Screening Methods for Antiarrhythmic Drugs

Introduction & the screening problem

• Definition — Antiarrhythmic screening is the ordered set of in-vitro, isolated-organ and in-vivo assays used to detect, quantify and classify a compound's ability to prevent or terminate a disorder of cardiac rhythm — and to expose its converse liability, proarrhythmia.
• Why the topic is hard — arrhythmias are difficult to model: the primary aetiologies are largely unknown, so the link between abnormal excitability, conduction and repolarization and the underlying molecular biology remains poorly defined.
• The surrogate strategy — because the human disease cannot be copied, the experimenter induces an arrhythmia of known mechanism with a defined stimulus, then asks whether the compound raises its threshold, delays its onset, shortens it, or prevents death.
• No single model suffices — no animal model resembles the human condition accurately and species differences exist; the answer is deliberate choice of model plus species, and reliance on the combination of tiers — expression systems, single cells, excised tissue, isolated hearts, anaesthetized and conscious animals.