What causes sudden death in heart failure?

Patients with heart failure experience a number of changes in the electrical function of the heart that predispose to potentially lethal cardiac arrhythmias. Action potential prolongation, the result of functional downregulation of K currents, and aberrant Ca²⁺ handling is a recurrent theme. Significant alterations in conduction and activation of a number of initially adaptive but ultimately maladaptive signaling cascades contribute to the generation of a highly arrhythmogenic substrate. We review the changes in active and passive membrane properties, neurohumoral signaling, and genetic determinants that predispose to sudden arrhythmic death in patients with heart failure and highlight the critical unanswered questions that are ripe for future investigation.