Druggable targets for sudden cardiac death prevention: lessons from the past and strategies for the future

Abstract

Sudden cardiac death (SCD) is most commonly caused by ventricular fibrillation (VF). The single largest cohort of victims is the population with little or no prior overt heart disease. Effective prevention will require long-term prophylaxis by drugs in large numbers of people identified by risk factors. This means that safe as well as effective drugs are required. Drugs with overt effects on cardiac electrophysiology have failed in the clinic owing to poor effectiveness and/or adverse effects. This article examines possible new drug targets. We have focused on acute myocardial ischaemia as it is the most strikingly proarrhythmic pathology, and the most common cause of coronary artery disease-related VF and SCD according to inferences from epidemiology, drug trials and decades of animal research. To set the scene we have briefly explored drugs that have failed in the clinic in order to identify possible targets that have been overlooked or underexploited. We conclude that the best strategy is identification of pathology-specific targets that render drugs active only where and when their action is required.