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Cardiac myocytes transduce changes in mechanical loading into cellular responses via interacting cell signalling pathways. We previously reported a logic-based ordinary differential equation model of the myocyte mechanosignalling network that correctly predicts 78% of independent experimental results not used to formulate the original model. Here, we use Monte Carlo and polynomial chaos expansion simulations to examine the effects of uncertainty in parameter values, model logic and experimental validation data on the assessed accuracy of that model. The prediction accuracy of the model was robust to parameter changes over a wide range being least sensitive to uncertainty in time constants and most affected by uncertainty in reaction weights. Quantifying epistemic uncertainty in the reaction logic of the model showed that while replacing 'OR' with 'AND' reactions greatly reduced model accuracy, replacing 'AND' with 'OR' reactions was more likely to maintain or even improve accuracy. Finally, data uncertainty had a modest effect on assessment of model accuracy. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.

To identify how cardiomyocyte mechanosensitive signaling pathways are regulated by anisotropic stretch, micropatterned mouse neonatal cardiomyocytes were stretched primarily longitudinally or transversely to the myofiber axis. Four hours of static, longitudinal stretch induced differential expression of 557 genes, compared with 30 induced by transverse stretch, measured using RNA-seq. A logic-based ordinary differential equation model of the cardiac myocyte mechanosignaling network, extended to include the transcriptional regulation and expression of 784 genes, correctly predicted measured expression changes due to anisotropic stretch with 69% accuracy. The model also predicted published transcriptional responses to mechanical load in vitro or in vivo with 63-91% accuracy. The observed differences between transverse and longitudinal stretch responses were not explained by differential activation of specific pathways but rather by an approximately twofold greater sensitivity to longitudinal stretch than transverse stretch. In vitro experiments confirmed model predictions that stretch-induced gene expression is more sensitive to angiotensin II and endothelin-1, via RhoA and MAP kinases, than to the three membrane ion channels upstream of calcium signaling in the network. Quantitative cardiomyocyte gene expression differs substantially with the axis of maximum principal stretch relative to the myofilament axis, but this difference is due primarily to differences in stretch sensitivity rather than to selective activation of mechanosignaling pathways. [ABSTRACT FROM AUTHOR]