Skip to main content

Advertisement

SpringerLink
Log in

The Myofilament Force-Calcium Relationship as a Target for Positive Inotropic Therapy in Congestive Heart Failure

  • Review
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

To-date positive inotropic therapy in the treatment of congestive heart failure has resulted in adverse effects on long term survival. These agents increase calcium cycling through β-adrenergic stimulation or phosphodiesterase inhibition. An alternative method of producing positive inotropy is to increase the myofilament sensitivity to calcium. This can occur at several levels within the myofilament, and has potential benefits with respect to avoiding increased calcium cycling and producing a more favourable energy efficient positive inotropy. A potential adverse effect of increasing calcium sensitivity is slowed relaxation and diastolic dysfunction. We have learnt a considerable amount about the function of specific sites within the myofilament by the use of genetically engineered mouse models, which have shown diverse effects of various myofilament sites on global left ventricular function. Levosimendan is a novel inotropic agent that has several mechanisms of action including calcium sensitization, and is undergoing clinical trials at present. This review article will provide a comprehensive molecular, biophysical and physiological insight into the concepts underlying the myofilament force-calcium relationship and its potential as a target for positive inotropic therapy in heart failure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Berger DS, Fellner SK, Robinson KA, Vlasica K, Godoy IE, Shroff SG. Disparate effects of three types of extracellular acidosis on left ventricular function. Am J Physiol 1999;276(Heart Circ. Physiol.)45:H582–H594.

    Google Scholar 

  • Brandes R, Bers DM. Analysis of the mechanisms of mitochondrial NADH regulation in cardiac trabculae. Biophys J 1999;77:1666–1682.

    PubMed  Google Scholar 

  • Brenner B. Effect of Ca2+ on cross-bridge turnover kinetics in skinned single rabbit psoas fibers: Implications for regulation of muscle contraction. Proc Natl Acad Sci 1988;85:3265–3269.

    PubMed  Google Scholar 

  • Bodor GS, Oakeley AE, Allen PD, Crimmins DL, Ladenson JH, Anderson PAW. Troponin I phosphorylation in the normal and failing adult human heart. Circulation 1997;96:1495–1500.

    PubMed  Google Scholar 

  • Bowman P, Haikala H, Paul RJ. Levosimendan, a calcium sensitizer in cardiac muscle, induces relaxation in coronary smooth muscle through calcium desensitization. J Pharmacol Exp Ther 1999;288:316–325.

    PubMed  Google Scholar 

  • Burton D, Abdulrazzak H, Knott A, et al. Two mutations in troponin I that cause hypertrophic cardiomyopathy have contrasting effects on cardiac muscle contractility. Biochem J 2002;362:443–451.

    Article  PubMed  Google Scholar 

  • Campbell K. Rate constant of muscle force redevelopment reflects cooperative activation as well as cross-bridge kinetics. Biophys J 1997;72:254–262.

    PubMed  Google Scholar 

  • Cappola TP, Kass DA, Nelson GS, {et al}. Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy. Circulation 2001;104:2407–2411.

    PubMed  Google Scholar 

  • Chen Q, Camara AKS, Rhodes SS, Riess ML, Novalija E, Stowe DF. Cardiotonic drugs differentially alter cytosolic [Ca2+] to left ventricular relationships before and after ischemia in isolated guinea pig hearts. Cardiovasc Res 2003;59:912–925.

    Article  PubMed  Google Scholar 

  • Ekelund UEG, Harrison RW, Shokek O, {et al}. Intravenous allopurinol decreases myocardial oxygen consumption and increases mechanical efficiency in dogs with pacing-induced heart failure. Circ Res 1999;85:437–445.

    PubMed  Google Scholar 

  • Endoh M. Mechanisms of action of novel cardiotonic agents. J Cardiovasc Pharm 2002;40:323–338.

    Article  Google Scholar 

  • Fentzke RC, Buck SH, Patel JR, et al. Impaired cardiomyocyte relaxation and diastolic function in transgenic mice expressing slow skeletal troponin I in the heart. J Physiol 1999;517:143–57.

    Article  PubMed  Google Scholar 

  • Follath F, Cleland JGF, Just H, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): A randomised double-blind trial. Lancet 2002;360:196–202.

    Article  PubMed  Google Scholar 

  • Gao WD, Atar D, Backx PH, Marban E. 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. Circ Res 1995;76:1036–1048.

    PubMed  Google Scholar 

  • Grandis DJ, DelNido PJ, Koretsky AP. Functional and energetic effects of the inotropic agents EMD-57033 and BAPTA on the isolated rat heart. Am J Physiol 1995(Cell Physiol. 38);269:C472–C479.

    Google Scholar 

  • Grandis DJ, MacGowan GA, Koretsky AP. Comparison of the effects of ORG 30029, dobutamine and high perfusate calcium on function and metabolism in rat heart. J Mol Cell Cardiol 1998;30:2605–2612.

    Article  PubMed  Google Scholar 

  • Haikala H, Kaivola J, Nissinen E, Wall P, Levijoki J, Linden IB. Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan. J Mol Cell Cardiol 1995;27:1859–1866.

    Article  PubMed  Google Scholar 

  • Hajjar RJ, Schwinger RHG, Schmidt U, {et al}. Myofilament calcium regulation in human myocardium. Circulation 2000;101:1679–1685.

    PubMed  Google Scholar 

  • Harada K, Potter JD. Familial hypertrophic cardiomyopathy mutations from different functional regions of troponin T result in different effects on the pH and Ca2+ sensitivity of cardiac muscle contraction. J Biol Chem 2004;279:14488–14495.

    Article  PubMed  Google Scholar 

  • Hasenfuss G, Pieske B, Castell M, Kretschmann B, Maier LS, Just H. Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation 1998; 98:2141–2147.

    PubMed  Google Scholar 

  • Haworth RS, Cuello F, Herron TJ, et al. Protein kinase D is a novel mediator of cardiac troponin I phosphorylation and regulates myofilament function. Circ Res 2004;95:1091–1099.

    Article  PubMed  Google Scholar 

  • Hu TCC, Pautler RG, MacGowan GA, Koretsky AP. Non-invasive determination of altered myocardial intracellular calcium in the mouse heart with manganese enhanced MRI. Magn Reson Med 2001;46:884–890.

    Article  PubMed  Google Scholar 

  • Huxley AF. Muscle structure and theories of contraction. Prog Biophys Biophys Chem 1957;7:255–318.

    PubMed  Google Scholar 

  • Ishihara H, Yokota M, Sobue T, Saito H. Relation between ventriculoarterial coupling and myocardial energetics in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 1994;23:406–416.

    PubMed  Google Scholar 

  • Kaheinen P, Pollesello P, Levijoki J, Haikala H. Levosimendan increases diastolic coronary flow in isolated guinea-pig heart by opening ATP-sensitive potassium channels. J Cardiovasc Pharmacol 2001;37:367–374.

    Article  PubMed  Google Scholar 

  • Kaheinen P, Pollesello P, Levijoki J, Haikala H. Effects of levosimendan and milrinone on oxygen consumption in isolated guinea-pig heart. J Cardiovasc Pharmacol 2004;43:555–61.

    Article  PubMed  Google Scholar 

  • Kersten JR, Montgomery MW, Pagel PS, Warltier DC. Levosimendan, a new positive inotropic drug, decreases myocardial infarct size via activation of K(ATP) channels. Anesth Analg 2000;90:5–11.

    Article  PubMed  Google Scholar 

  • Lee JA, Allen DG. Altering the strength of the heart: Basic mechanisms. In Lee JA and Allen DG (eds.), Modulation of Cardiac Calcium Sensitivity, (Oxford: Oxford University Press, 1993) pp.~1–36.

    Google Scholar 

  • Lubsen J, Just H, Hjalmarsson AC, et al. Effect of Pimobendan on exercise capacity in patients with heart failure: Main results from the Pimobendan in congestive heart failure (PICO) trial. Heart 1996;76:223–231.

    PubMed  Google Scholar 

  • MacGowan GA, Koretsky AP. Inotropic and energetic effects of altering the force-calcium relationship: Mechanisms, experimental results, and potential molecular targets. J Card Fail 2000;6:144–156.

    PubMed  Google Scholar 

  • MacGowan GA, Du C, Cowan DB, et al. Ischemic dysfunction in transgenic mice expressing troponin I lacking protein kinase C phosphorylation sites. Am J Physiol (Heart Circ. Physiol.) 2001;280:H835–H843.

    Google Scholar 

  • MacGowan GA, Du C, Wieczorek DF, Koretsky AP. Compensatory changes in calcium and myocardial oxygen consumption in β-tropomyosin transgenic hearts. Am J Physiol (Heart Circ. Physiol.) 2001;281:H2539–H2548.

    Google Scholar 

  • MacGowan GA, Evans C, Hu TCC, et al. Troponin I protein kinase C phosphorylation sites and ventricular function. Cardiovasc Res 2004;63:245–255.

    Article  PubMed  Google Scholar 

  • MacGowan GA, Rager J, Shroff SG, Mathier MA. In-vivo α-Adrenergic responses and troponin I phosphorylation: Anesthesia interactions. J Appl Physiol 2005;98:1163–1170.

    Article  PubMed  Google Scholar 

  • The MERIT-HF Investigators. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001–2007.

    Google Scholar 

  • Michaels AD, McKeown B, Kostal M, et al. Effects of intravenous levosimendan on human coronary vasomotor regulation, left ventricular wall stress, and myocardial oxygen uptake. Circulation 2005;111:1504–1509.

    Article  PubMed  Google Scholar 

  • Moiseyev VS, Poder P, Andrejevs N, et al. Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. A placebo-controlled, double-blind study (RUSSLAN). Eur Heart J 2002;23:1422–32.

    Article  PubMed  Google Scholar 

  • Montgomery DE, Wolska BM, Pyle WG, et al. α-Adrenergic response and myofilament activity in mouse hearts lacking PKC phosphorylation sites on cardiac TnI. Am J Physiol (Heart Circ. Physiol.) 2002;282:H2397–2405.

    Google Scholar 

  • Mori M, Takeuchi M, Takaoka H, et al. Oxygen saving effect of a new cardiotonic agent, MCI-154, in diseased human hearts. J Am Coll Cardiol 1997;29:613–622.

    Article  PubMed  Google Scholar 

  • Nagueh SF, Chen S, Patel R, et al. Evolution of expression of cardiac phenotypes over a 4-year period in the beta-myosin heavy chain-Q403 transgenic rabbit model of human hypertrophic cardiomyopathy. J Mol Cell Cardiol 2004;36:663–673.

    Article  PubMed  Google Scholar 

  • Nieminen M, Akkila J, Hasenfuss G, et al. Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. J Am Coll Cardiol 2000;36: 903–912.

    Article  Google Scholar 

  • Noguchi T, Hunlich M, Camp PC, et al. Thin filament-based modulation of contractile performance in human heart failure. Circulation 2004;110:982–987.

    Article  PubMed  Google Scholar 

  • Noland TA Jr., Guo X, Raynor RL, et al. 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 1995;270:25445–25454.

    Article  PubMed  Google Scholar 

  • Packer M, Carver JR, Rodeheffer RJ, et al: Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med 1991;325:1468–1475.

    PubMed  Google Scholar 

  • Palmiter KA, Kitada Y, Muthuchamy M, Wieczorek DF, Solaro RJ. Exchange of β- for α-tropomyosin in hearts of transgenic mice induces changes in thin filament response to Ca2+ strong cross bridge binding, and protein phosphorylation. J Biol Chem 1996;271:11611–11614.

    Article  PubMed  Google Scholar 

  • Papp Z, Van Der Velden J, Borbely A, Edes I, Stienen GJ. Effects of Ca2+ sensitizers in permeabilized cardiac myocytes from donor and end-stage failing human hearts. J Muscle Res Cell Motil 2004;25:219–224.

    Article  PubMed  Google Scholar 

  • Perez NG, Gao WD, Marban E. Novel myofilament Ca2+-sensitizing property of xanthine oxidase inhibitors. Circ Res 1998;423–430.

  • Pyle WG, Sumandea MP, Solaro RJ, de Tombe PP. Troponin I serines 43/45 and regulation of cardiac myofilament function. Am J Physiol (Heart Circ. Physiol.) 2002;283:H1215–H1224.

    Google Scholar 

  • Sato S, Talukder MA, Sugawara H, Sawada H, Endoh M. Effects of levosimendan on myocardial contractility and Ca2+ transients in aequorin-loaded right-ventricular papillary muscles and indo-1-loaded single ventricular cardiomyocytes of the rabbit. J Mol Cell Cardiol 1998;30:115–128.

    Article  Google Scholar 

  • Schulz R, Cohen MV, Behrends M, Downey JM, Heusch G. Signal transduction of ischemic preconditioning. Cardiovasc Res 2001;52:181–198.

    Article  PubMed  Google Scholar 

  • Shroff SG, Vlasica K, Berger DS, Fentzke RC, Leiden JM. Left ventricular mechanics in transgenic mice expressing slow skeletal troponin I in the heart. Circulation 1999;100:I–59 (Abstract).

    Google Scholar 

  • Slawsky MT, Colucci WS, Gottlieb SS, et al. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Circulation 2000;102:2222–2227.

    PubMed  Google Scholar 

  • Solaro RJ, Gambassi G, Warshaw DM, et al. Stereoselective actions of thiadiazinones on canine cardiac mycytes and myofilaments. Circ Res 1993;73:981–990.

    PubMed  Google Scholar 

  • Sonntag S, Sundberg S, Lehtonen LA, Kleber FX. The calcium sensitizer levosimendan improves the function of stunned myocardium after percutaneous transluminal coronary angioplasty in acute myocardial ischemia. J Am Coll Cardiol 2004;43:2177–2182.

    Article  PubMed  Google Scholar 

  • Sorsa T, Pollesello P, Permi P, Drakenberg T, Kilpelainen I. Interaction of levosimendan with cardiac troponin C in the presence of cardiac troponin I peptides. J Mol Cell Cardiol 2003;35:1055–1061.

    Article  PubMed  Google Scholar 

  • Takeishi Y, Chu G, Kirkpatrick DM, et al. In vivo phosphorylation of cardiac troponin I by protein kinase Cβ2 decreases cardiomyocyte calcium responsiveness and contractility in transgenic mouse hearts. J Clin Invest 1998;102:72–78.

    PubMed  Google Scholar 

  • Takimoto E, Soergel DG, Janssen PM, Stull LB, Kass DA, Murphy AM. Frequency- and afterload-dependent cardiac modulation in vivo by troponin I with constituitively active protein kinase A phosphorylation sites. Circ Res 2004;94:496–504.

    Article  PubMed  Google Scholar 

  • Van der Velden, Papp Z, Zaremba R, et al. Increased Ca2+ sensitivity of the contractile apparatus in end-stage human heart failure results from altered phosphorylation of contractile proteins. Cardiovasc Res 2003;57:37–47.

    Article  PubMed  Google Scholar 

  • Wolff MR, Buck SH, Stoker SW, Greaser ML, Mentzer RM. Myofibrillar calcium sensitivity of isometric tension is increased in human dilated cardiomyopathies: Role of altered beta-adrenergically mediated protein phosphorylation. J Clin Invest 1996;98:167–176.

    PubMed  Google Scholar 

  • Wolska BM, Keller RS, Evans CC, et al. Correlation between myofilament response to Ca2+ and altered dynamics of contraction and relaxation in transgenic cardiac cells that express β-tropomyosin. Circ Res 1999;84:745–751.

    PubMed  Google Scholar 

  • Zhang R, Zhao J, Mandveno A, Potter JD. Cardiac troponin I phosphorylation increases the rate of cardiac muscle relaxation. Circ Res 1995;76:1028–1035.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dept of Cardiology, Freeman Hospital and University of Newcastle upon Tyne, Newcastle upon Tyne, NE7 7DN, United Kingdom

    Guy A. MacGowan MD FACC FRCPI

Authors
  1. Guy A. MacGowan MD FACC FRCPI
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guy A. MacGowan MD FACC FRCPI.

Rights and permissions

Reprints and permissions

About this article

Cite this article

MacGowan, G.A. The Myofilament Force-Calcium Relationship as a Target for Positive Inotropic Therapy in Congestive Heart Failure. Cardiovasc Drugs Ther 19, 203–210 (2005). https://doi.org/10.1007/s10557-005-2465-9

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-005-2465-9

Keywords

Search

Navigation