. H. Lange, III. Effects of phosphorylation of troponin I and C protein on isometric tension and velocity of unloaded shortening in skinned single cardiac myocytes from rats. Circ. Res. 74:718-726, 1994.
Hofmann, P. A., and R. L. Moss. Effects of calcium on shortening velocity in frog chemically skinned atrial myocytes and in mechanically disrupted ventricular myocardium from rat. Circ. Res. 70:885-892, 1992.
Hofmann, P. A., V. Menon, and K. F. Gannaway. Effects of diabetes on isometric tension as a function of [Ca2+] and pH in rat skinned cardiac myocytes. Am. J. Physiol. H269:H1656-H1663, 1995.
Holroyde, M. J., D. A. Small, E. Howe, and R. J. Solaro. Isolation of cardiac myofibrils and myosin light chains with in vivo levels of light chain phosphorylation. Biochim. Biophys. Acta 587:628-637, 1979.
Holubarsch, C., T. Ruf, D. J. Goldstein, R. C. Ashton, W. Nickl, B. Pieske, K. Pioch, J. Ludemann, S. Wiesner, G. Hasenfuss, H. Posival, H. Just, and D. Burkhoff. Existence of the Frank-Starling mechanism in the failing human heart. Investigations on the organ, tissue, and sarcomere levels. Circulation 94:683-689, 1996.
Hunkeler, N. M., J. Kullman, and A. M. Murphy. Troponin-I isoform expression in human heart. Circ. Res. 69:1409-1414, 1991.
Ito, N., Y. Kagaya, E. O. Weinberg, W. H. Barry, and B. H. Lorell. Endothelin and Angiotension-II stimulation of Na+ –H+ exchange is impaired in cardiac hypertrophy. J. Clin. Invest. 99:125-135, 1997.
Janssen, P. M., and P. P. de Tombe. Protein kinase A does not alter unloaded velocity of sarcomere shortening in skinned rat cardiac trabeculae. Am. J. Physiol. 273:H2415-H2422, 1997.
Jeck, C. D., R. Zimmermann, J. Schaper, and W. Schaper. Decreased expression of calmodulin mRNA in human end-stage heart failure. J. Mol. Cell. Cardiol. 26:99-107, 1994.
Kentish, J. C., H. E. D. J. ter Keurs, L. Ricciardi, J. J. J. Bucx, and M. I. M. Noble. Comparison between the sarcomere length-force relations of intact and skinned trabeculae from rat right ventricle: influence of calcium concentrations on these relations. Circ. Res. 58:755-768, 1986.
Komukai, K., and S. Kurihara. Length dependence of Ca(2+)-tension relationship in aequorin-injected ferret papillary muscles. Am. J. Physiol. 273:H1068-H1074, 1997.
Konhilas, J., B. M. Wolska, A. F. Martin, K. A. Palmiter, J. M. Leiden, R. Fentzke, R. J. Solaro, and P. P. de Tombe. Tropnin I isoform composition modulates length dependent activation in murine myocardium. Circulation 98:I-836, 1998.
Li, P., P. A. Hofmann, B. S. Li, A. Malhotra, W. Cheng, E. H. Sonnenblick, L. G. Meggs, and P. Anversa. Myocardial infarction alters myofilament calcium sensitivity and me-chanical behavior of myocytes. Am. J. Physiol.:H360-H370, 1997.
Liu, X. L., Q. M. Shao, and N. S. Dhalla. Myosin light chain phosphorylation in cardiac hypertrophy and failure due to myocardial infarction. J. Mol. Cell. Cardiol. 27:2613-2621, 1995.
Malhotra, A., M. C. Lopez, and A. Nakouzi. Troponin sub-units contribute to altered myosin ATPase activity in diabetic cardiomyopathy. Mol. Cell. Biochem. 151:165-172, 1995.
Malhotra, A., A. Nakouzi, J. Bowman, and P. Buttrick. Expression and regulation of mutant forms of cardiac TnI in a reconstituted actomyosin system: role of kinase dependent phosphorylation. Mol. Cell. Biochem. 170:99-107, 1997.
Malhotra, A., D. Reich, A. Nakouzi, V. Sanghi, D. L. Geenen, and P. M. Buttrick. Experimental diabetes is associated with functional activation of protein kinase C epsilon and phosphorylation of troponin I in the heart, which are prevented by angiotensin II receptor blockade. Circ. Res. 81:1027-1033, 1997.
Margossian, S. S., H. D. White, J. B. Caulfield, P. Norton, S. Taylor, and H. S. Slayter. Light chain 2 profile and activity of human ventricular myosin during dilated cardiomyopathy: Identification of a causal agent for impaired myocardial function. Circulation 85:1720-1733, 1992.
Meij, J. T. A., V. Panagia, N. Mesaeli, J. L. Peachell, N. Afzal, and N. S. Dhalla. Identification of changes in cardiac phospholipase C activity in congestive heart failure. J. Mol. Cell. Cardiol. 29:237-246, 1997.
Mercadier, J. J., P. Bouverett, L. Gorza, S. Schiaffino, W. A. Clark, R. Zak, B. Swynghedauw, and K. Schwartz. Myosin isoenzymes in normal and hypertrophied human ventricular myocardium. Circ. Res. 53:52-62, 1983.
Miyata, S., W. Minobe, M. R. Bristow, and L. A. Leinwand. Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ. Res. 86:386-390, 2000.
Molkentin, J. D., J. R. Lu, C. L. Antos, B. Markham, J. Richardson, J. Robbins, S. R. Grant, and E. N. Olson. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93:215-228, 1998.
Morano, I., O. Ritter, A. Bonz, T. Timek, C. F. Vahl, and G. Michel. Myosin light chain-actin interaction regulates cardiac contractility. Circ. Res. 76:720-725, 1995.
Moss, R. L. Ca2+ regulation of mechanical properties of striated muscle: Mechanistic studies using extraction and replacement of regulatory proteins. Circ. Res. 70:865-884, 1992.
Nadal-Ginard, B., and V. Mahdavi. Molecular basis of cardiac performance. Plasticity of the myocardium generated through protein isoform switches. J. Clin. Invest. 84:1693-1700, 1989.
Nakao, K., W. Minobe, R. Roden, M. R. Bristow, and L. A. Leinwand. Myosin heavy chain gene expression in human heart failure. J. Clin. Invest. 100:2362-2370, 1997.
Nassar, R., N. N. Malouf, M. B. Kelly, A. E. Oakeley, and P. A. Anderson. Force-pCa relation and troponin T isoforms of rabbit myocardium. Circ. Res. 69:1470-1475, 1991.
Naya, T., V. Manaves, Y. Mori, M. C. G. Daniels, V. L. M. Rundell, and P. P. de Tombe. Cross-bridge cycling rate during the development of heart failure. Biophys. J. 78:108A, 2000.
Nielsen-Kudsk, J. E., and J. Aldershville. Will calcium sensitizers play a role in the treatment of heart failure? J. Cardiovasc. Pharmacol. 26:S77-S84, 1995.
Noland, T. A., Jr., X. D. Guo, R. L. Raynor, N. M. Jideama, V. Averyhart-Fullard, R. J. Solaro, and J. F. Kuo. Cardiac troponin I mutants-Phosphorylation by protein kinases C and A and regulation of Ca2+-stimulated MgATPase of reconstituted actomyosin S-1. J. Biol. Chem. 270:25445-25454, 1995.
Pagani, E. D., A. A. Alousi, A. M. Grant, T. M. Older, S. W. Dziuban, and P. D. Allen. Changes in myofibrillar content and Mg-ATPase activity in ventricular tissue from patients with heart failure caused by coronary artery disease, cardiomyopathy, or mitral valve insufficiency. Circ. Res. 63:380-385, 1988.
Palmer, S., and J. C. Kentish. Roles of Ca2+ crossbridge kinetics in determining the maximum rates of Ca2+ activation and relaxation in rat and guinea pig skinned trabeculae. Circ. Res. 83:179-186, 1998.
Palmer, R. E., A. J. Brady, and K. P. Roos. Mechanical measurements from isolated cardiac myocytes using a pipette attachment system. Am. J. Physiol. Cell Physiol. 270:C697-C704, 1996.
Palmiter, K. A., and R. J. Solaro. Molecular mechanisms regulating the myofilament response to Ca2+: implications of mutations causal for familial hypertrophic cardiomyopathy. Basic Res. Cardiol. 92:63-74, 1997.
Paul, K., N. A. Ball, G. W. Dorn, 2nd., and R. A. Walsh. Left ventricular stretch stimulates angiotensin II-mediated phosphatidylinositol hydrolysis and protein kinase C epsilon isoform translocation in adult guinea pig hearts. Circ. Res. 81:643-650, 1997.
Perreault, C. L., O. H. L. Bing, W. W. Brooks, B. J. Ransil, and J. P. Morgan. Differential effects of cardiac hypertrophy and failure on right versus left ventricular calcium activation. Circ. Res. 67:707-712, 1990.
Pieske, B., K. Schlotthauer, J. Schattmann, F. Beyersdorf, J. Martin, H. Just, and G. Hasenfuss. Ca(2+)-dependent and Ca(2+)-independent regulation of contractility in isolated human myocardium. Basic Res. Cardiol. 92:75-86, 1997.
Pope, B., J. Hoh, and A. Weed. The ATPase activities of rat cardiac myosin isoenzymes. FEBS Lett. 118:205-208, 1980.
Rall, J. A. Sense and nonsense about the Fenn effect. Am. J. Physiol. 242:H1-H6, 1982.
Rarick, H. M., H. Tang, X. Guo, A. F. Martin, and R. J. Solaro. Interactions at the NH2-terminal interface of cardiac troponin I modulate myofilament activation. J. Mol. Cell. Cardiol. 31:363-375, 1999.
Robertson, S. P., J. D. Johnson, M. J. Holroyde, E. G. Kranias, J. D. Potter, and R. J. Solaro. The effect of troponin I phosphorylation on the Ca2+-binding properties of the Ca2+-regulatory site of bovine cardiac troponin. J. Biol. Chem. 257:260-263, 1982.
Ruf, T., H. Schulte-Baukloh, J. Ludemann, H. Posival, H. Just, and C. Holubarsch. Alterations of cross-bridge kinetics in human atrial and ventricular myocardium. Cardiovasc. Res. 40:580-590, 1998.
Saeki, Y., T. Kobayashi, S. Minamisawa, and H. Sugi. Protein kinase A increases the tension cost and unloaded shortening velocity in skinned rat cardiac muscle. J. Mol. Cell. Cardiol. 29:1655-1663, 1997.
Sakata, Y., B. D. Hoit, S. B. Liggett, R. A. Walsh, and G. W. Dorn, 2nd. Decompensation of pressure-overload hypertrophy in G alpha q-overexpressing mice [see comments]. Circulation 97:1488-1495, 1998.
Sasse, S., N. J. Brand, P. Kyprianou, G. K. Dhoot, R. Wade, M. Arai, M. Periasamy, M. H. Yacoub, and P. J. R. Barton. Troponin I gene expression during human cardiac development and in end-stage heart failure. Circ. Res. 72:932-938, 1993.
Sato, Y., D. G. Ferguson, H. Sako, G. W. Dorn, 2nd., V. J. Kadambi, A. Yatani, B. D. Hoit, R. A. Walsh, and E. G. Kranias. Cardiac-specific overexpression of mouse cardiac calsequestrin is associated with depressed cardiovascular function and hypertrophy in transgenic mice. J. Biol. Chem. 273:28470-28477, 1998.
Schwartz, K., K. R. Boheler, D. de la Bastie, A.-M. Lompre, and J.-J. Mercadier. Switches in cardiac muscle gene expression as a result of pressure and volume overload. Am. J. Physiol. Regul. Integr. Comp. Physiol. 262:R364-R369 1992.
Schwinger, R. H. G., M. Böhm, A. Koch, U. Schmidt, I. Morano, H.-J. Eissner, P. Ñberfuhr, B. Reichart, and E. Erdmann. The failing human heart is unable to use the Frank-Starling mechanism. Circ. Res. 74:959-969, 1994.
Sharir, T., M. D. Feldman, H. Haber, A. M. Feldman, A. Marmor, L. C. Becker, and D. A. Kass. Ventricular systolic assessment in patients with dilated cardiomyopathy by preload-adjusted maximal power. Validation and noninva-sive application. Circulation 89:2045-2053, 1994.
Solaro, R. J. Protein Phosphorylation in Heart Muscle. Boca Raton: Chemical Rubber Corp., 1986.
Solaro, R. J. Myosin and why hearts fail. Circulation 85:1945-1947, 1992.
Solaro, R. J., and H. M. Rarick. Troponin and tropomyosin: proteins that switch on and tune in the activity of cardiac myofilaments. Circ. Res. 83:471-480, 1998.
Solaro, R. J., and J. Van Eyk. Altered interactions among thin filament proteins modulate cardiac function. J. Mol. Cell. Cardiol. 28:217-230, 1996.
Solaro, R. J., A. J. Moir, and S. V. Perry. Phosphorylation of troponin I and the inotropic effect of adrenaline in the perfused rabbit heart. Nature (London) 262:615-617, 1976.
Solaro, R. J., J. A. Lee, J. C. Kentish, and D. G. Allen. Effects of acidosis on ventricular muscle from adult and neonatal rats. Circ. Res. 63:779-787, 1988.
Strang, K. T., and R. L. Moss. ?1-adrenergic receptor stimulation decreases maximum shortening velocity of skinned single ventricular myocytes from rats. Circ. Res. 77:114-120, 1995.
Strang, K. T., R. M. Mentzer, and R. L. Moss. Slowing of shortening velocity of rat cardiac myocytes by adenosine receptor stimulation regardless of ?-adrenergic stimulation. J. Physiol. (London) 486:679-688, 1995.
Strang, K. T., N. K. Sweitzer, M. L. Greaser, and R. L. Moss. ?-adrenergic receptor stimulation increases unloaded shortening velocity of skinned single ventricular myocytes from rats. Circ. Res. 74:542-549, 1994.
Sugden, P. H., and A. Clerk. Cellular mechanisms of cardiac hypertrophy. J. Mol. Med. 76:725-746, 1998.
Sütsch, G., U. T. Brunner, C. Von Schulthess, H. O. Hirzel, O. M. Hess, M. Turina, H. P. Krayenbuehl, and M. C. Schaub. Hemodynamic performance and myosin light chain-1 expression of the hypertrophied left ventricle in aortic valve disease before and after valve replacement. Circ. Res. 70:1035-1043, 1992.
Swynghedauw, B. Developmental and functional adaptation of contractile proteins in cardiac and skeletal muscle. Physiol. Rev. 66:710-771, 1986.
Takeishi, Y., G. Chu, D. M. Kirkpatrick, Z. Li, H. Wakasaki, E. G. Kranias, G. L. King, and R. A. Walsh. In vivo phosphorylation of cardiac troponin I by protein kinase Cbeta2 decreases cardiomyocyte calcium responsiveness and contractility in transgenic mouse hearts. J. Clin. Invest. 102:72-78, 1998.
Vahl, C. F., A. Bonz, T. Timek, and S. Hagl. Intracellular calcium transient of working human myocardium of seven patients transplanted for congestive heart failure. Circ. Res. 74:952-958, 1994.
van Bilsen, M. Signal transduction revisited: recent developments in angiotensin II signaling in the cardiovascular system. Cardiovasc. Res. 36:310-322, 1997.
van der Velden, J., A. F. Moorman, and G. J. Stienen. Age-dependent changes in myosin composition correlate with enhanced economy of contraction in guinea-pig hearts. J. Physiol. (London) 507:497-510, 1998.
Wolff, M. R., S. H. Buck, S. W. Stoker, M. L. Greaser, and R. M. Mentzer. Myofibrillar calcium sensitivity of isometric tension is increased in human dilated cardiomyopathies: role of altered beta-adrenergically mediated protein phosphorylation. J. Clin. Invest. 98:167-176, 1996.
Wolff, M. R., L. F. Whitesell, and R. L. Moss. Calcium sensitivity of isometric tension is increased in canine experimental heart failure. Circ. Res. 76:781-789, 1995.
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de Tombe, P.P., Solaro, R.J. Integration of Cardiac Myofilament Activity and Regulation with Pathways Signaling Hypertrophy and Failure. Annals of Biomedical Engineering 28, 991–1001 (2000). https://doi.org/10.1114/1.1312189
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DOI: https://doi.org/10.1114/1.1312189