Is Depressed Contractility Centrally Involved in Heart Failure? What is the Role of -Adrenergic Signaling in Heart Failure? What Mechanisms Underlie Diastolic Dysfunction in Heart Failure? Is the Failing Heart Energy Starved? What Causes Sudden Death in H

Abstract—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. (Circ Res. 2004;95:754-763.) Key Words: arrhythmia Ca2 handling cardiac electrophysiology heart failure ionic remodeling Nearly 5 million Americans experience heart failure (HF)and 250 000 die annually. The incidence and preva-lence has continued to increase with the aging of the US population.1 Despite remarkable improvements in medical therapy, the prognosis of patients with myocardial failure remains poor, with almost 20 % of patients dying within 1 year of initial diagnosis and 80 % 8-year mortality. Of the deaths in patients with HF, up to 50 % are sudden an