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Calcium-sensitizing inotropic agents in the treatment of heart failure: a critical view

R J Hajjar1, J K Gwathmey

  • 1Charles A. Dana Research Institute, Beth Israel Hospital, Boston, MA 02215.

Cardiovascular Drugs and Therapy
|December 1, 1991
PubMed

Insights

Calcium-sensitizing drugs worsen relaxation in myopathic hearts by increasing diastolic calcium. This impairs contractile reserve and reduces overall heart muscle force production.

Area of Science:

  • Cardiology
  • Cardiovascular Physiology
  • Biochemistry

Background:

  • Contractile function of heart muscles is influenced by alterations in calcium (Ca2+) handling.
  • New inotropic agents enhance cardiac contractility by increasing myofilament sensitivity to Ca2+.

Purpose of the Study:

  • To investigate the impact of calcium-sensitizing agents on force development in normal and myopathic human hearts.
  • To measure intracellular Ca2+ concentration and establish Ca2+-force relationships.

Main Methods:

  • Utilized the bioluminescent calcium indicator aequorin to measure systolic and diastolic intracellular Ca2+ concentration ([Ca2+]i).
  • Constructed [Ca2+]i-force relationships in isolated human heart muscle preparations (normal and myopathic).

Main Results:

  • Diastolic [Ca2+]i was significantly higher in myopathic hearts (361 +/- 68 nM) compared to normal hearts (225 +/- 52 nM).
  • Calcium-sensitizing agents increased diastolic force more substantially in myopathic hearts than in normal hearts.

Conclusions:

  • Inotropic agents that boost myofilament Ca2+ sensitivity exacerbate diastolic dysfunction in myopathic hearts.
  • These agents impair relaxation, reduce contractile reserve, and diminish active force production in failing heart muscle.

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