Virtual population generator for human cardiomyocytes parameters: in silico drug cardiotoxicity assessment

Abstract

Background: The anatomical and histological parameters of the human ventricle depend on many factors including age and sex. Myocyte volume and electric capacitance are significant physiological parameters of left ventricle cardiomyocyte mathematical models. They allow the assessment of inter-individual variability during in vitro–in vivo extrapolation of the drug cardiotoxic effect.

Objective: The current research was carried out to analyze the relationship between age, human left ventricle cardiomyocyte volume, and electric capacitance in a healthy population.

Methods: In order to collect data describing cardiomyocyte volume and membrane area, literature searches were performed. It was assumed that the cardiomyocyte volume (VOL) and area (AREA) distribution have non-negative support and are skewed to the right. A log-linear model with constant variance was used. A simulation study was run to assess the influence of physiological parameters on action potential duration.

Results: The coefficient of determination for the proposed model R² = 0.95, that is, 95% of the variability observed in log cardiomyocyte volume can be explained by the estimated regression equation. To allow simple calculation and model performance validation, a simple Excel file was developed (Supplementary material).

Conclusions: To the best of our knowledge, there is no other model available, combining age, cardiomyocyte volume, and area. The main limitations of the proposed models result from the assumptions made at the data analysis stage. The limited amount of information available in the literature and the lack of differentiation between sexes results in one common equation. The developed model is a part of the computational system for drug cardiotoxicity assessment.

Keywords::

• Cardiomyocyte
• cardiomyocyte volume
• cardiomyocyte electric capacitance
• age correlation
• virtual population