ADVANCING PRECLINICAL ASSESSMENT OF HIDDEN CARDIOTOXICITY: MECHANISTIC INSIGHTS AND TRANSLATIONAL APPLICATIONS IN DRUG DEVELOPMENT
Bennet Weber
Cardiovascular Medicine and Research Division
Dr. Merkely Béla
SE Farmakológiai és Farmakoterápiás Intézet Knoll József terem
2026-11-11 12:30:00
Cardiovascular Disorders: Physiology and Medicine of Ischaemic Circulatory Diseases
Dr. Merkely Béla
Dr. Görbe Anikó és Dr. Giricz Zoltán
Dr. Sayour Alex Ali
Dr. Priksz Dániel
Dr. Szökő Éva
Dr. Bagyura Zsolt
Dr. Szőke Éva
Current preclinical safety testing fails to detect drug-induced cardiac adverse effects that manifest only under stress or in the presence of comorbidities. If preclinical testing in healthy tissues fails to detect these effects, as demonstrated by rosiglitazone and rofecoxib, we termed this phenomenon hidden cardiotoxicity.
The objective of this thesis is to advance the preclinical safety testing to improve drug development and increase patient safety. To this end, the aims of this thesis are twofold: First, to determine whether rosiglitazone exhibits hidden cardiotoxicity in a rat model of I/R injury. Second, to elucidate the molecular mechanisms that underlie rofecoxib-induced hidden cardiotoxicity by applying an unbiased multi-omics analysis.
To address these aims, 28-day drug-treatment studies were performed in rats. For rosiglitazone, we employed an I/R model, including IPC as a cardioprotective intervention. Infarct size, arrhythmias, and acute mortality were assessed. For rofecoxib, cardiac tissue collected 24 hours after the final dose underwent transcriptomic (mRNA, miRNA) and proteomic analysis combined with network-based pathway reconstruction.
The results show that rosiglitazone did not aggravate I/R injury; however, rosiglitazone abolished the antiarrhythmic effects of IPC, indicating a subtle form of hidden cardiotoxicity. Investigating the previously demonstrated hidden cardiotoxicity of rofecoxib, which manifested as an increase in fatal arrhythmias during I/R, the unbiased multi-omics analysis revealed drug-induced alterations in cardiac protein expression and phosphorylation. Importantly, an interconnected cluster of dysregulated proteins affects calcium-handling and conduction-related pathways under baseline conditions. In contrast, transcriptomic changes were comparatively limited and poorly correlated with protein-level effects.
In conclusion, this thesis demonstrates that the subtle, hidden cardiotoxicity of rosiglitazone can be detected in a preclinical model of I/R injury, which remains undetected in conventional safety testing but manifests under cardiac stress. Moreover, the hidden cardiotoxicity induced by rofecoxib arises from baseline alterations in protein expression and phosphorylation that affect, for example, calcium handling. The findings support the incorporation of comorbidity-relevant models and calcium-mediated arrhythmia testing into preclinical safety pipelines to better protect vulnerable patient populations and improve the translational reliability of drug development.
