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Increased Cell Membrane Capacitance is the Dominant Mechanism of Stretch-Dependent Conduction Slowing in the Rabbit Heart: A Computational Study

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Abstract

Volume loading of the cardiac ventricles is known to slow electrical conduction in the rabbit heart, but the mechanisms remain unclear. Previous experimental and modeling studies have investigated some of these mechanisms, including stretch-activated membrane currents, reduced gap junctional conductance, and altered cell membrane capacitance. In order to quantify the relative contributions of these mechanisms, we combined a monomain model of rabbit ventricular electrophysiology with a hyperelastic model of passive ventricular mechanics. First, a simplified geometric model with prescribed homogeneous deformation was used to fit model parameters and characterize individual MEF mechanisms, and showed good qualitative agreement with experimentally measured strain-CV relations. A 3D model of the rabbit left and right ventricles was then compared with experimental measurements from optical electrical mapping studies in the isolated rabbit heart. The model was inflated to an end-diastolic pressure of 30 mmHg, resulting in epicardial strains comparable to those measured in the anterior left ventricular free wall. While the effects of stretch activated channels did alter epicardial conduction velocity (CV), an increase in cellular capacitance was required to explain previously reported experimental results. The new results suggest that for large strains, various mechanisms can combine and produce a biphasic relationship between strain and CV. However, at the moderate strains generated by high end-diastolic pressure, a stretch-induced increase in myocyte membrane capacitance is the dominant driver of conduction slowing during ventricular volume loading.

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Acknowledgments

Supported by The Research Council of Norway through a grant from the eVITA program and a Centre of Excellence grant to the Center for Biomedical Computing at Simula Research Laboratory, and by NIH Grants 8 P41 GM1034268, P50 GM094503, 1 R01 HL105242, and 1 R01 HL96544.

Conflict of interest

Bernardo L. de Oliveira, Emily R. Pfeiffer, Joakim Sundnes, Samuel T. Wall, and Andrew D. McCulloch declare that they have no conflicts of interest.

Ethical standards

No human studies or animal studies were carried out by the authors for this article. Studies were conducted on murine myocytes, which were isolated and cultured according to institutional, national, and international guidelines, and approved by the UCSD Animal Subjects Committee.

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Authors and Affiliations

  1. Simula Research Laboratory, P.O. Box 134, 1325, Lysaker, Norway

    Bernardo L. de Oliveira, Joakim Sundnes & Samuel T. Wall

  2. Department of Informatics, University of Oslo, Oslo, Norway

    Joakim Sundnes

  3. Bioengineering Department, University of California, San Diego, CA, USA

    Emily R. Pfeiffer & Andrew D. McCulloch

Authors
  1. Bernardo L. de Oliveira
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  2. Emily R. Pfeiffer
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Correspondence to Joakim Sundnes.

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Associate Editor Aleksander S. Popel oversaw the review of this article.

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Oliveira, B.L.d., Pfeiffer, E.R., Sundnes, J. et al. Increased Cell Membrane Capacitance is the Dominant Mechanism of Stretch-Dependent Conduction Slowing in the Rabbit Heart: A Computational Study. Cel. Mol. Bioeng. 8, 237–246 (2015). https://doi.org/10.1007/s12195-015-0384-9

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