Book of Abstracts - New Frontiers 2022

Abstracts of oral presentations

HIDDEN CARDIOTOXICITY - CARDIAC SAFETY TESTING IN ISCHEMIC AND COMORBID CONDITIONS: DEVELOPMENT OF PRECLINICAL TEST PLATFORMS

A. Görbe 1,2 , Z. Giricz 1,2 , P. Ferdinandy 1,2

1 System pharmacology group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary; 2 Pharmahungary, Szeged, Hungary Unexpected cardiac adverse events are one of the leading causes of interruption of clinical trials and drug withdrawals. It has been shown that cardiovascular risk factors and comorbidities (such as aging, metabolic diseases, etc) and their medications (e.g. nitrates, antidiabetic drugs, statins, etc) may interfere with cardiac ischemic tolerance and molecular signaling of endogenous cardioprotection. Indeed certain drugs may exert adverse events on the diseased heart that is hidden in the healthy myocardium. Hidden cardiotoxic effects of drugs may occur due to (i) enhancement of unwanted signaling due to ischemia/reperfusion injury and/or the presence of risk factors and/or (ii) inhibition of cardioprotective signaling pathways, both of which may lead to ischemia-related cell death and pro-arrhythmic ev ents. This led to novel concept of “hidden cardiotoxicity”, i.e. cardiotoxity seen only in the diseased heart, i.e. ischemia/reperfusion injury and/or its major comorbidities (Ferdinandy et al, Eur Heart J, 2018). Hidden cardiotoxicity cannot be revealed by the routinely used cardiac safety testing methods in “healthy” test systems, moreover, the mechanism of hidden cardiotoxocity is largely unknown. Therefore, we aimed to develop a preclinical in vivo and vitro platform and some examples of already withdrawn drugs with hidden cardiotoxic properties and new drugs with potential cardiotoxic properties. Here we summarize the current knowledge on hidden cardiotoxicity and urge the need for development of novel cardiac safety testing platforms for early detectio n of yet “hidden” cardiotoxicity.

Keywords: hidden cardiotoxicity, drug safety, comorbidity, cardioprotection

Funding:NVKP_16-1-2016-0017 National Heart Program, Thematic Excellence Programme (2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary, within the framework of the Therapeutic Development and Bioimaging thematic programmes of the Semmelweis University, National Research, Development and Innovation Office (NKFIH) of Hungary (K139237).

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