[Show abstract][Hide abstract] ABSTRACT: Potassium channels encoded by human ether-à-go-go-related gene (hERG) mediate the cardiac rapid delayed rectifier K+ current (IKr), which participates in ventricular repolarization and has a protective role against unwanted premature stimuli late in repolarization and early in diastole. Ionic current carried by hERG channels (IhERG) is known to exhibit a paradoxical dependence on external potassium concentration ([K+]e), but effects of acute [K+]e changes on the response of IhERG to premature stimulation have not been characterized. Whole-cell patch-clamp measurements of hERG current were made at 37°C from hERG channels expressed in HEK293 cells. Under conventional voltage-clamp, both wild-type (WT) and S624A pore-mutant IhERG during depolarization to +20 mV and subsequent repolarization to −40 mV were decreased when superfusate [K+]e was decreased from 4 to 1 mmol/L. When [K+]e was increased from 4 to 10 mmol/L, pulse current was increased and tail IhERG was decreased. Increasing [K+]e produced a +10 mV shift in voltage-dependent inactivation of WT IhERG and slowed inactivation time course, while lowering [K+]e from 4 to 1 mmol/L produced little change in inactivation voltage dependence, but accelerated inactivation time course. Under action potential (AP) voltage-clamp, lowering [K+]e reduced the amplitude of IhERG during the AP and suppressed the maximal IhERG response to premature stimuli. Raising [K+]e increased IhERG early during the AP and augmented the IhERG response to premature stimuli. Our results are suggestive that during hypokalemia not only is the contribution of IKr to ventricular repolarization reduced but its ability to protect against unwanted premature stimuli also becomes impaired.
[Show abstract][Hide abstract] ABSTRACT: The antianginal drug ranolazine, which combines inhibitory actions on rapid and sustained sodium currents with inhibition of the hERG/IKr potassium channel, shows promise as an antiarrhythmic agent. This study investigated the structural basis of hERG block by ranolazine, with lidocaine used as a low-potency, structurally similar comparator. Recordings of hERG current (IhERG) were made from cell lines expressing wild-type (WT) or mutant hERG channels. Docking simulations were performed using homology models built on MthK and KvAP templates. In conventional voltage clamp, ranolazine inhibited IhERG with an IC50 of 8.03μM; peak IhERG during ventricular action potential clamp was inhibited ~62% at 10μM. The IC50 values for ranolazine inhibition of the S620T inactivation-deficient and N588K attenuated-inactivation mutants were respectively ~73-fold and ~15-fold that for WT IhERG. Mutations near the bottom of the selectivity filter (V625A, S624A, T623A) exhibited IC50s between ~8 and 19-fold that for WT IhERG, whilst the Y652A and F656A S6 mutations had IC50s ~22-fold and 53-fold WT controls. Low potency lidocaine was comparatively insensitive to both pore-helix and S6 mutations, but was sensitive to direction of K(+) flux and particularly to loss of inactivation, with an IC50 for S620T-hERG ~49-fold that for WT IhERG. Docking simulations indicated that the larger size of ranolazine gives it potential for a greater range of interactions with hERG pore side chains compared to lidocaine, in particular enabling interaction of its two aromatic groups with side chains of both Y652 and F656. The N588K mutation is responsible for the SQT1 variant of short QT syndrome and our data suggest that ranolazine is unlikely to be effective against IKr/hERG in SQT1 patients.
Journal of Molecular and Cellular Cardiology 05/2014; · 5.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: human Ether-à-go-go-Related Gene (hERG) encodes the pore-forming subunit of cardiac rapid delayed rectifier K(+) current (I Kr) channels, which play important roles in ventricular repolarization, in protecting the myocardium from unwanted premature stimuli, and in drug-induced Long QT Syndrome (LQTS). KCNE1, a small transmembrane protein, can coassemble with hERG. However, it is not known how KCNE1 variants influence the channel's response to premature stimuli or if they influence the sensitivity of hERG to pharmacological inhibition. Accordingly, whole-cell patch-clamp measurements of hERG current (I hERG) were made at 37°C from hERG channels coexpressed with either wild-type (WT) KCNE1 or with one of three KCNE1 variants (A8V, D76N, and D85N). Under both conventional voltage clamp and ventricular action potential (AP) clamp, the amplitude of I hERG was smaller for A8V, D76N, and D85N KCNE1 + hERG than for WT KCNE1 + hERG. Using paired AP commands, with the second AP waveform applied at varying time intervals following the first to mimic premature ventricular excitation, the response of I hERG carried by each KCNE1 variant was reduced compared to that with WT KCNE1 + hERG. The I hERG blocking potency of the antiarrhythmic drug quinidine was similar between WT KCNE1 and the three KCNE1 variants. However, the I hERG inhibitory potency of the antibiotic clarithromycin and of the prokinetic drug cisapride was altered by KCNE1 variants. These results demonstrate that naturally occurring KCNE1 variants can reduce the response of hERG channels to premature excitation and also alter the sensitivity of hERG channels to inhibition by some drugs linked to acquired LQTS.
[Show abstract][Hide abstract] ABSTRACT: Mutations in transmembrane domains of the KCNQ1 subunit of the IKs potassium channel have been associated with familial atrial fibrillation. We have investigated mechanisms by which the S1 domain S140G KCNQ1 mutation influences atrial arrhythmia risk and, additionally, whether it can affect ventricular electrophysiology. In perforated-patch recordings, S140G-KCNQ1+KCNE1 exhibited leftward-shifted activation, slowed deactivation and marked residual current. In human atrial action potential (AP) simulations, AP duration and refractoriness was shortened and rate-dependence flattened. Simulated IKs but not IKr block offset AP shortening produced by the mutation. In atrial tissue simulations, temporal vulnerability to re-entry was little affected by the S140G mutation. Spatial vulnerability was markedly increased, leading to more stable and stationary spiral wave re-entry in 2D stimulations, which was offset by IKs block, and to scroll waves in 3D simulations. These changes account for vulnerability to AF with this mutation. Ventricular AP clamp experiments indicate a propensity for increased ventricular IKs with the S140G KCNQ1 mutation and ventricular AP simulations showed model-dependent ventricular AP abbreviation.
Journal of electrocardiology 01/2013; · 1.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The familial Short QT Syndrome (SQTS) is associated with an increased risk of cardiac arrhythmia and sudden death. Gain-of-function mutations in the hERG K(+) channel protein have been linked to variant 1 of the SQTS. A hERG channel pore (T618I) mutation has recently been identified in families with heritable SQTS. This study aimed to determine effects of the T618I-hERG mutation on (i) hERG current (I(hERG)) elicited by ventricular action potentials; (ii) the sensitivity of I(hERG) to inhibition by four clinically used antiarrhythmic drugs.
Electrophysiological recordings of I(hERG) were made at 37°C from HEK 293 cells expressing wild-type (WT) or T618I hERG. Whole-cell patch clamp recording was performed using both conventional voltage clamp and ventricular action potential (AP) clamp methods.
Under conventional voltage-clamp, WT I(hERG) peaked at 0-+10 mV, whilst for T618I I(hERG) maximal current was right-ward shifted to ∼ +40 mV. Voltage-dependent activation and inactivation of T618I I(hERG) were positively shifted (respectively by +15 and ∼ +25 mV) compared to WT I(hERG). The I(hERG) 'window' was increased for T618I compared to WT hERG. Under ventricular AP clamp, maximal repolarising WT I(hERG) occurred at ∼ -30 mV, whilst for T618I hERG peak I(hERG) occurred earlier during AP repolarisation, at ∼ +5 mV. Under conventional voltage clamp, half-maximal inhibitory concentrations (IC(50)) for inhibition of I(hERG) tails by quinidine, disopyramide, D-sotalol and flecainide for T618I hERG ranged between 1.4 and 3.2 fold that for WT hERG. Under action potential voltage clamp, T618I IC(50)s ranged from 1.2 to 2.0 fold the corresponding IC(50) values for WT hERG.
The T618I mutation produces a more modest effect on repolarising I(hERG) than reported previously for the N588K-hERG variant 1 SQTS mutation. All drugs studied here appear substantially to retain their ability to inhibit I(hERG) in the setting of the SQTS-linked T618I mutation.
PLoS ONE 12/2012; 7(12):e52451. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: One form of the short QT syndrome (SQT3) has been linked to the D172N gain-in-function mutation to Kir2.1, which preferentially increases outward current through channels responsible for inward rectifier K(+) current (I(K1)). This study investigated mechanisms by which the Kir2.1 D172N mutation facilitates and perpetuates ventricular arrhythmias.
The ten Tusscher et al. model for human ventricular action potentials (APs) was modified to incorporate changes to I(K1) based on experimentally observed changes to Kir2.1 function: both heterozygous (WT-D172N) and homozygous (D172N) mutant scenarios were studied. Cell models were incorporated into heterogeneous one-dimensional (1D), 2D tissue, and 3D models to compute the restitution curves of AP duration (APD-R), effective refractory period (ERP-R), and conduction velocity (CV). Temporal and spatial vulnerability of ventricular tissue to re-entry was measured and dynamic behaviour of re-entrant excitation waves (lifespan and dominant frequency) in 2D and 3D models of the human ventricle was characterized. D172N 'mutant' I(K1) led to abbreviated APD and ERP, as well as steeper APD-R and ERP-R curves. It reduced tissue excitability at low excitation rates but increased it at high rates. It increased tissue temporal vulnerability for initiating re-entry, but reduced the minimal substrate size necessary to sustain re-entry. SQT3 'mutant' I(K1) also stabilized and accelerated re-entrant excitation waves, leading to sustained rapid re-entry.
Increased I(K1) due to the Kir2.1 D172N mutation increases arrhythmia risk due to increased tissue vulnerability, shortened ERP, and altered excitability, which in combination facilitate initiation and maintenance of re-entrant circuits.
Cardiovascular Research 02/2012; 94(1):66-76. · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Class Ia antiarrhythmic drug disopyramide (DISO) causes QT interval prolongation that is potentially dangerous in acquired Long QT Syndrome but beneficial in short QT syndrome, through inhibition of the hERG-encoded channels responsible for rapid delayed rectifier K(+) current (I(Kr)). In this study, alanine mutants of hERG S6 and pore helix residues and MthK-based homology modelling and ligand docking were used to investigate molecular determinants of DISO binding to hERG. Whole-cell hERG current (I(hERG)) recordings were made at 37°C from HEK-293 cells expressing WT or mutant hERG channels. WT outward I(hERG) tails were inhibited with an IC(50) of 7.3μM, whilst inward I(hERG) tails in a high [K(+)](e) of 94mM were blocked with an IC(50) of 25.7μM. The IC(50) for the Y652A mutation was ~55-fold that of WT I(hERG); this mutation also abolished a leftward shift in voltage-dependent I(hERG) activation present for WT hERG. The IC(50) for F656A I(hERG) was ~51 fold its corresponding WT control. In contrast to previously studied methanesulphonanilide hERG inhibitors, neither the G648A S6 nor the T623A and S624A pore helical mutations modified DISO IC(50). Computational docking with the hERG model showed that DISO did not exhibit a single unique binding pose; instead several low energy binding poses at the lower end of the pore cavity favoured interactions with Y652 and F656. In the WT hERG model DISO did not interact directly with residues at the base of the pore helix, consistent with the minimal effect of mutation of these residues on drug block.
Journal of Molecular and Cellular Cardiology 01/2012; 52(1):185-95. · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Complete atrioventricular block (CAVB) and related ventricular bradycardia are known to induce ventricular hypertrophy and arrhythmias. Different animal models of CAVB have been established with the most common being the dog model. Related studies were mainly focused on the consequences on the main repolarizing currents in these species, i.e. IKr and IKs, with a limited time point kinetics post-AVB. In order to explore at a genomic scale the electrical remodeling induced by AVB and its chronology, we have developed a novel model of CAVB in the mouse using a radiofrequency-mediated ablation procedure. We investigated transcriptional changes in ion channels and contractile proteins in the left ventricles as a function of time (12h, 1, 2 and 5 days after CAVB), using high-throughput real-time RT-PCR. ECG in conscious and anesthetized mice, left ventricular pressure recordings and patch-clamp were used for characterization of this new mouse model. As expected, CAVB was associated with a lengthening of the QT interval. Moreover, polymorphic ventricular tachycardia was recorded in 6/9 freely-moving mice during the first 24h post-ablation. Remarkably, myocardial hypertrophy was only evident 48 h post-ablation and was associated with increased heart weight and altered expression of contractile proteins. During the first 24 hours post-CAVB, genes encoding ion channel subunits were either up-regulated (such as Nav1.5, +74%) or down-regulated (Kv4.2, -43%; KChIP2, -47%; Navβ1, -31%; Cx43, -29%). Consistent with the transient alteration of Kv4.2 expression, I(to) was reduced at day 1, but restored at day 5. In conclusion, CAVB induces two waves of molecular remodeling: an early one (≤24 h) leading to arrhythmias, a later one related to hypertrophy. These results provide new molecular basis for ventricular tachycardia induced by AV block.
Journal of Molecular and Cellular Cardiology 07/2011; 51(5):713-21. · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human ether-à-go-go related gene (hERG) is responsible for channels that mediate the rapid delayed rectifier K(+) channel current (I(Kr) ), which participates in repolarization of the ventricles and is a target for some antiarrhythmic drugs. Acidosis occurs in the heart in some pathological situations and can modify the function and responses to drugs of ion channels. The aim of this study was to determine the effects of extracellular and intracellular acidosis on the potency of hERG channel current (I(hERG)) inhibition by the antiarrhythmic agents dofetilide, flecainide, and amiodarone at 37 °C.
Whole-cell patch-clamp recordings of I(hERG) were made at 37 °C from hERG-expressing Human Embryonic Kidney (HEK293) cells. Half-maximal inhibitory concentration (IC(50)) values for I(hERG) tail inhibition at -40 mV following depolarizing commands to +20 mV were significantly higher at external pH 6.3 than at pH 7.4 for both flecainide and dofetilide, but not for amiodarone. Lowering pipette pH from 7.2 to 6.3 altered neither I(hERG) kinetics nor the extent of observed I(hERG) blockade by any of these drugs.
Conditions leading to localized extracellular acidosis may facilitate heterogeneity of action of dofetilide and flecainide, but not amiodarone via modification of hERG channel blockade. Such effects depend on the external pH change rather than intracellular acidification.
Journal of Cardiovascular Electrophysiology 04/2011; 22(10):1163-70. · 3.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Extracellular acidosis occurs in the heart during myocardial ischemia and can lead to dangerous arrhythmias. Potassium channels encoded by hERG (human ether-à-go-go-related gene) mediate the cardiac rapid delayed rectifier K+ current (IKr), and impaired hERG function can exacerbate arrhythmia risk. Nearly all electrophysiological investigations of hERG have centred on the hERG1a isoform, although native IKr channels may be comprised of hERG1a and hERG1b, which has a unique shorter N-terminus. This study has characterised for the first time the effects of extracellular acidosis (an extracellular pH decrease from 7.4 to 6.3) on hERG channels incorporating the hERG1b isoform. Acidosis inhibited hERG1b current amplitude to a significantly greater extent than that of hERG1a, with intermediate effects on coexpressed hERG1a/1b. IhERG tail deactivation was accelerated by acidosis for both isoforms. hERG1a/1b activation was positively voltage-shifted by acidosis, and the fully-activated current-voltage relation was reduced in amplitude and right-shifted (by ∼10 mV). Peak IhERG1a/1b during both ventricular and atrial action potentials was both suppressed and positively voltage-shifted by acidosis. Differential expression of hERG isoforms may contribute to regional differences in IKr in the heart. Therefore inhibitory effects of acidosis on IKr could also differ regionally, depending on the relative expression levels of hERG1a and 1b, thereby increasing dispersion of repolarization and arrhythmia risk.
Biochemical and Biophysical Research Communications 02/2011; 405(2):222-7. · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The short QT syndrome (SQTS) is characterised by abbreviated QT intervals on the electrocardiogram and by an increased risk
of atrial and ventricular arrhythmias and of sudden death. Gain-of-function mutations to three potassium channel genes, KCNH2, KCNQ1 and KCNJ2, are responsible for distinct forms of SQTS (SQT1, SQT2 and SQT3, respectively), whilst loss-of-function mutations to the
L-type calcium channel genes CACNB2b and CACNA1C give rise to abbreviated QT intervals accompanied by ST-segment elevation and a combined short QT-Brugada phenotype. Shortened
effective refractory periods and altered transmural dispersal of repolarisation are implicated in increased ventricular arrhythmia
risk. Current treatment focusses on implantable defibrillators to protect against fatal ventricular arrhythmia. There is also
evidence that Class 1a anti-arrhythmic drugs may be beneficial in restoring towards normal the QT intervals of some patients.
[Show abstract][Hide abstract] ABSTRACT: KCNQ1 is responsible for the pore-forming subunit of channels that mediate the cardiac 'IKs' potassium channel current. The S140G KCNQ1 gain-of-function mutation is responsible for a form of heritable atrial fibrillation. Here the action potential (AP) voltage clamp technique was used to elucidate the effect of S140G KCNQ1 on the profile of recombinant I(Ks) during atrial and ventricular APs applied to KCNQ1+KCNE1 expressing CHO cells, at 37°C. Under conventional voltage clamp the S140G KCNQ1 mutation shifted voltage-dependent activation by ≈-62 mV, with a marked instantaneous current component evident on membrane depolarisation. Under atrial AP clamp, cells expressing wild-type (WT) KCNQ1 exhibited modest outward currents during atrial repolarisation, whilst those expressing S140G KCNQ1 exhibited a marked instantaneous outward current and peak repolarising current >4-fold that for WT KCNQ1. Under ventricular AP clamp, both WT and mutant KCNQ1 conditions showed greater peak repolarising current than when an atrial AP command was used and the S140G mutation resulted in peak repolarising current that was >3-fold that for WT KCNQ1. We conclude that the S140G KCNQ1 mutation would be predicted to augment substantially repolarising current both early and throughout atrial APs and, in principle, also to influence markedly ventricular AP repolarisation.
Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 12/2010; 61(6):759-64. · 2.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The slow delayed rectifier potassium current, 'I(Ks)', contributes to repolarisation of cardiac ventricular action potentials and thereby to the duration of the QT interval of the electrocardiogram. Mutations to I(Ks) channel subunits occur in clinically significant cardiac repolarisation disorders. The short QT syndrome (SQTS) is associated with accelerated ventricular repolarisation and with an increased risk of arrhythmia and sudden death. The SQT2 variant of the SQTS has been linked to a gain-of-function amino-acid substitution (V307L) in the KCNQ1-encoded I(Ks) channel alpha-subunit. This study reports the first action potential (AP) voltage-clamp comparison between wild-type (WT) and V307L KCNQ1 (co-expressed with KCNE1 to recapitulate I(Ks)) and identifies an effective pharmacological inhibitor of recombinant 'I(Ks)' channels incorporating the V307L KCNQ1 mutation. Perforated-patch voltage-clamp recordings at 37 degrees C of whole-cell current carried by co-expressed KCNQ1 and KCNE1 showed a marked (-36 mV) shift in half-maximal activation for V307L compared to WT KCNQ1; a significant slowing of current deactivation was also observed. Under AP clamp, peak repolarising current was significantly augmented for V307L KCNQ1 compared to WT KCNQ1 for both ventricular and atrial AP commands, consistent with an ability of the V307L mutation to increase repolarising I(Ks) in both regions. The quinoline agent mefloquine inhibited WT KCNQ1+KCNE1 with an IC(50) of 3.4 muM compared to 3.3 muM for V307L KCNQ1+KCNE1 (P >0.05). This establishes mefloquine as an effective inhibitor of recombinant 'I(Ks)' channels incorporating this SQT2 KCNQ1 mutation.
Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 04/2010; 61(2):123-31. · 2.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Studies in Shaker, a voltage-dependent potassium channel, suggest a coupling between activation and inactivation. This coupling is controversial in hERG, a fast-inactivating voltage-dependent potassium channel. To address this question, we transferred to hERG the S3-S4 linker of the voltage-independent channel, rolf, to selectively disrupt the activation process. This chimera shows an intact voltage-dependent inactivation process consistent with a weak coupling, if any, between both processes. Kinetic models suggest that the chimera presents only an open and an inactivated states, with identical transition rates as in hERG. The lower sensitivity of the chimera to BeKm-1, a hERG preferential closed-state inhibitor, also suggests that the chimera presents mainly open and inactivated conformations. This chimera allows determining the mechanism of action of hERG blockers, as exemplified by the test on ketoconazole.
[Show abstract][Hide abstract] ABSTRACT: Recently identified genetic forms of short QT syndrome (SQTS) are associated with an increased risk of arrhythmia and sudden death. The SQT3 variant is associated with an amino-acid substitution (D172N) in the KCNJ2-encoded Kir2.1 K+ channel. In this study, whole-cell action potential (AP) clamp recording from transiently transfected Chinese Hamster Ovary cells at 37 degrees C showed marked augmentation of outward Kir2.1 current through D172N channels, associated with right-ward voltage-shifts of peak repolarizing current during both ventricular and atrial AP commands. Peak outward current elicited by ventricular AP commands was inhibited by chloroquine with an IC50 of 2.45 microM for wild-type (WT) Kir2.1, of 3.30 microM for D172N-Kir2.1 alone and of 3.11 microM for co-expressed WT and D172N (P>0.05 for all). These findings establish chloroquine as an effective inhibitor of SQT3 mutant Kir2.1 channels.
Journal of Molecular and Cellular Cardiology 04/2009; 47(5):743-7. · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The beta(3)-adrenoceptors (beta(3)-ARs) have been identified and characterized in the human heart. Specific beta(3)-AR stimulation, unlike beta(1)-AR or beta(2)-AR stimulation, decreases cardiac contractility, partly via the G(i)-NO pathway. However, the precise role of cardiac beta(3)-ARs is not yet completely understood. Indeed, under normal conditions, the beta(3)-AR response is present only to a very low degree in rats and mice. Therefore, we evaluated whether beta(3)-ARs were present and functional in rabbit ventricular cardiomyocytes, and whether the rabbit could serve as a relevant model for the study of cardiac beta(3)-ARs. We used RT-PCR and Western blot to measure the beta(3)-AR transcripts and protein levels in rabbit ventricular cardiomyocytes. We also analysed the effect of beta(3)-AR stimulation using isoproterenol in combination with nadolol or SR 58611A on cardiomyocyte shortening, Ca(2+) transient, L-type Ca(2+) current (I(Ca,L)), delayed rectifier potassium current (I(Ks)) and action potential duration (APD). For the first time, we show that beta(3)-ARs are expressed in rabbit ventricular cardiomyocytes. The mRNA and protein sequences present a high homology to those of rat and human beta(3)-ARs. Furthermore, beta(3)-AR stimulation decreases cardiomyocyte shortening, Ca(2+) transient and I(Ca,L) amplitudes, via a G(i)-NO pathway. Importantly, beta(3)-AR stimulation enhances I(Ks) amplitude and shortens the APD. Taken together, our results indicate that the rabbit provides a relevant model, easily used in laboratories, to study the roles of cardiac beta(3)-ARs in physiological conditions.
[Show abstract][Hide abstract] ABSTRACT: Drug-induced torsades de pointes (TdP) arrhythmia is a major safety concern in the process of drug design and development. The incidence of TdP tends to be low, so early pre-clinical screens rely on surrogate markers of TdP to highlight potential problems with new drugs. hERG (human ether-à-go-go-related gene, alternative nomenclature KCNH2) is responsible for channels mediating the ‘rapid’ delayed rectifier K+ current (IKr) which plays an important role in ventricular repolarization. Pharmacological inhibition of native IKr and of recombinant hERG channels is a shared feature of diverse drugs associated with TdP. In vitro hERG assays therefore form a key element of an integrated assessment of TdP liability, with patch-clamp electrophysiology offering a ‘gold standard’. However, whilst clearly necessary, hERG assays cannot be assumed automatically to provide sufficient information, when considered in isolation, to differentiate ‘safe’ from ‘dangerous’ drugs. Other relevant factors include therapeutic plasma concentration, drug metabolism and active metabolites, severity of target condition and drug effects on other cardiac ion channels that may mitigate or exacerbate effects of hERG blockade. Increased understanding of the nature of drug-hERG channel interactions may ultimately help eliminate potential hERG blockade early in the design and development process. Currently, for promising drug candidates integration of data from hERG assays with information from other pre-clinical safety screens remains essential.