Late sodium current is a new therapeutic target to improve contractility and rhythm in failing heart.
Most cardiac Na+ channels open transiently within milliseconds upon membrane depolarization and are responsible for the excitation propagation. However, some channels remain active during hundreds of milliseconds, carrying the so-called persistent or late Na+ current (I(NaL)) throughout the action potential plateau. I(NaL) is produced by special gating modes of the cardiac-specific Na+ channel isoform. Experimental data accumulated over the past decade show the emerging importance of this late current component for the function of both normal and especially failing myocardium, where I(NaL) is reportedly increased. Na+ channels represent a multi-protein complex and its activity is determined not only by the pore-forming alpha subunit but also by its auxiliary beta subunits, cytoskeleton, and by Ca2+ signaling and trafficking proteins. Remodeling of this protein complex and intracellular signaling pathways may lead to alterations of I(NaL) in pathological conditions. Increased I(NaL) and the corresponding Na+ influx in failing myocardium contribute to abnormal repolarization and an increased cell Ca2+ load. Interventions designed to correct I(NaL) rescue normal repolarization and improve Ca2+ handling and contractility of the failing cardiomyocytes. New therapeutic strategies to target both arrhythmias and deficient contractility in HF may not be limited to the selective inhibition of I(NaL) but also include multiple indirect, modulatory (e.g. Ca(2+)- or cytoskeleton- dependent) mechanisms of I(NaL) function.
Undrovinas
Albertas
A
Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202-2689, USA. aundrov1@hfhs.org
Maltsev
Victor A
VA
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003599:Cytoskeleton / Q000502:physiology; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects*; D010743:Phospholipids / Q000378:metabolism; D021122:Protein Subunits; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000627:therapeutic use*
D010743:Phospholipids; D021122:Protein Subunits; D026941:Sodium Channel Blockers; D012964:Sodium; D002118:Calcium