Experimental assessment of a myocyte-based multiscale model of cardiac contractile dysfunction

Elena C Lascano1, Juan I Felice2, Sandra Wray1

  • 1Instituto de Medicina Translacional, Transplante y Bioingeniería, Universidad Favaloro-CONICET, Solís 453, Buenos Aires 1078, Argentina.

Insights

Mathematical modeling of cardiac contractile dysfunction (CD) using a multiscale model accurately simulated halothane

Area of Science:

  • Cardiovascular Physiology
  • Computational Biology
  • Pharmacology

Background:

  • Cardiac contractile dysfunction (CD) is a complex syndrome with multifactorial causes, making it challenging to isolate underlying mechanisms.
  • Mathematical modeling offers a powerful approach to dissecting the intricate processes contributing to CD and quantifying their impact.

Purpose of the Study:

  • To develop and validate a myocyte-based multiscale model of the circulatory system to simulate acute cardiac contractile dysfunction.
  • To investigate the effects of halothane, a volatile anesthetic known to induce CD, on cardiac function at both cellular and systemic levels.

Main Methods:

  • A multiscale model was constructed, integrating a human myocyte model with a circulatory system model comprising resistances and capacitances.
  • The model incorporated known halothane-induced alterations in ionic currents (SERCA2a, Ito, INCX, ICaL), ryanodine receptor (RyR2) function, and myofilament Ca2+ sensitivity.
  • Simulated myocyte and circulatory system responses were compared with established experimental data.

Main Results:

  • The model successfully replicated halothane-induced changes in action potential duration and intracellular Ca2+ concentration at the myocyte level.
  • Simulations showed reductions in mean arterial pressure, cardiac output, and regional wall thickening fraction, consistent with experimental findings in halothane-overdosed sheep.
  • The model's effective performance validates its ability to reproduce key physiological responses to anesthetic-induced cardiac dysfunction.

Conclusions:

  • The developed myocyte-based multiscale model accurately simulates acute cardiac contractile dysfunction induced by halothane.
  • This computational framework provides a valuable tool for studying the impact of various molecular targets on cardiac function and CD.
  • The model's predictive capability can aid in understanding CD mechanisms and potentially guide therapeutic strategies.

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