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Schlüsselrolle des Ca2+ in der Herzinsuffizienz und mögliche neue therapeutische Ansatzpunkte

The key role of Ca2+ in heart failure und possible new options for treatment

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Der Kardiologe Aims and scope

Zusammenfassung

Bei chronischer Herzinsuffizienz kommt es unabhängig von der jeweiligen Ätiologie zu ausgeprägten Alterationen des zellulären Ca2+-Stoffwechsels und einer daraus resultierenden Störung der elektromechanischen Kopplung. Es findet sich eine Erniedrigung der systolischen Ca2+-Transienten bei gleichzeitiger Erhöhung der diastolischen Ca2+-Konzentration. Wissenschaftliche Untersuchungen der letzten Jahre konnten diese Veränderungen mit einer verminderten Expression und Aktivität der Ca2+-ATPase (SERCA2a) des sarkoplasmatischen Retikulums (SR) sowie einer vermehrten diastolischen Undichtigkeit der Ryanodinrezeptoren des SR in Verbindung bringen. Außerdem ist der bei Herzinsuffizienz erhöhte späte Na+-Strom (late INa) an der Na+-Überladung der Zelle beteiligt und behindert damit die Ca2+-Elimination aus dem Zytosol durch den Na+/Ca2+-Austauscher (NCX). Dieser Übersichtsbeitrag erläutert die entscheidende Rolle der veränderten Ca2+-Homöostase in der Pathogenese der Herzinsuffizienz und illustriert hierbei v. a. neue Erkenntnisse über zugrunde liegende Pathomechanismen. Außerdem werden daraus abgeleitete neue Therapiemöglichkeiten zusammengefasst und deren Entwicklungsstand und Potenzial hinsichtlich ihrer klinischen Anwendung erörtert.

Abstract

Chronic heart failure is characterized by distinct alterations in intracellular Ca2+ homeostasis leading to perturbations of excitation-contraction coupling. Systolic Ca2+ transients are typically lowered with diastolic Ca2+ levels being increased. Recent studies showed that these alterations of Ca2+ cycling are tightly linked to a reduced expression and activity of SERCA2a in heart failure as well as to an increased diastolic leakage of ryanodine receptors. In addition to that, the late inward current for Na+ ions (late INa) is increased and leads to an intracellular accumulation of Na+. The driving force for the Na+/Ca2+ exchanger (NCX) is thus reduced, compromising diastolic Ca2+ elimination out of the cytosol. This review article outlines the decisive role of Ca2+ cycling alterations in the pathogenesis of heart failure and focuses on new insights into underlying pathomechanisms. Furthermore, new therapeutic options are summarized and the stage of development with regard to their clinical application is analyzed.

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Danksagung

Prof. Maier wird seit Jahren durch die DFG unterstützt (Ma 1982/2-2, Ma 1982/4-1) sowie durch Fondation Leducq.

Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehungen hin: Prof. Maier steht im Rahmen seiner Forschung in Beziehung mit GILEAD, weiter bestehen Beziehungen mit Berlin-Chemie, Menarini und Servier.

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  1. Abt. Kardiologie und Pneumologie/Herzzentrum Göttingen, Georg-August-Universität Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Deutschland

    T.H. Fischer, A.G. Rokita &  L.S. Maier

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  1. T.H. Fischer
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Fischer, T., Rokita, A. & Maier, L. Schlüsselrolle des Ca2+ in der Herzinsuffizienz und mögliche neue therapeutische Ansatzpunkte. Kardiologe 5, 80–90 (2011). https://doi.org/10.1007/s12181-011-0325-3

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