Smiljana Tomasevic1,2*, Miljan Milosevic2,3, Bogdan Milicevic1,2, Vladimir Simic2,3, Momcilo Prodanovic2,3,4, Srboljub M. Mijailovich4,5, Nenad Filipovic1,2
1Faculty of Engineering, University of Kragujevac, Sestre Janjic 6, 34000 Kragujevac, Serbia
2Bioengineering Research and Development Center (BioIRC), Prvoslava Stojanovica 6, 34000 Kragujevac, Serbia
3Institute for Information Technologies, University of Kragujevac, Jovana Cvijica bb, 34000 Kragujevac, Serbia
4FilamenTech, Inc., Newton, MA 02458, USA
5BioCAT, Department of Biology, Illinois Institute of Technology, Chicago, IL 60616, USA
smiljana [at] kg.ac.rs
Abstract
Analysis of myocardial work is essential in determination of left ventricle ejection fraction (LVEF) and non-invasive assessment of different types of cardiomyopathies. Two major classifications of cardiomyopathy are: dilated (DCM) and hypertrophic (HCM) cardiomyopathy. Although there are clinical improvements in cardiomyopathy risk assessment, patients are still under high risk of severe events. Computational modeling of and computer-aided drug design can significantly advance the understanding of cardiac muscle activity in DCM and HCM cardiomyopathies, speed up the drug discovery and reduce the risk of severe events, aiming to improve the treatment of cardiomyopathy.
The main advantage and novelty of presented study are coupled macro and micro simulations into the integrated Fluid Solid Interaction (FSI) system and its application for examination of heart behavior and drug interactions. In contrary to detailed and patient-specific models where FSI analyses are very time-consuming, our models are parametric and based on dimensions of specific LV components. FSI algorithm within the PAK software is used for modeling the LV with nonlinear material model, together with stretches integration along muscle fibers. The methods are integrated within the SILICOFCM platform, and aim to propose an advanced approach for the assessment of work indices and biomechanical characteristics of cardiomyopathies and drugs effects, based on computational modelling.
In this study, simulations of the effect of drugs on improving performance of DCM LV parametric model include the drugs that affect calcium transients (Dygoxin) and changes in kinetic parameters (2-deoxy adenosine triphosphate – dATP). Myocardial word is presented through changes of pressures and volumes (P-V diagrams) for DCM LV model at basic condition (without administered drug) and with using Dygoxin and dATP. Due to increased LV size, the P-V loop for the DCM model without administered drug is shifted toward lower ventricular pressure and lager ventricular volume, with LVEF = 56.83%. Effects of drugs on DCM show an increase in ventricular peak pressures and LVEFs, while the P-V loops are shifted toward decreased volumes, corresponding to healthy hearts.
Computational modeling and drug design approaches can speed up the drug discovery and significantly reduce expenses aiming to improve the treatment of cardiomyopathy.
Keywords: Computational modelling, Myocardial work, Dilated cardiomyopathy, Drug effects
Acknowledgement: This work is supported by the European Union’s Horizon 2020 research and innovation pro-grammes SILICOFCM (Grant agreement 777204) and SGABU (Grant agreement 952603). The Commission is not responsible for any use that may be made of the information it contains. The research was also funded by Serbian Ministry of Education, Science, and Technological Development, grants [451-03-47/2023-01/200378 (Institute for Information Technologies, University of Kragujevac)] and [451-03-47/2023-01/200107 (Faculty of Engineering, University of Kragujevac)].
