| Popis: |
The assessment of drug safety and efficacy remains one of the biggest challenges in preclinical and clinical drug development. The prediction of drug action on cardiac contraction and electrophysiology is especially complex and diseased cardiac substrates are at a higher risk of developing potentially lethal reactions to pharmacological therapy. A deep mechanistic understanding of drug action in the context of specific cardiac pathophysiology is needed to guide the development and administration of effective and safe patient-specific therapies. These mechanistic understandings are still unknown for many cardiac diseases in particular cardiomyopathies. Most cardiomyopathy treatments focus on symptom relief, which do not specifically target disease pathophysiology. Therefore, defining key mechanisms in inherited cardiomyopathies due to specific genetic mutations is needed to develop novel effective pharmacological interventions that are patient specific. Human-based modelling and simulation can accelerate the mechanistic understanding of cardiac pathophysiology and the development and evaluation of therapeutic interventions through human in-silico trials. Thus, the overall goal of this thesis is to develop computational methodologies integrated with experimental and clinical data to investigate the mechanisms explaining the cardiac safety and efficacy of pharmacological therapies in health and hypertrophic cardiomyopathy. To achieve this goal a novel in-silico human electromechanical ventricular modelling and simulation framework was developed, and mechanistic simulations conducted to assess drug-induced pro-arrhythmia and inotropic risk in healthy cardiac function. Next, a novel software tool was developed to provide automated high-throughput analysis of calcium transients in cardiomyocytes. This was used to phenotype primary and induced pluripotent stem cell-derived cardiomyocytes under pharmacological action and hypertrophic cardiomyopathy variants. Analysed data was used to inform a computational investigation into the pathophysiology of three different hypertrophic cardiomyopathy-causing mutations and their response to the novel pharmacological compound Mavacamten. To conduct in-silico trials of Mavacamten, the cellular electromechanical model was extended to include representation of myosin sequestration and release from the energy-conserving state SRX. Overall, this thesis contributes towards a better understanding of how cardiac electromechanical substrates are affected by disease and pharmacological action and holds both preclinical and translational potential for precision medicine in inherited cardiomyopathies. |
