<p>In every heartbeat, cardiac muscle cells (cardiomyocytes) generate contractile forces to pump blood to the body, and the heart has a remarkable capability to maintain sufficient blood flow despite the changes in a person’s daily activities. Part of this capability resides within each cardiomyocyte, which has an intrinsic mechano-chemo-transduction (MCT) mechanism that automatically converts mechanical load into biochemical signals to enhance the amplitude and speed of contraction. The exact cellular and molecular mechanisms, however, are unclear and currently under investigation. To help decipher these mechanisms, we developed an in vitro experimental setup, called the Cell-in-Gel system, wherein isolated live cardiomyocytes are paced to contract periodically within a soft hydrogel. This provides a way to exercise a cardiac cell under a controlled mechanical load by adjusting the stiffness of the hydrogel. Most data (cell shortening and calcium ion dynamics) can be directly measured during the experiments. Some data (mechanical force and stress) must be inferred by analysis, which is the subject of this study. As computational tools to interpret ongoing experiments, we develop analytical and numerical 3-D mechanical analysis of a single cardiomyocyte contracting in a viscoelastic medium. The analytical model is based on approximating the cell as an ellipsoid entity and seeking the computationally eﬃcient solution of viscoelastic generalization of the elastic Eshelby inclusion problem, which provides realistic predictions of the time-dependent mechanical ﬁelds in the Cell-in-Gel system. The model is used for quantifying the cell’s mechanical stress and exploring the cell’s response to diﬀerent levels of afterload as well as studying the parametric sensitivities of the system including the relative stiffness of the cell, cell’s aspect ratio, and cross-link density of the hydrogel matrix. Consistent with experimental data, the model also identiﬁes a closed-loop MCT control that autoregulates the cell’s contraction, thereby adding a new feedback feature to the current paradigm of feed-forward cardiac excitation-Ca2<sup>+</sup> signaling-contraction coupling. The numerical model is based on the ﬁnite-element analysis (FEA) of the time- dependent mechanical ﬁelds using actual geometries of various cells. In both modeling approaches, the cardiomyocytes are treated as isotropic continuum objects for which the details of the internal structure are neglected. Comparison of the simulation results show very good agreements between the average stress and strain ﬁelds using both modeling approaches. In conclusion, our analytical model combining MCT with viscoelastic Eshelby inclusion model provides eﬃcient calculation of the time- dependent mechanical ﬁelds in the Cell-in-Gel system. Our FEA computational model can provide realistic predictions of the mechanical ﬁelds in cardiomyocytes with various geometries. Importantly, our modeling study reveals intrinsic autoregulation of contractility within a single cardiomyocyte, which should contribute to the heart’s adaptive response to mechanical load changes.</p>

Single-Cell Computational Modeling of Cardiomyocyte Contractility Autoregulation in a 3-D Hydrogel

Paper Proceedings: https://asmedigitalcollection.asme.org/IMECE/IMECE2021/volume/85543

ASME 2021 International Mechanical Engineering Congress and Exposition (IMECE2021)

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