Hidden cardiotoxicity of drugs ‐ paradigm change in cardiac safety testing in ischemic and comorbid conditions

Abstract

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 events. This led to novel concept of “hidden cardiotoxicity”, i.e. cardiotoxicity seen only in the diseased heart, i.e. ischemia/reperfusion injury and/or its major comorbidities (Ferdinandy et al, Eur Heart J, 2019). 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, here we summarize the current knowledge on hidden cardiotoxicity and urge the need for development of novel cardiac safety testing platforms for early detection of yet “hidden” cardiotoxicity. We also show an example of rofecoxib a COX2 inhibitor with hidden cardiotoxic properties.Support or Funding InformationThis study was supported by the National Research, Development and Innovation Office of Hungary (NKFIH; NVKP‐16‐1‐2016‐0017 National Heart Program). The research was also financed by the Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the Therapeutic development thematic programme of the Semmelweis University