Familial and acquired long QT syndrome and the cardiac rapid delayed rectifier potassium current

1. Long QT syndrome (LQTS) is a cardiac disorder characterized by syncope, seizures and sudden death; it can be congenital, idiopathic, or iatrogenic. 2. Long QT syndrome is so-named because of the connection observed between the distinctive polymorphic ventricular tachycardia torsade de pointes and prolongation of the QT interval of the electrocardiogram, reflecting abnorm ally slowed ventricular action potential (AP) repolarization. Acquired LQTS has many similar clinical features to congenital LQTS, but typically affec ts older individuals and is often associated with specific pharmacological agents. 3. A growing number of drugs associated with QT prolongation and its concom itant risks of arrhythmia and sudden death have been shown to block the 'ra pid' cardiac delayed rectifier potassium current (I-Kr) or cloned channels encoded by the human ether-a-go-go-related gene (HERG; the gene believed to encode native I-Kr). Because I-Kr plays an important role in ventricular A P repolarization, its inhibition would be expected to result in prolongatio n of both the AP and QT interval of the electrocardiogram. 4. The drugs that produce acquired LQTS are structurally heterogeneous, inc luding anti-arrhythmics, such as quinidine, non-sedating antihistamines, su ch as terfenadine, and psychiatric drugs, such as haloperidol. In addition to heterogeneity in their structure, the electrophysiological characteristi cs of HERG/I-Kr inhibition differ between agents. 5. Here, clinical observations are associated with cellular data to correla te acquired LQTS with the I-Kr/HERG potassium (K+) channel. One strategy fo r developing improved compounds in those drug classes that are currently as sociated with LQTS could be to design drug structures that preserve clinica l efficacy but are modified to avoid pharmacological interactions with I-Kr . Until such time, awareness of the QT-prolongation risk of particular agen ts is important for the clinician.