Definition of hidden drug cardiotoxicity: paradigm change in cardiac safety testing and its clinical implications

Abstract

Unexpected cardiac adverse effects are the leading causes of discontinuation of clinical trials and withdrawal of drugs from the market. Since the original observations in the mid-90s, it has been well established that cardiovascular risk factors and comorbidities (such as ageing, hyperlipidaemia, and diabetes) and their medications (e.g. nitrate tolerance, adenosine triphosphate-dependent potassium inhibitor antidiabetic drugs, statins, etc.) may interfere with cardiac ischaemic tolerance and endogenous cardioprotective signalling pathways. Indeed drugs may exert unwanted effects on the diseased and treated heart that is hidden in the healthy myocardium. Hidden cardiotoxic effects may be due to (i) drug-induced enhancement of deleterious signalling due to ischaemia/reperfusion injury and/or the presence of risk factors and/or (ii) inhibition of cardioprotective survival signalling pathways, both of which may lead to ischaemia-related cell death and/or pro-arrhythmic effects. This led to a novel concept of 'hidden cardiotoxicity', defined as cardiotoxity of a drug that manifests only in the diseased heart with e.g. ischaemia/reperfusion injury and/or in the presence of its major comorbidities. Little is known on the mechanism of hidden cardiotoxocity, moreover, hidden cardiotoxicity cannot be revealed by the routinely used non-clinical cardiac safety testing methods on healthy animals or tissues. Therefore, here, we emphasize the need for development of novel cardiac safety testing platform involving combined experimental models of cardiac diseases (especially myocardial ischaemia/reperfusion and ischaemic conditioning) in the presence and absence of major cardiovascular comorbidities and/or cotreatments.

Hidden Cardiotoxicity of Rofecoxib Can be Revealed in Experimental Models of Ischemia/Reperfusion

“…However, a subgroup analysis of patients with ischemic heart diseases was not performed in this meta-analysis, which might have revealed its cardiotoxicity even earlier. These results clearly show that the exclusion of patients with preexisting cardiovascular diseases from clinical studies and the lack of subgroup analyses on patients with underlying co-morbidities in clinical trials may lead to the loss of valuable safety information on drugs with potential hidden cardiotoxic effects [2,31]. Our current preclinical results are in line with previous clinical data.…”

“…Our present data imply that the increased mortality due to rofecoxib treatment can be attributed to its proarrhythmic property that only manifests following I/R. Myocardial ischemia per se renders myocardial tissue more susceptible to ventricular arrhythmias and I/R injury may exacerbate proarrhythmic effects of drugs [2]. To further analyze the hidden cardiotoxic effects of rofecoxib, we subjected left ventricular papillary muscles to sI/R.…”

“…Here we also investigated the interaction of rofecoxib with IPC since the hidden cardiotoxic effect of drugs mightb manifest not only as aggravation of I/R injury, but also as attenuation of ischemic adaptation of the myocardium by ischemic conditioning [2]. We found that rofecoxib alone decreased infarct size and did not interfere with the protective effect of IPC.…”

“…Unexpected clinical cardiotoxicity is still the leading cause of discontinuation of clinical trials and the withdrawal of drugs from the market despite great efforts to detect cardiotoxicity in the preclinical phase of drug development programs [1]. Such cardiotoxic effects remain undetected during preclinical and early clinical safety studies and they may manifest in the presence of cardiac diseases e.g., in myocardial I/R conditions; therefore, we termed this phenomenon "hidden cardiotoxicity" [2].…”

“…Thus, drugs with hidden cardiotoxic properties may present as a serious risk to patients as drugs with overt cardiotoxicity, such as certain cancer treatments [3]. The mechanisms of hidden cardiotoxicity may include the activation of cell death-or pro-arrhythmic processes during cardiac I/R, as well as the inhibition of cardioprotective signaling pathways (e.g., ischemic conditioning-induced protection), either of which may be aggravated by the presence of cardiovascular comorbidities [2]. The mechanism of cardiovascular toxicity of cancer treatments is described elsewhere in detail.…”