Journal of Molecular Medicine

, Volume 85, Issue 9, pp 911–921

Tuning cardiac performance in ischemic heart disease and failure by modulating myofilament function

  • Sharlene M. Day
  • Margaret V. Westfall
  • Joseph M. Metzger


The cardiac myofilaments are composed of highly ordered arrays of proteins that coordinate cardiac contraction and relaxation in response to the rhythmic waves of [Ca2+] during the cardiac cycle. Several cardiac disease states are associated with altered myofilament protein interactions that contribute to cardiac dysfunction. During acute myocardial ischemia, the sensitivity of the myofilaments to activating Ca2+ is drastically reduced, largely due to the effects of intracellular acidosis on the contractile machinery. Myofilament Ca2+ sensitivity remains compromised in post-ischemic or “stunned” myocardium even after complete restoration of blood flow and intracellular pH, likely because of covalent modifications of or proteolytic injury to contractile proteins. In contrast, myofilament Ca2+ sensitivity can be increased in chronic heart failure, owing in part to decreased phosphorylation of troponin I, the inhibitory subunit of the troponin regulatory complex. We highlight, in this paper, the central role of the myofilaments in the pathophysiology of each of these distinct disease entities, with a particular focus on the molecular switch protein troponin I. We also discuss the beneficial effects of a genetically engineered cardiac troponin I, with a histidine button substitution at C-terminal residue 164, for a variety of pathophysiologic conditions, including hypoxia, ischemia, ischemia–reperfusion and chronic heart failure.


Cardiac ischemia Heart failure Myofilament Sarcomere Troponin I Heart function 


  1. 1.
    Bers DM (2002) Cardiac excitation–contraction coupling. Nature 415(6868):198–205PubMedCrossRefGoogle Scholar
  2. 2.
    Orchard CH, Kentish JC (1990) Effects of changes of pH on the contractile function of cardiac muscle. Am J Physiol 258:C967–C981PubMedGoogle Scholar
  3. 3.
    Bolli R, Marban E (1999) Molecular and cellular mechanisms of myocardial stunning. Physiol Rev 79(2):609–634PubMedGoogle Scholar
  4. 4.
    Piacentino V III et al (2003) Cellular basis of abnormal calcium transients of failing human ventricular myocytes. Circ Res 92(6):651–658PubMedCrossRefGoogle Scholar
  5. 5.
    Morgan JP (1991) Abnormal intracellular modulation of calcium as a major cause of cardiac contractile dysfunction. N Engl J Med 325(9):625–632PubMedCrossRefGoogle Scholar
  6. 6.
    Perez NG et al (1999) Origin of contractile dysfunction in heart failure: calcium cycling versus myofilaments. Circulation 99(8):1077–1083PubMedGoogle Scholar
  7. 7.
    Brixius K et al (2002) Increased Ca2+-sensitivity of myofibrillar tension in heart failure and its functional implication. Basic Res Cardiol 97(Suppl 1):I111–I117PubMedGoogle Scholar
  8. 8.
    Wolff MR et al (1996) Myofibrillar calcium sensitivity of isometric tension is increased in human dilated cardiomyopathies: role of altered beta-adrenergically mediated protein phosphorylation. J Clin Invest 98(1):167–176PubMedGoogle Scholar
  9. 9.
    Noguchi T et al (2004) Thin filament-based modulation of contractile performance in human heart failure. Circulation 110:982–987PubMedCrossRefGoogle Scholar
  10. 10.
    VanBuren P, Okada Y (2005) Thin filament remodeling in failing myocardium. Heart Fail Rev 10(3):199–209PubMedCrossRefGoogle Scholar
  11. 11.
    LeWinter MM (2005) Functional consequences of sarcomeric protein abnormalities in failing myocardium. Heart Fail Rev 10(3):249–257PubMedCrossRefGoogle Scholar
  12. 12.
    Metzger JM, Westfall MV (2004) Covalent and noncovalent modification of thin filament action: the essential role of troponin in cardiac muscle regulation. Circ Res 94:146–158PubMedCrossRefGoogle Scholar
  13. 13.
    Thom T et al (2006) Heart disease and stroke statistics—2006 update. A report from the American heart association statistics committee and stroke statistics subcommittee. Circulation 113:e85PubMedCrossRefGoogle Scholar
  14. 14.
    Farah CS, Reinach FC (1995) The troponin complex and regulation of muscle contraction. FASEB J 9(9):755–767PubMedGoogle Scholar
  15. 15.
    Tobacman LS (1996) Thin filament-mediated regulation of cardiac contraction. Annu Rev Physiol 58:447–481PubMedCrossRefGoogle Scholar
  16. 16.
    Takeda S et al (2003) Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form. Nature 424:35–41PubMedCrossRefGoogle Scholar
  17. 17.
    Li MX, Spyracopoulos L, Sykes BD (1999) Binding of cardiac troponin-I147-163 induces a structural opening in human cardiac troponin-C. Biochemistry 38(26):8289–8298PubMedCrossRefGoogle Scholar
  18. 18.
    Li MX, Wang X, Sykes BD (2004) Structural based insights into the role of troponin in cardiac muscle pathophysiology. J Muscle Res Cell Motil 25(7):559–579PubMedCrossRefGoogle Scholar
  19. 19.
    Pirani A et al (2006) An atomic model of the thin filament in the relaxed and Ca2+-activated states. J Mol Biol 357(3):707–717PubMedCrossRefGoogle Scholar
  20. 20.
    Vinogradova MV et al (2005) Ca(2+)-regulated structural changes in troponin. Proc Natl Acad Sci USA 102(14):5038–5043PubMedCrossRefGoogle Scholar
  21. 21.
    Hoffman RM, Blumenschein TM, Sykes BD (2006) An interplay between protein disorder and structure confers the Ca2+ regulation of striated muscle. J Mol Biol 361(4):625–633PubMedCrossRefGoogle Scholar
  22. 22.
    Murakami K et al (2005) Structural basis for Ca2+-regulated muscle relaxation at interaction sites of troponin with actin and tropomyosin. J Mol Biol 352(1):178–201PubMedCrossRefGoogle Scholar
  23. 23.
    Saggin L et al (1989) Troponin I switching in the developing heart. J Biol Chem 264(27):16299–16302PubMedGoogle Scholar
  24. 24.
    Reiser PJ et al (1994) Tension production and thin-filament protein isoforms in developing rat myocardium. Am J Physiol 36:H1589–H1596Google Scholar
  25. 25.
    Siedner S et al (2003) Developmental changes in contractility and sarcomeric proteins from the early embryonic to the adult stage in the mouse heart. J Physiol 548(Pt 2):493–505PubMedCrossRefGoogle Scholar
  26. 26.
    Hunkeler NM, Kullman J, Murphy AM (1991) Troponin I isoform expression in human heart. Circ Res 69(5):1409–1414PubMedGoogle Scholar
  27. 27.
    Kruger M, Kohl T, Linke WA (2006) Developmental changes in passive stiffness and myofilament Ca2+ sensitivity due to titin and troponin-I isoform switching are not critically triggered by birth. Am J Physiol Heart Circ Physiol 291(2):H496–H506PubMedCrossRefGoogle Scholar
  28. 28.
    Westfall MV et al (2001) Troponin I chimera analysis of the cardiac myofilament tension response to protein kinase A. Am J Physiol 280:C324–C332Google Scholar
  29. 29.
    Westfall MV, Metzger JM (2001) Troponin I isoforms and chimeras: tuning the molecular switch of cardiac contraction. News Phyiol Sci 16:278–281Google Scholar
  30. 30.
    Westfall MV, Rust EM, Metzger JM (1997) Slow skeletal troponin I gene transfer, expression, and myofilament incorporation enhances adult cardiac myocyte contractile function. Proc Natl Acad Sci 94:5444–5449PubMedCrossRefGoogle Scholar
  31. 31.
    Wolska BM et al (2001) Expression of slow skeletal troponin I in adult transgenic mouse heart muscle reduces the force decline observed during acidic conditions. J Physiol 536(3):863–870PubMedCrossRefGoogle Scholar
  32. 32.
    Westfall MV, Albayya FP, Metzger JM (1999) Functional analysis of troponin I regulatory domains in the intact myofilament of adult single cardiac myocytes. J Biol Chem 274(32):22508–22516PubMedCrossRefGoogle Scholar
  33. 33.
    Westfall MV et al (2000) Chimera analysis of troponin I domains that influence Ca2+-activated myofilament tension in adult cardiac myocytes. Circ Res 86:470–477PubMedGoogle Scholar
  34. 34.
    Westfall MV, Rust EM, Metzger JM (2001) Specific charge differences in troponin I isoforms influence myofilament calcium sensitivity of tension in adult cardiac myocytes. Biophys J 80:356AGoogle Scholar
  35. 35.
    Dargis R et al (2002) Single mutation (A162H) in human cardiac troponin I corrects acid pH sensitivity of Ca2+-regulated actomyosin S1 ATPase. J Biol Chem 277(38):34662–34665PubMedCrossRefGoogle Scholar
  36. 36.
    Day SM et al (2006) Histidine button engineered into cardiac troponin I protects the ischemic and failing heart. Nat Med 12(2):181–189PubMedCrossRefGoogle Scholar
  37. 37.
    Katz AM et al (2001) Physiology of the heart. Lippincott Williams and Wilkins, Philadelphia, pp 630–657Google Scholar
  38. 38.
    Solaro RJ et al (1988) Effects of acidosis on ventricular muscle from adult and neonatal rats. Circ Res 63:779–787PubMedGoogle Scholar
  39. 39.
    Kim SJ, Depre C, Vatner SF (2003) Novel mechanisms mediating stunned myocardium. Heart Fail Rev 8(2):143–153PubMedCrossRefGoogle Scholar
  40. 40.
    Gao WD et al (1996) Intrinsic myofilament alterations underlying the decreased contractility of stunned myocardium. Circ Res 78:455–465PubMedGoogle Scholar
  41. 41.
    Van Eyk JE et al (1998) Breakdown and release of myofilament proteins during ischemia and ischemia/reperfusion in rat hearts. Circ Res 82:261–271PubMedGoogle Scholar
  42. 42.
    Zhao K et al (2004) Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem 279(33):34682–34690PubMedCrossRefGoogle Scholar
  43. 43.
    McDonough JL, Arrell DK, Van Eyk JE (1999) Troponin I degradation and covalent complex formation accompanies myocardial ischemia/reperfusion injury. Circ Res 84:9–20PubMedGoogle Scholar
  44. 44.
    Murphy AM et al (2000) Transgenic mouse model of stunned myocardium. Science 287:488–491PubMedCrossRefGoogle Scholar
  45. 45.
    Thomas SA et al (1999) Absence of troponin I degradation or altered sarcoplasmic reticulum uptake protein expression after reversible ischemia in swine. Circ Res 85:446–456PubMedGoogle Scholar
  46. 46.
    Canty JM, Lee TC (2002) Troponin I proteolysis and myocardial stunning: now you see it—now you don’t. J Mol Cell Cardiol 34:375–377PubMedCrossRefGoogle Scholar
  47. 47.
    Feng J et al (2001) Preload induces troponin I degradation independently of myocardial ischemia. Circulation 103:2035–2037PubMedGoogle Scholar
  48. 48.
    Gonzalez MR, Pharmacologic AD (2006) Treatment of heart failure due to ventricular dysfunction by myocardial stunning. Am J Cardiovasc Drugs 6(2):69–75CrossRefGoogle Scholar
  49. 49.
    Piper HM, Meuter K, Schafer C (2003) Cellular mechanisms of ischemia-reperfusion injury. Ann Thorac Surg 75:S644–S648PubMedCrossRefGoogle Scholar
  50. 50.
    Garcia-Dorado D (2004) Myocardial reperfusion injury: a new view. Cardiovasc Res 61(3):363–364PubMedCrossRefGoogle Scholar
  51. 51.
    Ohtsuka M et al (2004) Role of Na+–Ca2+ exchanger in myocardial ischemia/reperfusion injury: evaluation using a heterozygous Na+–Ca2+ exchanger knockout mouse model. Biochem Biophys Res Commun 314(3):849–853PubMedCrossRefGoogle Scholar
  52. 52.
    Stromer H et al (2000) Na(+)/H(+) exchange inhibition with HOE642 improves postischemic recovery due to attenuation of Ca(2+) overload and prolonged acidosis on reperfusion. Circulation 101(23):2749–2755PubMedGoogle Scholar
  53. 53.
    Taylor MD et al (2005) Ethyl pyruvate enhances ATP levels, reduces oxidative stress and preserves cardiac function in a rat model of off-pump coronary bypass. Heart Lung Circ 14(1):25–31PubMedCrossRefGoogle Scholar
  54. 54.
    Cross HR et al (2002) Ablation of PLB exacerbates ischemic injury to a lesser extent in female and male mice: protective role of NO. Am J Physiol 284:H683–H690Google Scholar
  55. 55.
    del Monte F et al (2004) Abrogation of ventricular arrhythmias in a model of ischemia and reperfusion by targeting myocardial calcium cycling. Proc Natl Acad Sci 101:5622–5627PubMedCrossRefGoogle Scholar
  56. 56.
    Pieske B, Maier LS, Schmidt-Schweda S (2002) Sarcoplasmic reticulum Ca2+ load in human heart failure. Basic Res Cardiol 97(Suppl 1):I63–I71PubMedGoogle Scholar
  57. 57.
    Pieske B et al (1999) Ca2+ handling and sarcoplasmic reticulum Ca2+ content in isolated failing and nonfailing human myocardium. Circ Res 85:38–46PubMedGoogle Scholar
  58. 58.
    Maier LS et al (2003) Transgenic CaMKIIdeltaC overexpression uniquely alters cardiac myocyte Ca2+ handling: reduced SR Ca2+ load and activated SR Ca2+ release. Circ Res 92(8):904–911PubMedCrossRefGoogle Scholar
  59. 59.
    Baartscheer A et al (2003) SR calcium handling and calcium after-transients in a rabbit model of heart failure. Cardiovasc Res 58(1):99–108PubMedCrossRefGoogle Scholar
  60. 60.
    Hobai IA, O’Rourke B (2001) Decreased sarcoplasmic reticulum calcium content is responsible for defective excitation–contraction coupling in canine heart failure. Circulation 103(11):1577–1584PubMedGoogle Scholar
  61. 61.
    Hasenfuss G (1998) Alterations of calcium-regulatory proteins in heart failure. Cardiovasc Res 37(2):279–289PubMedCrossRefGoogle Scholar
  62. 62.
    Hasenfuss G et al (1997) Calcium handling proteins in the failing human heart. Basic Res Cardiol 92(Suppl 1):87–93PubMedCrossRefGoogle Scholar
  63. 63.
    MacLennan DH, Kranias EG (2003) Phospholamban: a crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol 4(7):566–577PubMedCrossRefGoogle Scholar
  64. 64.
    Wehrens XH, Marks AR (2004) Novel therapeutic approaches for heart failure by normalizing calcium cycling. Nat Rev Drug Discov 3(7):565–573PubMedCrossRefGoogle Scholar
  65. 65.
    Hoshijima M (2005) Gene therapy targeted at calcium handling as an approach to the treatment of heart failure. Pharmacol Ther 105(3):211–228PubMedCrossRefGoogle Scholar
  66. 66.
    Haghighi K et al (2006) A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy. Proc Natl Acad Sci USA 103(5):1388–1393PubMedCrossRefGoogle Scholar
  67. 67.
    Haghighi K et al (2003) Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. J Clin Invest 111(6):869–876PubMedCrossRefGoogle Scholar
  68. 68.
    Nagueh SF et al (2004) Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy. Circulation 110(2):155–162PubMedCrossRefGoogle Scholar
  69. 69.
    Makarenko I et al (2004) Passive stiffness changes caused by upregulation of compliant titin isoforms in human dilated cardiomyopathy hearts. Circ Res 95(7):708–716PubMedCrossRefGoogle Scholar
  70. 70.
    van Heerebeek L et al (2006) Myocardial structure and function differ in systolic and diastolic heart failure. Circulation 113(16):1966–1973PubMedCrossRefGoogle Scholar
  71. 71.
    Nguyen TT et al (1996) Maximal actomyosin ATPase activity and in vitro myosin motility are unaltered in human mitral regurgitation heart failure. Circ Res 79(2):222–226PubMedGoogle Scholar
  72. 72.
    Alpert NR, Gordon MS (1962) Myofibrillar adenosine triphosphatase activity in congestive heart failure. Am J Physiol 202:940–946PubMedGoogle Scholar
  73. 73.
    Belin RJ et al (2006) Left ventricular myofilament dysfunction in rat experimental hypertrophy and congestive heart failure. Am J Physiol Heart Circ Physiol 291(5):H2344–H2353PubMedCrossRefGoogle Scholar
  74. 74.
    Fan D, Wannenburg T, de Tombe PP (1997) Decreased myocyte tension development and calcium responsiveness in rat right ventricular pressure overload. Circulation 95(9):2312–2317PubMedGoogle Scholar
  75. 75.
    Bristow MR et al (1993) Reduced beta 1 receptor messenger RNA abundance in the failing human heart. J Clin Invest 92(6):2737–2745PubMedCrossRefGoogle Scholar
  76. 76.
    Daaka Y, Luttrell LM, Lefkowitz RJ (1997) Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A. Nature 390(6655):88–91PubMedCrossRefGoogle Scholar
  77. 77.
    Messer AE, Jacques AM, Marston SB (2007) Troponin phosphorylation and regulatory function in human heart muscle: dephosphorylation of Ser23/24 on troponin I could account for the contractile defect in end-stage heart failure. J Mol Cell Cardiol 42(1):247–259PubMedCrossRefGoogle Scholar
  78. 78.
    van der Velden J et al (2006) Functional effects of protein kinase C-mediated myofilament phosphorylation in human myocardium. Cardiovasc Res 69(4):876–887PubMedCrossRefGoogle Scholar
  79. 79.
    Endoh M, Hori M (2006) Acute heart failure: inotropic agents and their clinical uses. Expert Opin Pharmacother 7(16):2179–2202PubMedCrossRefGoogle Scholar
  80. 80.
    Parissis JT et al (2006) Effects of serial levosimendan infusions on left ventricular performance and plasma biomarkers of myocardial injury and neurohormonal and immune activation in patients with advanced heart failure. Heart 92(12):1768–1772PubMedCrossRefGoogle Scholar
  81. 81.
    Follath F et al (2002) Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet 360(9328):196–202PubMedCrossRefGoogle Scholar
  82. 82.
    Moiseyev VS et al (2002) Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. A randomized, placebo-controlled, double-blind study (RUSSLAN). Eur Heart J 23(18):1422–1432PubMedCrossRefGoogle Scholar
  83. 83.
    Fentzke RC et al (1999) Impaired cardiomyocyte relaxation and diastolic function in transgenic mice expressing slow skeletal troponin I in the heart. J Physiol 517(1):143–157PubMedCrossRefGoogle Scholar
  84. 84.
    Chang AN et al (2005) Functional consequences of hypertrophic and dilated cardiomyopathy-causing mutations in alpha-tropomyosin. J Biol Chem 280(40):34343–34349PubMedCrossRefGoogle Scholar
  85. 85.
    Lang R et al (2002) Functional analysis of a troponin I (R145G) mutation associated with familial hypertrophic cardiomyopathy. J Biol Chem 277(14):11670–11678PubMedCrossRefGoogle Scholar
  86. 86.
    Michele DE et al (2002) Cardiac dysfunction in hypertrophic cardiomyopathy mutant tropomyosin mice is transgene-dependent, hypertrophy-independent, and improved by beta-blockade. Circ Res 92:255–262CrossRefGoogle Scholar
  87. 87.
    Gregorevic P et al (2006) rAAV6-microdystrophin preserves muscle function and extends lifespan in severely dystrophic mice. Nat Med 12(7):787–789PubMedCrossRefGoogle Scholar
  88. 88.
    Gregorevic P et al (2004) Systemic delivery of genes to striated muscles using adeno-associated viral vectors. Nat Med 10(8):828–834PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Sharlene M. Day
    • 1
  • Margaret V. Westfall
    • 2
    • 3
  • Joseph M. Metzger
    • 3
    • 4
  1. 1.Department of Internal MedicineUniversity of MichiganAnn ArborUSA
  2. 2.Department of Cardiac SurgeryUniversity of MichiganAnn ArborUSA
  3. 3.Department of Molecular and Integrative PhysiologyUniversity of MichiganAnn ArborUSA
  4. 4.Department of Internal MedicineUniversity of MichiganAnn ArborUSA

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