Investigating Clozapine-Induced Myocarditis in Stem Cell-Derived Cardiomyocytes from Treatment-Resistant Schizophrenia Patients: A Pharmacoepigenomic Approach

Clozapine, an antipsychotic with proven efficacy for treatment-resistant schizophrenia, is often underutilized due to the risk of severe side effects such as myocarditis (cardiac inflammation). This study explores whether epigenetic regulation may predispose individuals to clozapine-induced myocarditis, aiming to uncover biomarkers that can predict risk of this adverse effect and thus improve clinical outcomes. Utilizing a novel in vitro model, I used induced pluripotent stem cells (iPSCs) derived from patients with treatment-resistant schizophrenia who either experienced clozapine-induced myocarditis (cases) or did not (controls). These iPSCs were differentiated into cardiomyocytes (iPSC-CMs) and exposed to clozapine. My work focused on the integration of chromatin immunoprecipitation of H3K4me3 and H3K27ac, gene expression profiles and DNA methylation patterns to identify potential predictive markers of myocarditis risk. Our findings revealed significant epigenetic alterations associated with myocarditis risk. In cases, there was a notable hypermethylation at the promoter regions of genes such as GSTM1 and ZNF559, which was correlated with decreased gene expression. Conversely, hypermethylation in the gene bodies of AKAP7 and HLA-DRB1 was associated with increased expression. In conclusion, my study highlights the critical role of epigenetic profiles in mediating the effects of clozapine and suggests potential biomarkers for predicting clozapine-induced myocarditis. These insights pave the way for further research into the epigenetic regulation of drug responses in psychiatric disorders, with the long-term goal of enhancing therapeutic efficacy and safety through tailored treatment strategies.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Discipline thesis:degree_discipline

Medicine – Medical Sciences

Grantor dc:publisher.institution

Graduate Studies

Year dc:date.issued

2024

Author dc:creator

• Ferri Marques, Diogo

Advisors dc:contributor.advisor

• Bousman, Chad
• Greenway, Steven

Committee members dc:contributor.committeemember

• Hemberger, Myriam
• Dean, Wendy

• Epigenetics
• Schizophrenia
• Histone modifications
• DNA methylation
• Myocarditis
• Clozapine

Statement dc:rights

• University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.

Language dc:language.iso

en

DOI

https://dx.doi.org/10.11575/PRISM/47015

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:1880/119403