Supplementary Table 1. Selected reference drugs, testing concentrations and therapeutic exposure aC eff , the maximal therapeutic plasma concentration reported in the literature. bAs aspirin was metabolized rapidly in liver with a plasma half-life of ~ 20 min, 10 ��M was the median of plasma concentration over 4 h after dosing, assuming to take one 1200 mg dose every 4 h. C The clinical efficacy exposure not established, the plasmas concentration that induced TdP in the in-house telemetry monkey study was used. Drug Class/applications Conc. tested (��M) Ceff(nM) a Reference Aconitine Neurotoxin, antipyretic, analgesic 0.01-10 77 Ohta, Seto, and Tsunoda (1997), Wada et al. (2005) Alfuzosin ��1-adrenergic antagonist, anti- protatic hyperplasia 0.3-10 56 Lacerda et al. (2008) Amiodarone Class III antiarrhythmic 0.01-10 3,874 Redfern et al. (2003) Amoxicillin Antibiotic 1-1,000 17,036 Lawrence et al. ( 2006) Aspirin Anti-inflammatory 1-1,000 10,000 b Seymour & Rawlins (1982) DrugBank (protein binding) Astemizole Antihistamine 0.001-1 8.0 Redfern et al. (2003) Blebbistatin Myosin II inhibitor 0.03-30 ~ not available Captopril ACE inhibitor, antihypertensive 1-100 2,466 Lawrence et al. (2006) Cisapride Prokinetic 0.01-10 129 Redfern et al. (2003) Dofetilide Class III antiarrhythmic 0.001-1 6.0 Redfern et al. (2003) E-4031 Class III antiarrhythmic 0.003-1 13 Fossa et al. (2004) Erythromycin (i.v.) Antibiotic 0.1-100 34,064 Redfern e t al. (2003) Flecainide Class Ic antiarrhythmic 1.0 - 30 1,931 Redfern et al. (2003) Fluoxetine Antidepressant 0.03-30 485 Redfern et al. (2003) Isoproterenol ��-adrenergic agonist, bronchodilator 0.001-1 ~ not available Moxifloxacin Antibiotic 0.1-100 10,276 FDA label (1999) for Avelox Nifedipine L-type Ca2+ channel blocker, antihypertensive 0.003-3 194 Redfern et al. (2003) Ouabain Na+/K+ ATPse inhibitor 0.003-3 170 Selden & Neill (1975) DrugBank (protein binding) Quinidine Class Ia antiarrhythmic 0.1-100 3,237 Redfern et al. (2003) Ranolazine Antianginal 0.1-100 6,009 FDA label (2006) for Ranexa RO5657 Anti-HIV 0.1-100 5,548 c Roche in-house data Rofecoxib Nonsteroidal anti-inflammatory 0.1-100 1,021 FDA label (1999) for Vioxx Sotalol Class III antiarrhythmic 0.1-100 14,733 Redfern et al. (2003) Terfenadine Antihistamine 0.01-10 300 Redfern et al. (2003) Tetrodotoxin (TTX) Na+ channel blocker 0.03-30 ~ not available Thioridazine Antipsychotic 0.01-10 1,781 Redfern et al. (2003) Verapamil Anithypertensive, antianginal 0.3-10 815 Redfern et al. (2003) ZD7288 Ichannel f blocker 1-30 ~ not available

Supplementary Figure 1. Suppl Fig. 1:Illustration of Irregular Beat Ratio (IBR) calculation. The screen-shots were taken from a 20 s-sweep window after exposure to the vehicle (0.1% DMSO, top trace) and E-4031 at 30 nM (middle trace) and 1000 nM (bottom trace), respectively. The regular (R) and irregular (I) beats were denoted by the blue-dots and red-arrowheads, respectively. The total (T) beat s was a sum of R and I in each sweeps, and the IBR was calculated as the ratio of I/T. R I T IBR 12 0 12 0 11 3 14 0.21 4 28 32 0.88

Amoxicillin Supplementary Figure 2. Suppl Fig. 2:Representative impedance traces for amoxicillin and captopril. No obvious irregular beats nor significant alteration in beat amplitude were observed during drug exposure from 1 to 100 ��M and up to 72 h. The vertical scale bar = 0.08 CI. A Pre-drug Post-drug 30 min 1 h 6 h 24 h 72 h 10 s 0 ��M 1 10 100 B Captopril Pre-drug Post-drug 30 min 1 h 6 h 24 h 72 h 10 s 0 ��M 1 10 100