Keeping the Rhythm: hERG and Beyond in Cardiovascular Safety Pharmacology

Clemens Möller


Expert Rev Clin Pharmacol. 2010;3(3):321-329. 

In This Article

hERG Ion Channel and Drug-induced Cardiac Arrhythmia

The K+ ion channel coded by hERG plays a major role during the late repolarization phase of the human cardiac action potential. Blockade of the rapid delayed rectifier current IKr, the current mediated by the hERG ion channel,[4,8] can lead to prolongation of the cardiac action potential;[7] however, the extent to which (and if at all) cardiac repolarization is prolonged, and the actual proarrhythmic effect of this, depends on many factors; in particular, the effects of a compound on other cardiac ion channels. Under certain conditions, action potential prolongation can trigger life-threatening cardiac arrhythmias of the torsades de pointes (TdP) type. Cases of sudden cardiac death following drug-induced TdP have been described, and several drug discovery companies were obliged to withdraw, or voluntarily withdrew, drugs from the market that induced this side effect. Among the drugs withdrawn have been blockbuster drugs. hERG channel inhibition became the single most frequent cause for drug withdrawal in the late 1990s. Prolongation of the QT interval measured in the surface ECG has been used as a surrogate marker for prolonged repolarization and torsadogenic liability of a compound.

It has been recognized that risk factors increasing the likelihood for TdP arrhythmias and, thus, potentiating the QT prolonging effects of drugs, include (subclinical) congenital (long QT [LQT]) syndrome, female gender, hypokalemia, use of sympathomimetics, bradycardia, recent conversion from atrial fibrilliation, congestive heart failure, particular cardiac ion channel polymorphisms and severe hypomagnesia.[9,10]

Many drugs from different classes and diverse chemical structures have the potential to inhibit the hERG-coded ion channel. Besides antiarrhythmics, antihistamines and psychiatric medications appear particularly prone to interactions with the hERG channel,[11,12] but other examples of drugs interacting with hERG currents include antimicrobial, antimalarial, gastrointestinal and antitussive drugs.[13–17] Less publicly noticed, a large number of projects in pharmaceutical drug discovery and development have been significantly (thus expesively) delayed, or even stopped owing to hERG-related safety concerns of lead compounds. Consequently, current regulatory guidelines[18] consider hERG assays a major component of an integrated cardiac risk assessment, with the final integrated risk assessment taking into account results from different studies, as well as other relevant information, such as chemical class of the compound, assay sensitivity and specificity, potency of test compound in repolarization assays in comparison to reference compounds and in comparison to proposed therapeutic concentrations, and contribution of metabolites.[18]

Despite a propensity to block hERG channel function, as determined by electrophysiology, for a limited number of compounds no cardiac arrhythmias have been detected so far. Among others, these drugs include the examples verapamil and pentobarbital. Both compounds have been shown to simultaneously block other cardiac ion channels, thus counteracting the torsadogenic effect of hERG channel blockade. Verapamil has been shown to block hERG and slow repolarization; however, owing to its effect on Ca2+ channels, it actually shortens the action potential. The slowed repolarization with shortened action potential duration, however, is not likely to produce TdP.

On the contrary, LQT syndrome (and TdP) can also develop without the hERG ion channel being affected, which was first described for genetic mutations causing LQT1[19] or LQT3. These dominantly inherited genetic disorders stem from mutations in the genes coding for KCNQ1/KCNE1 (LQT1) and NaV1.5 (LQT3) and lead to subclinical or clinical prolongation of the QT interval. A potential cause for the prolongation of the QT interval and the proarrhythmic risk induced by alfuzosin has recently been ascribed to the observation that the drug slows the inactivation of the cardiac NaV1.5 ion channel.[20] One would, thus, also expect a potent, selective inhibitor of the KCNQ1/KCNE1 ion channel to potentially cause a prolonged QT interval, similar to the LQT1 syndrome.

Besides compounds directly acting on cardiac ion channels, new mechanisms for cardiac arrhythmias are being unraveled. One such mechanism is the inhibition of hERG trafficking to the cell membrane. This has been observed for arsenic trioxide,[21] pentamidine,[22] fluoxetine,[23] and recently digoxin – a cardiac glycoside clinically used for the treatment of congestive heart failure – and is being discussed as a probable cause for the potential of these compounds to induce cardiac arrhythmia.[24] As trafficking defects can take many hours to develop, they require a long exposure to the drug, and are, thus, easily missed in assays with short exposure times.

The structural and molecular features leading to the promiscuity of the hERG ion channel and its susceptibility to blockade by small molecules are becoming increasingly understood.[25–27] The large, hydrophobic cavity of the hERG channel pore allows binding of pharmacophores common to many drugs. The hERG electrophysiological patch clamp assay has an established role for the early assessment of the torsadogenic liability of a compound and scientific rationale for this approach is good, as hERG channel inhibition is indeed the major mechanism underlying most forms of drug-induced TdP.[28] While the hERG channel assay still proves a relatively simple and predictive method for determining the torsadogenic potential of a compound, it needs to be kept in mind that it constitutes an in vitro assay, not capable of mirroring the full physiological response of a cardiac cell, let alone the heart, or the body. As previously outlined, the hERG channel is not the only ion channel that shapes the cardiac action potential, and that plays an important role in drug-induced cardiac arrhythmias. Thus, the predictive power of the hERG assay for the torsadogenicity of a specific compound is far from ideal, and data from other test systems need to be taken into account. Consequently, the quest for more predictive novel test systems is ongoing, and novel cardiac test systems are continuously being developed.[29]