QT interval prolongation and cardiac risk assessment for novel drugs.
Fatal cardiac arrhythmias, known as torsades de pointes, can occur with a wide variety of medicinal drugs and are associated with prolongation of the QT interval. This review critically evaluates the major strategies for assessing QT prolongation risk: ion channel studies, in vitro cardiac electrophysiology, and in vivo cardiac electrophysiology and hemodynamics. Disease- or drug-induced QT prolongation is mainly associated with reduced amplitude of the repolarizing outward K+ current in myocardial cells, particularly those carried by the human ether-a-go-go-related gene (HERG) channel. Thus, measuring HERG currents using patch-clamp technology and cloned HERG channels represents a first approach for evaluating adverse effects of drugs on ion channel function, under physiological conditions. Evaluation of changes in transmembrane action potential in isolated rabbit or dog Purkinje fibers reflects mixed ion channel blocking properties of the test substance and therefore permits a greater understanding of the mechanisms underlying the genesis of arrhythmias. Both HERG channel and Purkinje fiber procedures are clinically predictive, however, no in vitro technique can fully reproduce the in vivo situation. Therefore, both in vitro and in vivo approaches should be employed to maximize the chances of an accurate assessment of risk in an area where prolonged QT can result in death.
Porsolt and Partners Pharmacology, 9 bis, rue Henri Martin, 92100 Boulogne Billancourt, France.
Sandra
S
Picard
Pierre
P
Lacroix
D000818:Animals; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D064420:Drug-Related Side Effects and Adverse Reactions; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated; D011690:Purkinje Fibers / Q000187:drug effects; D018570:Risk Assessment; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C568320:SCN5A protein, human; D015222:Sodium Channels; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG