Modeling cardiomyocyte mechanics and autoregulation of contractility by mechano-chemo-transduction feedback

Mohammad A Kazemi-Lari; Rafael Shimkunas; Zhong Jian; Bence Hegyi; Leighton Izu; John A Shaw; Alan S Wineman; Ye Chen-Izu

doi:10.1016/j.isci.2022.104667

Modeling cardiomyocyte mechanics and autoregulation of contractility by mechano-chemo-transduction feedback

iScience. 2022 Jun 26;25(7):104667. doi: 10.1016/j.isci.2022.104667. eCollection 2022 Jul 15.

Authors

Mohammad A Kazemi-Lari¹, Rafael Shimkunas¹, Zhong Jian¹, Bence Hegyi¹, Leighton Izu¹, John A Shaw², Alan S Wineman³, Ye Chen-Izu^{1

4

5}

Affiliations

¹ Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA.
² Department of Aerospace Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616, USA.
⁵ Department of Internal Medicine, Division of Cardiology, University of California, Davis, Davis, CA 95616, USA.

Abstract

The heart pumps blood into circulation against vascular resistance and actively regulates the contractile force to compensate for mechanical load changes. Our experimental data show that cardiomyocytes have a mechano-chemo-transduction (MCT) mechanism that increases intracellular ${Ca}^{2 +}$ transient to enhance contractility in response to increased mechanical load. This study advances the cardiac excitation- ${Ca}^{2 +}$ signaling-contraction (E-C) coupling model on conceptual and technical fronts. First, we developed analytical and computational models to perform 3-dimensional mechanical analysis of cardiomyocytes contracting in a viscoelastic medium under mechanical load. Next, we proposed an MCT feedback loop in the E-C coupling dynamic system to shift the feedforward paradigm of cardiac E-C coupling to an autoregulation model. Our combined modeling and experimental studies reveal that MCT enables autoregulation of E-C coupling and contractility in single cardiomyocytes, which underlies the heart's intrinsic autoregulation in compensatory response to load changes in order to maintain the stroke volume and cardiac output.

Keywords: Bioinformatics; Biomechanics; Biophysics; Mathematical biosciences.

Abstract

Grants and funding