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.

Keywords: Cardiac; Comedication; Comorbidity; Conditioning; Heart; Ischaemia; Post-conditioning; Pre-conditioning; Remote conditioning; Safety; Toxicity.

Figure 1

Schematic illustration of the role of impaired repolarization reserve in drug-induced arrhythmias in healthy and diseased cardiac tissue (hidden cardiotoxicity). In healthy myocardium (upper panel), the slow delayed rectifier (I_Ks), and the inward rectifier (I_K1) potassium currents, key components of repolarization reserve, counteract the mild repolarization prolonging (mostly due to hERG/I_Kr blocking) effect of drugs. Therefore, repolarization (action potential duration) is only slightly prolonged and no arrhythmias occur. The proarrhythmic side effect of the drug remains hidden in normal conditions. However, in the diseased heart (lower panel), a number of congenital, and acquired pathological conditions lead to electrical and/or structural remodelling featuring impaired function and/or down-regulation of repolarizing currents, consequently, leading to reduced repolarization reserve and increased arrhythmia susceptibility. Without the compensating effect of I_Ks/I_K1 activation, drug administration can lead to lethal ventricular arrhythmias. The hidden cardiotoxicity of the drug is revealed.

Figure 2

Influence of ischemia/reperfusion injury and cardiovascular risk factors on cardiotoxic effects of drugs. Hidden cardiotoxicity of a drug is revealed if the drug inhibits cell survival signalling or activates deleterious cell signalling induced by cardiac diseases especially ischemia/reperfusion injury and/or its major risk factors including their comedications. APD, action potential duration; HERG, human ether-a-go-go-related gene potassium channel; LQTs, long QT syndromes; SCD, sudden cardiac death.

Figure 3

Benefits of pre-clinical prediction of hidden cardiotoxicity by pre-clinical testing platforms (Hiddentox) in drug development. Hiddentox may lead to potential savings of drug development cost and development time by timely pre-clinical termination of compounds that show hidden cardiotoxic properties in diseased experimental models. Moreover, Hiddentox may increase success rate of drug development by pre-clinical determination of certain comorbidities in the presence of which hidden cardiotoxicity may manifest, thereby, improving knowledge for rational design of clinical trials on targeted patient populations. Finally, Hiddentox will increase patient safety during clinical trials and clinical use of drugs in the market by preventing potentially cardiotoxic drugs entering into clinical trials or to market.