Long QT

The QT interval represents the duration of ventricular depolarization and repolarization measured in the ECG. Long QT syndrome (LQTS) is a prolongation of the QT interval during normal rhythm which can cause ventricular tachycardia and in particular torsades de pointes, which if it persists for 1-2 minutes can cause syncope and sudden death. LQTS can be either congenital (predominantly mutations in hERG, KvLQT1 and Nav1.5) or more commonly, drug-induced.

A large variety of drugs from different therapeutic classes can prolong the QT interval (e.g. antiarrhythmics, gastrointestinal prokinetics, antihistamines, antibiotics and antipsychotics). Although a variety of ion channels underlie the ventricular action potential, potassium channels causing ventricular repolarization are the target for drug-induced long QT. In particular, the rapid delayed rectifier, hERG is the channel target.

The structural basis for the drug sensitivity of hERG is probably due to two key factors. Firstly, the internal pore cavity of hERG is larger than some of the other voltage-gated potassium channels due to the absence of two specific proline residues in each subunit that produce a kink in the pore-lining region. Secondly, hERG subunits each contain two aromatic residues facing the inner cavity of the channel, providing a high affinity pi-bonding drug binding site.