PhD Scientific Days 2024

Budapest, 9-10 July 2024

Poster Session R - Pharmaceutical Sciences and Health Technologies 2.

Characterization of a Mouse Model of Clozapine-Induced Myocarditis

Author(s)

Jakab Márk1,2, Hegedűs I. Zsombor1,2,3, Kovács Tamás1,2,3, Kovács Andrea1,2,3, Varga V. Zoltán1,2,3
1: HCEMM-SU Cardiometabolic Immunology Research Group, Budapest
2: MTA-SE Momentum Cardio-oncology and Cardio-immunology Research Group, Budapest
3: Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary

Text of the abstract

Introduction: According to the WHO pharmacovigilance database, nearly 60% of drug-associated myocarditis cases is attributable to clozapine treatment. Despite its prevalence, the underlying mechanism remains poorly understood. Animal models that accurately reflect clozapine-induced myocarditis are limited, and comprehensive studies on the functional changes are lacking.
Aims: Our study aimed to establish an animal model that mimics clozapine-induced myocarditis and to characterize the resulting cardiac abnormalities using imaging and electrophysiological techniques.
Methods: Male BALB/c mice aged 8 weeks were divided into three treatment groups: two experimental groups receiving clozapine at doses of 25 mg/kg and 35 mg/kg respectively, and a control group receiving vehicle, in the form of intraperitoneal injections. Cardiac function was assessed weekly via echocardiography and electrocardiogram. After 21 days of treatment, the mice were euthanized, and heart samples were collected and histologically evaluated for inflammatory infiltration.
Results: Clozapine treatment led to a significant decrease in body weight in the experimental groups. Both doses of clozapine resulted in a sudden reduction in left ventricular end-systolic and end-diastolic volumes. However, the ejection fraction was maintained with increased fractional shortening. Initially, there was an elevation in heart rate, likely as a compensatory response. Histological analysis confirmed the development of myocarditis, characterized by well-defined foci of infiltrating leucocytes and necrosis.
Conclusion: Our findings confirm that clozapine induces myocarditis in a dose-dependent manner in the BALB/c mouse model. Functional changes include alterations in ventricular volumes and heart rate, indicating cardiac dysfunction. Further investigations are needed to elucidate the underlying causes of these alterations
Funding: Momentum Research Grant from the Hungarian Academy of Sciences (LP- 2021-38 to ZVV)