ARRHYTHMOGENIC ION-CHANNEL REMODELING IN HEART FAILURE
Heart failure carries a poor prognosis, about half of the affected patients die within five years after er initial diagnosis, and half of these deaths are due to severe arrhythmia. The underlying proarrhythmic mechanisms in heart failure consist of abnormal excitability and impulse conduction resulting in triggered activity, reentrant wave fronts and/or rotors, that are related to aberrant intracellular Ca2+-cycling. Cardiac disease modiWes the operation of ion channels and transporters in a way that promotes the occurrence of cardiac rhythm disturbances, a process called “arrhythmogenic remodeling.” Arrhythmogenic remodeling involves alterations in ion channel and transporter expression, regulation and association with important protein partners, and has important pathophysiological implications that contribute in major ways to cardiac morbidity and mortality. We review the changes in ion channel and transporter properties associated with congestive heart failure. We pay particular attention to K, Na and Ca channels; Ca transporters; connexins; and hyperpolarization-activated nonselective cation channels and discuss the mechanisms through which changes in ion handling processes lead to cardiac arrhythmias. We highlight areas of future investigation, important opportunities for improved therapeutic approaches that are being opened by an improved understanding of the mechanisms of arrhythmogenic remodeling.