Table 5.

Key cardiac liabilities reported by pharmaceutical industry (adapted from Laverty et al. [139]).

Toxicity	Common standard assessment strategies§
Proarrhythmic potential	Drug discovery: hERG screening, other cardiac ion channel screening, in vitro profiling in cardiac tissue, in silico hERG and cardiac action potential assessment Drug development: QT interval determination in telemetry and or toxicology studies and mechanistic investigations (e.g., hERG trafficking, metabolites effects) Clinical practice: QT interval determination including concentration QTc modeling and assessment of other ECG parameters
Myocardial ischemia	Drug discovery: assessment of ECG morphology changes, histological examinations and functional assessments (e.g. LVEF) Drug development: observation of clinical signs, assessment of ECG morphology changes, histological examinations and functional assessments (e.g. LVEF)
Myocardial necrosis	Drug discovery: few predictive in vitro methods, histological examination from early repeated-dose toxicity studies Drug development: some reflective biomarkers available (e.g., troponin), histological examinations, imaging (e.g., echocardiography)
Heart failure	Drug discovery: assessment of some functional endpoints in vitro and in vivo (e.g., contractility), histological examinations and cardiac biomarkers (e.g. pro NT-BNP) Drug development: observation of clinical signs, imaging and cardiac biomarkers
Coronary artery disorders	Drug development: observation of clinical signs and imaging
Cardiac valve disorders	Drug discovery: evaluation of alerts from receptor (e.g., 5-HT2B) binding data Drug development: imaging, histological examinations
Endocardial disorders	Drug development: histological examinations

^§hERG (human ether-à-go-go related gene); ECG (electrocardiogram); LVEF (left ventricular ejection fraction); pro-N terminal B-type natriuretic peptide; QT (duration of ventricular depolarization and repolarization); QTc (corrected QT interval); 5-HT2B (5-Hydroxytryptamine receptor 2B).