Increased Cell Membrane Capacitance is the Dominant Mechanism of Stretch-Dependent Conduction Slowing in the Rabbit Heart: A Computational Study
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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.
KeywordsMechano-electric feedback Stretch-activated currents Cell membrane Bidomain model Tissue conductivity Multiscale model Pressure loaded heart
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.
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.
- 10.Kuijpers, N., H. T. Eikelder, P. Bovendeerd, S. Verheule, and T. A. P. Hilbers. Mechano-electric feedback leads to conduction slowing and block in acutely dilated atria: a modeling study of cardiac electromechanics. Am. J. Physiol. Heart Circ. Physiol., 292(6):H2832–H2853, 2007.CrossRefGoogle Scholar
- 11.Lee, A. A., T. Delhaas, L. Waldman, D. A. MacKenna, F. J. Villarreal, and A. D. McCulloch. An equibiaxial strain system for cultured cells. Am. J. Physiol., 271(4):1400–1408, 1996.Google Scholar
- 13.Mahajan, A., Y. Shiferaw, D. Sato, A. Baher, R. Olcese, L.-H. Xie, M.-J. Yang, P.-S. Chen, J. G. Restrepo, A. Karma, A. Garfinkel, Z. Qu, and J. N. Weiss. A rabbit ventricular action potential model replicating cardiac dynamics at rapid heart rates. Biophys. J., 94:392–410, 2008.CrossRefGoogle Scholar
- 16.Niederer, S. A., E. Kerfoot, A. P. Benson, M. O. Bernabeu, O. Bernus, C. Bradley, E. M. Cherry, R. Clayton, F. H. Fenton, A. Garny, E. Heidenreich, S. Land, M. Maleckar, P. Pathmanathan, G. Plank, J. F. Rodrguez, I. Roy, F. B. Sachse, G. Seemann, O. Skavhaug, and N. P. Smith. Verification of cardiac tissue electrophysiology simulators using an n-version benchmark. Philos. Trans. R. Soc. A, 369:4331–4351, 2011.CrossRefGoogle Scholar
- 17.Niederer, S., L. Mitchell, N. Smith, and G. Plank. Simulating human cardiac electrophysiology on clinical time-scales. Fronti. Physiol., 2:14, 2011.Google Scholar
- 18.Pfeiffer, E. R., A. T. Wright, A. G. Edwards, J. C. Stowe, K. McNall, J. Tan, I. Niesman, H. H. Patel, D. M. Roth, J. H. Omens, and A. D. McCulloch. Caveolae in ventricular myocytes are required for stretch-dependent conduction slowing. J. Mol. Cell. Cardiol., 76:265–274, 2014.CrossRefGoogle Scholar
- 19.Reed, A., P. Kohl, and R. Peyronnet. Molecular candidates for cardiac stretch-activated ion channels. Global Cardiol. Sci. Pract., 2014(2):9–25, 2014.Google Scholar
- 21.Sachse, F., G. Seemann, and C. Riedel. Modeling of cardiac excitation propagation taking deformation into account. Proceedings of BIOMAG, pp. 839–841, 2002.Google Scholar
- 22.Sachse, F., B. Steadman, J. Bridge, B. Punske, and B. Taccardi. Conduction velocity in myocardium modulated by strain: measurement instrumentation and initial results. Conf. Proc. IEEE Eng. Med. Biol. Soc., 5:3593–3596, 2004.Google Scholar
- 23.Sinha, B., D. Kster, R. Ruez, P. Gonnord, M. Bastiani, D. Abankwa, R. V. Stan, G. Butler-Browne, B. Vedie, L. Johannes, N. Morone, R. G. Parton, G. Raposo, P. Sens, C. Lamaze, and P. Nassoy. Cells respond to mechanical stress by rapid disassembly of caveolae. Cell, 144(3):402–413, 2011.CrossRefGoogle Scholar
- 29.Sung, D., R. Mills, J. Schettler, S. M. Narayan, J. H. Omens, and A. D. McCulloch. Ventricular filling slows epicardial conduction and increases action potential duration in an optical mapping study of the isolated rabbit heart. J. Cardiovasc. Electrophysiol., 14(7):739–749, 2003.CrossRefGoogle Scholar
- 34.Wall, S. T., J. M. Guccione, M. B. Ratcliffe, and J. Sundnes. Electromechanical feedback with reduced cellular connectivity alters electrical activity in an infarct injured left ventricle: a finite element model study. AJP: Heart Circ. Physiol., 302(1):H206–H214, Dec. 2011.Google Scholar