The development of drugs designed for cardiovascular diseases is a drawn-out, expensive, and inefficient process, as less than 10% of clinically tested drugs are approved to market, and the development of a single drug can cost over 1.5 billion USD. Moreover, many other types of drugs are withdrawn from sale because of their side effects, especially of cardiovascular nature. Computational models of cardiac cells enable high-throughput drug screening and disease risk stratification, e.g., vulnerability to arrhythmia, and enhance our quantitative understanding of cardiac disease mechanisms at cellular and molecular levels.
In his doctoral research, Amin Forouzandehmehr investigated the molecular mechanisms and cellular crosstalks contributing to mutation-specific hypertrophic cardiomyopathy and acute ischemia by advancing computer modeling and simulations (i.e., in silico investigations) of electro-mechano-energetic coupling in cardiomyocytes. The goal was to provide robust and accurate computational tools for fast pre-clinical drug screening, find potential therapeutic targets, and offer new models of drug mechanism modeling specifically for sarcomere-targeting and Ca2+-sensitizing compounds.
“Resolving the ethical concerns regarding animal-based experiments, human induced pluripotent stem cell-derived cardiomyocytes, i.e. hiPSC-CMs, represent a virtually limitless pool of human in vitro models in cardiology. They open new opportunities for patient-specific safety cardiac pharmacology as they share the same genotype with patients and exhibit the same pathological traits as their real-life counterparts”, Forouzandehmehr says.
Computational models of the function of hiPSC-CMs assist us in bridging important vital gaps. Namely, first, enhancing our quantitative understanding of intracellular interactions in drug trials and exploring genotype-phenotype relationships affecting the cardiac function. Second, high-throughput risk stratification and prediction of vulnerability to adverse conditions such as arrhythmia and third, addressing functional differences between in vitro hiPSC-CMs and human adult ventricular CMs, and provide the bridge from in vitro to actual human cardiac functions, aligning with a promising new paradigm in drug screening by the FDA (the comprehensive proarrhythmia assay).
The first aim of this thesis was to develop a robust whole-cell model of hiPSC-CMs electromechanics capturing the mechano-electric feedback by integrating a reparametrized contractile element (CE) into the ionic model of hiPSC-CMs. The second aim was proposing a computational approach toward deep-phenotyping mutation-specific hypertrophic cardiomyopathy (HCM), specifically MYH7R403Q/+ and exploring the effects and action mechanisms of Mavacamten (MAVA), Blebbistatin (BLEB), and Omecamtive mecarbil (OM).
The final aim was refining the hiPSC-CMs model of electro-mechano-energetic coupling to explore the interorganellar crosstalks in ischemia/reperfusion (I/R). A novel oxygen dynamic formulation was introduced to link the capillary level to extracellular oxygen concentrations affected by Na+/K+ exchanger, sarcolemmal Ca2+ pump current, and the contractile ATPase rate. The common methodology in the thesis articles is use of a set of in vitro data for model calibrations and another set of in vitro data for quantitative/qualitative results validations prioritizing hiPSC-CMs in vitro findings.
“My research offers novel and robust computational frameworks of electro-mechano-energetic coupling in hiPSC-CMs, leveraging recent advances in human-based in vitro data acquisition. Ultimately, the in silico models I developed can serve as a platform for fast drug screening and testing advanced treatment ideas according to the temporal evolution of metabolites and molecular mechanisms in cardiomyocytes”, Forouzandehmehr says.
Amin Forouzandehmehr is from Isfahan, Iran. He works in the Computational Biophysics & Imaging Group at Faculty of Medicine and Health Technology of Tampere University and specializes in developing mathematical models of cardiac cells.
Public defence on Friday 16 February
The doctoral dissertation of MSc (Tech) Mohamadamin Forouzandehmehr in the field of Biomedical Engineering titled Mathematical Modeling of Cardiomyocytes Pathophysiology and Biomechanics will be publicly examined at the Faculty of Medicine and Health Technology at Tampere University at 12 o’clock on Friday 16 February 2024 at Hervanta Campus, Tietotalo building, auditorium TB109 (Korkeakoulunkatu 1, Tampere). The Opponent will be Professor Axel Loewe from Karlsruhe Institute of Technology. The Custos will be Professor Jari Hyttinen from Tampere University.
Photo: Santiago Laguna Castro