Skip to main content
SpringerLink
Log in

Cardiac Contractility Modulation With the Impulse Dynamics Signal: Studies in Dogs With Chronic Heart Failure

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

The intravenous use of positive inotropic agents, such as sympathomimetics and phosphodiesterase inhibitors, in heart failure is limited by pro-arrhythmic and positive chronotropic effects. Chronic use of these agents, while eliciting an improvement in the quality of life of patients with advanced heart failure, has been abandoned because of marked increase in mortality when compared to placebo. Nevertheless, patients with advanced heart failure can benefit from long-term positive inotropic support if the therapy can be delivered ‘on demand’ and in a manner that is both safe and effective. In this review, we will examine the use of a novel, non-stimulatory electrical signal that can acutely modulate left ventricular (LV) contractility in dogs with chronic heart failure in such a way as to elicit a positive inotropic support. Cardiac contractility modulation (CCM) with the Impulse Dynamic™ signal was examined in dogs with chronic heart failure produced by intracoronary microembolizations. Delivery of the CCM signal from a lead placed in the great coronary vein for periods up to 10 minutes resulted in significant improvements in cardiac output, LV peak+dP/dt, LV fractional area of shortening and LV ejection fraction measured angiographically. Discontinuation of the signal resulted in a return of all functional parameters to baseline values. In cardiomyocytes isolated from dogs with chronic heart failure, application of the CCM signal resulted in improved shortening, rate of change of shortening and rate of change of relengthening suggesting that CCM application is associated with intrinsic improvement of cardiomyocyte function. The improvement in isolated cardiomyocyte function after application of the CCM signal was accompanied by an increase in the peak and integral of the Ca2+ transient suggesting modulation of calcium cycling by CCM application. In a limited number of normal dogs, intermittent chronic delivery of the CCM signal for up to 7 days showed chronic maintenance of LV functional improvement. In conclusion, pre-clinical results to date with the Impulse Dynamics CCM signal indicate that this non-pharmacologic therapeutic modality can provide short-term positive inotropic support to the failing heart and as such, may be a useful adjunct in the treatment of advanced heart failure. Additional, long-term studies in dogs with heart failure are needed to establish the safety and efficacy of this therapeutic modality for the chronic treatment of this disease syndrome.

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

  1. Packer M. Vasodilator and inotropic drugs for the treatment of chronic heart failure: Distinguishing hype from hope. J Am Coll Cardiol 1988;12:1299–1317.

    Google Scholar 

  2. Rahimtoola SH. The pharmacologic treatment of chronic congestive heart failure. Circulation 1989; 80:693–699.

    Google Scholar 

  3. Erlemeier H-H, Kupper W, Bleifeld W. Intermittent infusion of dobutamine in the therapy of severe congestive heart failure-long-term effects and the lack of tolerance. Cardiovasc Drugs Ther 1992; 6:391–398.

    Google Scholar 

  4. Chatterjee K. Phosphodiesterase inhibitors: Alterations in systemic and coronary hemodynamics. Basic Res Cardiol 1989;84 (suppl 1):213–224.

    Google Scholar 

  5. Kanayama H, Ban M, Ogawa K, Satake T. Myocardial concentration of norepinephrine and cyclic AMP in ventricular fibrillation during acute myocardial ischemia. J Cardiovasc Pharmacol 1982;4:1018–1023.

    Google Scholar 

  6. Lubbe WF, Podquweit T. Opie LH. Potential arrhythmogenic role of cyclic adenosine monophosphate (AMP) and cytosolic calcium overload: Implications for prophylactic effects of beta-blockers in myocardial infarction and proarrhythmic effects of phosphodiesterase inhibitors. J Am Coll Cardiol 1992;19: 1622–1633.

    Google Scholar 

  7. Tisdale JE, Patel R, Webb CR, Borzak S, Zarowitz BJ. Electrophysiologic and proarrhythmic effects of intravenous inotropic agents. Prog Cardiovasc Dis 1995; 38:167–180.

    Google Scholar 

  8. Tisdale JE, Patel R, Webb CR, Borzak S, Zarowitz BJ. Proarrhythmic effects of intravenous vasopressors. Ann of Pharmacotherapy 1995;29:269–281.

    Google Scholar 

  9. Baumgart D, Ehring T. Krajcar M. Skyschally A, Heusch G. Characterization of the inotropic and arrhythmogenic action of the sodium channel activator BDF 9148: A comparison to its S-enantiomer BDF 9196, to its congener DPI 201±106, to norepinephrine, and to ouabain. Basic Res Cardiol 1994;89:61–79.

    Google Scholar 

  10. Raap A, Mest H-J, Stenzel W. Schloos J, Blechacz W. Investigation of the mechanism of the positive inotropic action of BDF 9148; comparison with DPI 201–106 and the enantiomers. J Cardiovasc Pharmacol 1997; 29:164–173.

    Google Scholar 

  11. Steinberg MI, McCall E, Mest H-J, Raap A. Wright T. Cardiac sodium channels as targets for new inotropic agents. Heart Failure Rev 1998;2:173–193.

    Google Scholar 

  12. Buggisch D, Isenberg G, Ravens U, Scholtysik GJ. The role of sodium channels in the effect of the cardiotonic compound DPI 201–106 on contractility and membrane potentials in isolated mammalian heart preparation. Eur J Pharmacol 1985;118: 303–311.

    Google Scholar 

  13. Bers DM. Excitation-Contraction Coupling and Cardiac Contractile Force. Kluwer Academic Press, Dordrecht, The Netherlands, 1991.

    Google Scholar 

  14. Raap A, Armah B, Hofferber E, Stenzel W, Schloos J, Blechacz W. BDF 9148: Comparison of action potential duration in vitro and prolongation of Q-T interval in anesthetized dogs (time course study) (Abstract). Naunyn-Schmiedebergs Arch Pharmacol 1991; 344:R85.

    Google Scholar 

  15. Rüegg PC, Nüesch E. The effect of a new inotropic agent, DPI 201–106, on systolic time intervals and the electrocardiogram in healthy subjects. Br J Clin Pharmacol 1987;24:453–458.

    Google Scholar 

  16. Algra A, Tijssen GJP, Roelandt JRTC, Pool J, Lubsen J. QTc prolongation measured by standard 12-lead electrocardiography is an independent risk factor for sudden death due to cardiac arrest. Circulation 1991; 83:1888–1894.

    Google Scholar 

  17. Cooper, MW. Postextrasystolic potentiation. Do we really know what it means and how to use it? Circulation 1993;88:2962–2971.

    Google Scholar 

  18. King, AJ, Taylor, DE. The inotropic action of paired pulse stimulation in the normal and failing heart: An experimental study. Cardiovasc Res 1968;2:122–129.

    Google Scholar 

  19. Hoffman BF, Artelstone HJ, Scherlag BJ, Cranefield Pf. Effects of postextrasystolic potentiation on normal and failing hearts. Bull N Y Acad Med 1965;41:498–534.

    Google Scholar 

  20. Sabbah HN, Mika Y, Aviv R, Haddad W, Darvish N, Ben-Haim SA, Chaudhry PA, Mishima T, Goldstein S. Delivery of non-excitatory contractility-modulation electric signals improve left ventricular performance in dogs with heart failure (Abstract). Circulation 1999;100:1–122.

    Google Scholar 

  21. Sabbah HN, Stein PD, Kono T, Gheorghiade M, Levine TB, Jafri S, Hawkins ET, Goldstein S. A canine model of chronic heart failure produced by multiple sequential coronary microembolizations. Am. J Physiol 1991;260:H1379-H1384.

    Google Scholar 

  22. Sabbah HN, Shimoyama H. Kono T, Gupta RS, Sharov VG, Scicli G, Levine TB, Goldstein S. Effects of longterm monotherapy with enalapril, metoprolol and digoxin on the progression of left ventricular dysfunction and dilation in dogs with reduced ejection fraction. Circulation 1994;89:2852–2859.

    Google Scholar 

  23. Tanimura M, Mishima T, Steinberg MI, Borzak S, Goldstein S, Sabbah HN: Hemodynamic effects of a novel sodium channel activator in dogs with chronic heart failure. Cardiovasc Drugs and Therapy, 2000; 14:77–82.

    Google Scholar 

  24. Lue WM, Boyden PA. Abnormal electrical properties of myocytes from chronically infarcted canine heart. Alterations in Vmax and the transient outward current. Circulation 1992;85:1175–1188.

    Google Scholar 

  25. Maltsev VA, Sabbah HN, Tanimura M, Lesch M, Goldstein S, Undrovinas AI. Relationship between action potential, contraction-relaxation and intracellular Ca2+ transient in cardiomyocytes of dogs with chronic heart failure. Cell Mol Life Sciences 1998;54:597–605. Electrical Modulation of Cardiac Contractility 53

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine & Division of Cardiovascular Medicine, Henry Ford Heart & Vascular Institute, Detroit, Michigan, U.S.A

    Hani N. Sabbah PhD, Omar Nass MD, Victor G. Sharov MD, PhD, Victor Maltsev PhD, Albertas I. Undrovinas PhD & Sidney Goldstein MD

  2. Impulse Dynamics, Tirat Hacarmel, Israel

    Walid Haddad PhD, Yuval Mika DSc, Ricardo Aviv PhD, Bella Felzen PhD, Nissim Darvish MD & Shlomo A. Ben-Haim MD, PhD

  3. Department of Physiology and Biophysics, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel

    Shlomo A. Ben-Haim MD, PhD

Authors
  1. Hani N. Sabbah PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Walid Haddad PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuval Mika DSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Omar Nass MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ricardo Aviv PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Victor G. Sharov MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Victor Maltsev PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bella Felzen PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Albertas I. Undrovinas PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sidney Goldstein MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nissim Darvish MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shlomo A. Ben-Haim MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sabbah, H.N., Haddad, W., Mika, Y. et al. Cardiac Contractility Modulation With the Impulse Dynamics Signal: Studies in Dogs With Chronic Heart Failure. Heart Fail Rev 6, 45–53 (2001). https://doi.org/10.1023/A:1009855208097

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1009855208097

Search

Navigation