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Septic cardiomyopathy in rat LPS-induced endotoxemia: relative contribution of cellular diastolic Ca2+ removal pathways, myofibrillar biomechanics properties and action of the cardiotonic drug levosimendan

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Abstract

Cardiac dysfunction is a common complication in sepsis and is characterized by forward pump failure. Hallmarks of septic cardiomyopathy are decreased myofibrillar contractility and reduced Ca2+ sensitivity but it is still not clear whether reduced pump efficiency is predominantly a diastolic impairment. Moreover, a comprehensive picture of upstream Ca2+ handling mechanisms and downstream myosin biomechanical parameters is still missing. Ca2+-sensitizing agents in sepsis may be promising but mechanistic insights for drugs like levosimendan are scarce. Here, we used an endotoxemic LPS rat model to study mechanisms of sepsis on in vivo hemodynamics, multicellular myofibrillar Ca2+ sensitivity, in vitro cellular Ca2+ homeostasis and subcellular actomyosin interaction with intracardiac catheters, force transducers, confocal Fluo-4 Ca2+ recordings in paced cardiomyocytes, and in vitro motility assay, respectively. Left ventricular ejection fraction and myofibrillar Ca2+ sensitivity were depressed in LPS animals but restored by levosimendan. Diastolic Ca2+ transient kinetics was slowed down by LPS but ameliorated by levosimendan. Selectively blocking intracellular and sarcolemmal Ca2+ extrusion pathways revealed minor contribution of sarcoplasmic reticulum Ca2+ ATPase (SERCA) to Ca2+ transient diastole in LPS-evoked sepsis but rather depressed Na+/Ca2+ exchanger and plasmalemmal Ca2+ ATPase. This was mostly compensated by levosimendan. Actin sliding velocities were depressed in myosin heart extracts from LPS rats. We conclude that endotoxemia specifically impairs sarcolemmal diastolic Ca2+ extrusion pathways resulting in intracellular diastolic Ca2+ overload. Levosimendan, apart from stabilizing Ca2+-troponin C complexes, potently improves cellular Ca2+ extrusion in the septic heart.

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Acknowledgments

This work was partly supported by the ELAN Fonds of the Erlangen Medical Faculty (13-02-25-1). The authors acknowledge excellent technical help from R Galmbacher and C Weber for catheter experiments and in vitro motility assays.

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Authors and Affiliations

  1. Institute of Medical Biotechnology, Friedrich-Alexander-University Erlangen-Nürnberg, Paul-Gordan-Str.3, 91052, Erlangen, Germany

    S. Wagner, S. Schürmann & O. Friedrich

  2. Department for Anesthesiology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany

    S. Wagner & J. Schüttler

  3. Medical Clinic III, Cardiology, Heidelberg University Hospitals, Heidelberg, Germany

    S. Hein

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  1. S. Wagner
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Correspondence to O. Friedrich.

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Wagner, S., Schürmann, S., Hein, S. et al. Septic cardiomyopathy in rat LPS-induced endotoxemia: relative contribution of cellular diastolic Ca2+ removal pathways, myofibrillar biomechanics properties and action of the cardiotonic drug levosimendan. Basic Res Cardiol 110, 50 (2015). https://doi.org/10.1007/s00395-015-0507-4

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