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Updated: Jul 31, 2026
Assessment of Myofilament Ca2+ Sensitivity Underlying Cardiac Excitation-contraction Coupling
Published on: August 1, 2016
Responsiveness of the myofilaments to Ca2+ in human heart failure: implications for Ca2+ and force regulation
R J Hajjar1, W Grossman, J K Gwathmey
1Medical Services, Massachusetts General Hospital, Boston.
Insights
Heart failure does not alter basic contractile properties but affects myofilament response to inotropic agents. Novel drug DPI 201-106 sensitizes myofilaments in failing hearts, suggesting therapeutic potential for heart muscle disease.
Area of Science:
- Cardiovascular Physiology
- Cardiac Muscle Mechanics
- Pharmacology
Background:
- Myofilament calcium sensitivity and maximal force are key determinants of cardiac contractility.
- Human right-ventricular trabeculae carneae from healthy and end-stage heart failure (HF) patients provide a model for studying cardiac muscle properties.
- Understanding alterations in HF is crucial for developing targeted therapies.
Purpose of the Study:
- To compare myofilament calcium sensitivity and maximal calcium-activated force between normal and failing human hearts.
- To investigate the effects of the novel inotropic agent DPI 201-106 on myofilament properties in both normal and failing human cardiac muscle.
- To explore the relationship between twitch and steady-state calcium-force relationships and the impact of protein kinase C.
Main Methods:
- Experiments utilized chemically-skinned and intact tetanized human right-ventricular trabeculae carneae.
- Calcium-force relationships were analyzed under varying calcium concentrations.
- The effects of DPI 201-106 (a novel inotropic agent) and protein kinase C stimulation were assessed.
Main Results:
- No significant differences were found in calcium-activation or maximal calcium-activated force between normal and myopathic muscles.
- 1 microM DPI 201-106 significantly sensitized myofilaments to Ca2+ in myopathic muscles but not in control muscles.
- The twitch calcium-force relationship was dissociated from the steady-state relationship and influenced by the time-course of calcium transients, not myofilament sensitivity.
Conclusions:
- While fundamental contractile properties are preserved in end-stage heart failure, there are alterations in thin filament regulation.
- Myopathic human hearts exhibit enhanced myofilament sensitivity to the inotropic agent DPI 201-106.
- These findings suggest potential for novel therapeutic strategies targeting thin filament regulation in heart failure.
Abstract:
Myofilament calcium sensitivity and maximal calcium-activated force are fundamental properties of the contractile proteins in the heart. We examined these properties in normal human right-ventricular trabeculae carneae obtained from hearts of brain-dead patients with no known cardiac disease, and from patients with end-stage heart failure undergoing cardiac transplantation. There were no differences in calcium-activation of the control and myopathic muscles from chemically-skinned trabeculae or from intact tetanized preparations. We then tested the effect of DPI 201-106 (4-[3-(4-diphenylmethyl-1-piperazinyl)-2-hydroxypropoxy]-1H-indole - carbonitrile), a new inotropic agent, in both preparations. In myopathic muscles, 1 microM DPI sensitized the myofilaments to Ca2+, as evidenced by a significant shift of the [Ca2+]-force relationship towards lower [Ca2+], in both skinned and intact preparations. On the other hand, the same concentration of DPI did not affect the calcium-activation in control muscles in both preparations. We also found that the twitch [Ca2+]-force relationship, which has been used as an indication of myofilament sensitivity, was dissociated from the steady-state [Ca2+]-force relationship, and was shifted along the [Ca2+] axis by modulation in the time-course of the twitch and [Ca2+]i, and not by the sensitivity of the myofilaments to Ca2+. Protein kinase C stimulation differentially altered the responsiveness of the myofilaments to Ca2+ in normal and myopathic muscle fibers. We propose that even though calcium activation and maximal calcium-activated force are unaltered in myopathic hearts there are changes in thin filament regulation in myopathic hearts that result in altered responses to agents that directly act on the thin filaments, and that the potential for force development is similar in normal and myopathic human hearts.
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