Cellular mechanisms of Torsade de Pointes.
Torsade de Pointes (TdP) is a life-threatening arrhythmia closely linked to abnormal cardiac repolarization. It has been demonstrated that cardiac ion channel alterations underlying cellular repolarization results in the phenotypic expression of long QT syndrome, which is closely associated with TdP. However, the mechanisms by which prolonged repolarization leads to TdP remain controversial. Prolonged repolarization is associated with triggered activity, and multiple foci of triggered activity can underlie a TdP phenotype. Action potential shortening associated with rapid ventricular rhythms, in theory, removes conditions for triggered activity. Therefore, while triggered activity may initiate TdP, another mechanism may be responsible for the maintenance of TdP. Re-entrant arrhythmias can also give rise to a TdP phenotype. In intact myocardium significant inhomogeneities of repolarization are manifest in the presence of IKr blockade. Large repolarization gradients between subepicardial and midmyocardial cells formed zones of conduction block responsible for sustained reentrant TdP. Gap junction proteins responsible for intercellular coupling between subepicardial and midmyocardial cells are reduced in normal myocardium which may maintain arrhythmogenic gradients of repolarization. Therefore, the mechanism of TdP is multi-factorial and related to triggered activity and spatial inhomogeneities of ion channel expression combined with regional expression patterns of gap junctions.
Poelzing
Steven
S
The Heart and Vascular Research Center, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44109-1998, USA.
Rosenbaum
David S
DS
D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics* / Q000378:metabolism; D016171:Torsades de Pointes / Q000235:genetics*; D014693:Ventricular Fibrillation / Q000235:genetics*
D027682:Cation Transport Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D024642:Potassium Channels, Voltage-Gated