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Altered communication between L-type calcium channels and ryanodine receptors in heart failure
Jean-Pierre Bénitah1, Benoît Gilles Kerfant, Guy Vassort
1INSERM U-390, Montpellier, France.
Insights
Heart failure (HF) impairs cardiomyocyte contraction by disrupting excitation-contraction coupling. Reduced efficiency of calcium (Ca2+) release from the sarcoplasmic reticulum, linked to T-tubule reorganization, underlies this depressed function in failing hearts.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Physiology
Background:
- Heart failure (HF) is a progressive syndrome characterized by decreased cardiac contractile function.
- Cardiomyocyte contraction relies on excitation-contraction (EC) coupling, involving calcium (Ca2+) influx through DHPRs and subsequent Ca2+ release from the sarcoplasmic reticulum (SR) via RyRs.
- Understanding the mechanisms of depressed cardiac function in HF is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the underlying mechanisms of impaired EC coupling in failing cardiomyocytes.
- To analyze the efficiency of Ca2+ handling and release in the context of HF.
- To elucidate the role of structural changes in T-tubules and SR in HF-related contractile dysfunction.
Main Methods:
- Analysis of excitation-contraction coupling elements in cardiomyocytes from failing and non-failing hearts.
- Measurement of calcium (Ca2+) current density (ICa) and sarcoplasmic reticulum (SR) Ca2+ release.
- Assessment of DHPR-RyR coupling efficiency and Ca2+ spark frequency.
- Evaluation of T-tubule density in failing myocytes.
Main Results:
- While Ca2+ current (ICa) density is generally maintained in HF, SR Ca2+ release is significantly reduced.
- The efficacy of ICa in triggering SR Ca2+ release is diminished in failing myocytes.
- In terminal HF without hypertrophy, reduced SR Ca2+ load contributes to decreased SR Ca2+ release.
- In hypertrophied failing myocytes, fewer Ca2+ sparks are triggered by equivalent ICa, suggesting altered T-tubule/junctional SR organization.
- Reduced T-tubule density in failing cells supports theories of functional or spatial reorganization.
Conclusions:
- Impaired excitation-contraction coupling in heart failure is multifactorial, involving reduced SR Ca2+ release and diminished DHPR-RyR coupling efficiency.
- Structural alterations, particularly reduced T-tubule density, contribute to altered Ca2+ handling and contractile dysfunction in HF.
- Further research into these mechanisms can guide therapeutic strategies for heart failure.
Abstract:
Heart failure (HF) is a progressive syndrome that appears as the final phase of most cardiac diseases and is manifested as a decreased contractile function. Contraction in cardiomyocytes arises by the Ca2+ induced Ca2+ release mechanism, where Ca2+ entry (ICa) through Ca2+ channels (DHPRs) activates Ca2+ release channels (RyRs) in the junctional sarcoplasmic reticulum (SR). This is the base of cardiac excitation-contraction (EC) coupling. To elucidate the mechanisms underlying depressed function of the failing heart, analysis of EC coupling main elements have been undertaken. ICa density is usually maintained in HF. However, failing myocytes show a reduced SR Ca2+ release. Then, if the trigger of SR Ca2+ release is maintained, why is SR Ca2+ release depressed in HF? Analyses of the DHPR-RyR coupling efficiency have revealed a decrease in the ICa efficacy to trigger Ca2+ release in failing myocytes. In terminal heart failure without hypertrophy, a decrease in SR Ca2+ load can account for the decreased SR Ca2+ release. Fewer Ca2+ sparks (elementary units of SR Ca2+ release) are triggered by an equivalent ICa in hypertrophied failing myocytes, suggesting a functional or spatial reorganization of the space T-tubule junctional SR. This theory is supported by new data showing that the T-tubule density is reduced in failing cells.