Back to Search
Start Over
Definition of hidden drug cardiotoxicity: paradigm change in cardiac safety testing and its clinical implications
- Source :
- European Heart Journal
- Publication Year :
- 2018
-
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.
- Subjects :
- Drug
Pre-conditioning
medicine.medical_specialty
Clinical Review
Drug-Related Side Effects and Adverse Reactions
Heart Diseases
Clinical Update
Comedication
media_common.quotation_subject
Post-conditioning
Ischemia
Comorbidity
Remote conditioning
030204 cardiovascular system & hematology
Ischaemia
Cardiotoxins
03 medical and health sciences
Mice
0302 clinical medicine
Drug Development
Diabetes mellitus
Internal medicine
medicine
Animals
Humans
Adverse effect
media_common
Cardiotoxicity
Toxicity
business.industry
Heart
030229 sport sciences
medicine.disease
Discontinuation
Clinical trial
Cardiology
Patient Safety
Safety
Cardiology and Cardiovascular Medicine
business
Reperfusion injury
Cardiac
Conditioning
Subjects
Details
- ISSN :
- 15229645
- Volume :
- 40
- Issue :
- 22
- Database :
- OpenAIRE
- Journal :
- European heart journal
- Accession number :
- edsair.doi.dedup.....67f7774ae973adcece318052a79310fb