Skip to main content
SpringerLink
Log in

A mechanistic analysis of the force-frequency relation in non-failing and progressively failing human myocardium

  • Conference paper
Heart rate as a determinant of cardiac function

  • 176 Accesses

Abstract

This review focuses on the role of the myocardial force-frequency relation (FFR) in human ventricular performance and how changes in the FFR can reduce cardiac output and, ultimately, can contribute to altering the stability of the in-vivo cardiovascular system in a way that contributes to the progression of heart failure. Changes in the amplitude, shape, and position of the myocardial FFR occurring in various forms of heart failure are characterized in terms of maximal isometric twitch tension, slope of the ascending limb (myocardial reserve), and position of the peak of the FFR on the frequency axis (optimum stimulation frequency). All three of these parameters decline according to severity of myocardial disease in the following order: non-failing atrial septal defect, non-failing coronary artery disease, non-failing coronary artery disease with diabetes mellitus, failing mitral regurgitation, failing viral myocarditis, failing idiopathic dilated cardiomyopathy. Evidence is presented supporting a sarcoplasmic reticulum Ca-pump based mechanism for this progressive depression of the FFR. Intracellular calcium cycling and concentration and Ca-pump content all diminish in proportion to degree of depression of the FFR. Additional evidence from myocyte culture studies suggests a cause of diminished Ca-pump content is sustained, elevated levels of plasma norepinephrine. A hypothesis is presented to explain the mechanism of myocardial failure and its progression in terms of changes in the cardiovascular feedback control system that are triggered by reduced moycardial reserve. Sustained elevation of plasma norepinephrine levels depresses expression of sarcoplasmic reticulum Ca-pump protein causing depression of the FFR and this causes a compensatory further increase in norepinephrine levels and a further depression of Ca-pump protein.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Aquilla TT, Absher M, Alpert NR, Rovner AS (1997) Norepinephrine reduces the expression of SERCA2 and PLN in vitro in both the presence and absence of T3. Biochem J (in press)

    Google Scholar 

  2. Aquilla TT, Rovner AS, Absher M, Fisher SA, Periasamy M, Alpert NR (1995) Catecholamines decrease the expression of Ca2+ cycling protein mRNAs in cultured cardiomyocytes. (Abstract) J Mol Cell Cardiol 27: ((5) May) A35

    Google Scholar 

  3. Chidsey CA, Harrison DC, Braunwald E (1962) Augmentation of the plasma nor-epinephrine response to exercise in patients with congestive heart failure. New England J Medicine 267: 650–4

    Article  CAS  Google Scholar 

  4. Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB, Rector T (1984) Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 311: 819–23

    Article  PubMed  CAS  Google Scholar 

  5. Fisher SA, Buttrick PM, Sukovich D, Periasamy M (1993) Characterization of promoter elements of the rabbit cardiac sarcoplasmic reticulum Ca(2+)-ATPase gene required for expression in cardiac muscle cells. Circ Res 73: 622–8

    PubMed  CAS  Google Scholar 

  6. Francis GS, Benedict C, Johnstone DE, Kiriin PC, Nicklas J, Liang CS, Kubo SH, Rudin-Toretsky E, Yusuf S (1990) Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 82: 1724–9

    Article  PubMed  CAS  Google Scholar 

  7. Gilbert EM, Abraham WT, Olsen S, Hattler B, White M, Mealy P, Larrabee P, Bristow MR (1996) Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus Carvedilol in the failing heart. Circulation 94: 2817–25

    PubMed  CAS  Google Scholar 

  8. Hasenfuss G, Mulieri LA, Leavitt BJ, Allen PD, Haeberle JR, Alpert NR (1992) Alteration of contractile function and excitation-contraction coupling in dilated cardiomyopathy. Circ Res 70: 1225–32

    PubMed  CAS  Google Scholar 

  9. Hasenfuss G, Reinecke H, Studer R, Meyer M, Pieske B, Holtz J, Holubarsch C, Posival H, Just H, Drexler H (1994) Relation between myocardial function and expression of sarcoplasmic reticulum Ca(2+)-ATPase in failing and nonfailing human myocardium. Circ Res 75: 434–42

    PubMed  CAS  Google Scholar 

  10. Higginbotham MB, Morris KG, Williams RS, McHale PA, Coleman RE, Cobb FR (1986) Regulation of stroke volume during submaximal and maximal upright exercise in normal man. Circ Res 58: 281–91

    PubMed  CAS  Google Scholar 

  11. Koch-Weser J, Blinks JR (1963) The influence if the interval between beats on myocardial contractility. Pharmacol Rev 15: 601–52

    PubMed  CAS  Google Scholar 

  12. Meyer M, Schillinger W, Pieske B, Holubarsch C, Heilmann C, Posival H, Kuwajima G, Mikoshiba K, Just H, Hasenfuss G (1995) Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. Circulation 92: 778–84

    PubMed  CAS  Google Scholar 

  13. Mulieri LA, Alpert NR (1997) The role of myocardial force-frequency relation in left ventricular function and progression of human heart failure. In: Altschuld R, Haworth R (eds.) Heart metabolism in failure. Greenwich, Connecticut: JAI Press, 2

    Google Scholar 

  14. Mulieri LA, Hasenfuss G, Ittleman F, Blanchard EM, Alpert NR (1989) Protection of human left ventricular myocardium from cutting injury with 2,3-butanedione monoxime. Circ Res 65: 1441–9

    PubMed  CAS  Google Scholar 

  15. Mulieri LA, Hasenfuss G, Leavitt B, Allen PD, Alpert NR (1992) Altered myocardial force-frequency relation in human heart failure. Circulation 85: 1743–50

    PubMed  CAS  Google Scholar 

  16. Mulieri LA, Leavitt BJ, Hasenfuss G, Allen PD, Alpert NR (1992) Contraction frequency dependence of twitch and diastolic tension in human dilated cardiomyopathy (tension-frequency relation in cardiomyopathy). Basic Res Cardiol 87 Suppl 1: 199–212

    Google Scholar 

  17. Mulieri LA, Leavitt BJ, Martin BJ, Haeberle JR, Alpert NR (1993) Myocardial force-frequency defect in mitral regurgitation heart failure is reversed by forskolin. Circulation 88: 2700–4

    PubMed  CAS  Google Scholar 

  18. Mulieri LA, Leavitt BJ, Wright RK, Alpert NR (1997) Role of cAMP in modulating relaxation kinetics and the force-frequency relation in mitral regurgitation heart failure. Basic Res Cardiol 92 (Suppl 1): 95–103

    Article  PubMed  CAS  Google Scholar 

  19. Packer M (1992) The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure (editorial). J Am Coll Cardiol 20: 248–54

    Article  PubMed  CAS  Google Scholar 

  20. Packer M (1992) Pathophysiology of chronic heart failure. Lancet 340: 88–92

    Article  PubMed  CAS  Google Scholar 

  21. Pieske B, Hasenfuss G, Holubarsch C, Schwinger R, Bohm M, Just H (1992) Alterations of the force-frequency relationship in the failing human heart depend on the underlying cardiac disease. Basic Res Cardiol 87 Suppl 1: 213–21

    PubMed  Google Scholar 

  22. Pieske B, Kretschmann B, Meyer M, Holubarsch C, Weirich J, Posival H, Minami K, Just H, Hasenfuss G (1995) Alterations in intracellular calcium handling associated with the inverse force-frequency relation in human dilated cardiomyopathy. Circulation 92: 1169–78

    PubMed  CAS  Google Scholar 

  23. Plotnick GD, Becker LC, Fisher ML, Gerstenblith G, Renlund DG, Fleg JL, Weisfeldt ML, Lakatta EG (1986) Use of the Frank-Starling mechanism during submaximal versus maximal upright exercise. Am J Physiol 251: H1101–5

    PubMed  CAS  Google Scholar 

  24. Ricci DR, Orlick AE, Alderman EL, Ingels NB Jr, Daughters GT 2d, Kusnick CA, Reitz BA, Stinson EB (1979) Role of tachycardia as an inotropic stimulus in man. J Clin Invest 63: 695–703

    Article  PubMed  CAS  Google Scholar 

  25. Schouten VJ (1990) Interval dependence of force and twitch duration in rat heart explained by Ca2+ pump inactivation in sarcoplasmic reticulum. J Physiol (Lond) 431: 427–44

    CAS  Google Scholar 

  26. Studer R, Reinecke H, Bilger J, Eschenhagen T, Bohm M, Hasenfuss G, Just H, Holtz J, Drexler H (1994) Gene expression of the cardiac Na(+)-Ca2+ exchanger in end-stage human heart failure. Circ Res 75: 443–53

    PubMed  CAS  Google Scholar 

  27. Thomas JA, Marks BH (1978) Plasma norepinephrine in congestive heart failure. Am J Cardiol 41: 233–43

    Article  PubMed  CAS  Google Scholar 

  28. Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A (1993) Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group (see comments). Lancet 342: 1441–6

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dept. Molecular Physiology and Biophysics, University of Vermont, Burlington, USA

    N. R. Alpert & L. A. Mulieri

  2. Dept. Surgery, University of Vermont, Burlington, USA

    B. J. Leavitt & F. P. Ittleman

  3. Medizinische Klinik III, Universität Freiburg, Germany

    G. Hasenfuss & B. Pieske

  4. Dept. Molecular Physiology and Biophysics, Given Building, University of Vermont, Burlington, VT, 05405, USA

    N. R. Alpert

Authors
  1. N. R. Alpert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. J. Leavitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. P. Ittleman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Hasenfuss
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B. Pieske
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. A. Mulieri
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Abteilung Kardiologie und Pneumologie, Universität Göttingen, Robert-Koch-Straße 40, 37075, Göttingen, Germany

    G. Hasenfuss

  2. Medizinische Fakultät, Ethik Kommission, Elsässer Straße 2a, Haus 1a, 79110, Freiburg, Germany

    H. Just

Rights and permissions

Reprints and permissions

Copyright information

© 2000 Steinkopff Verlag Darmstadt

About this paper

Cite this paper

Alpert, N.R., Leavitt, B.J., Ittleman, F.P., Hasenfuss, G., Pieske, B., Mulieri, L.A. (2000). A mechanistic analysis of the force-frequency relation in non-failing and progressively failing human myocardium. In: Hasenfuss, G., Just, H. (eds) Heart rate as a determinant of cardiac function. Steinkopff. https://doi.org/10.1007/978-3-642-47070-7_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-47070-7_2

  • Publisher Name: Steinkopff

  • Print ISBN: 978-3-642-47072-1

  • Online ISBN: 978-3-642-47070-7

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation