Torsades de Pointes Mechanism and Risk

Introduction to Torsades de Pointes

Torsades de pointes is initiated by early afterdepolarizations triggering premature ventricular contractions in the setting of increased transmural dispersion of repolarization, which then creates the substrate for reentrant excitation that perpetuates the characteristic polymorphic ventricular tachycardia 1

Most drugs that cause torsades inhibit the rapid component of the delayed rectifier potassium current (IKr), which reduces net repolarizing current and prolongs ventricular action potential duration, manifesting as QT prolongation on the ECG 2, 3, 4
In congenital forms, approximately two-thirds of cases stem from loss-of-function mutations in KCNQ1 or KCNH2 (potassium channel genes), while 5-10% involve gain-of-function mutations in SCN5A (sodium channel gene) that produce persistent late sodium current 1, 5, 6

The subepicardium has the shortest action potential duration, the subendocardium has intermediate duration, and the mid-myocardium (M cells) has the longest action potential duration 5, 3
Proarrhythmic states arise when medications or genetic mutations cause selective action potential prolongation in the M-cell region, leading to increased transmural repolarization gradients 5, 4
QT prolongation alone is insufficient to cause torsades—heterogeneity of repolarization is also necessary to produce an arrhythmogenic response 1, 5, 7

The trigger for torsades is a premature ventricular contraction (PVC) that results from an early afterdepolarization generated during the abnormally prolonged repolarization phase 1, 5, 4
A long preceding pause increases the amplitude of early afterdepolarizations, making them more likely to reach threshold and produce a PVC or ventricular couplet 1, 5, 4

The initial beat of torsades arises as subendocardial focal activity, whereas subsequent beats are due to reentrant excitation in the form of rotating scrolls 1, 3, 6
Because of marked delay of repolarization in certain myocardial areas, conduction of the PVC is blocked initially in some directions but not others, which sets up reentry that perpetuates torsades 1, 5, 7
The characteristic periodic transition of the QRS axis (the "twisting" pattern) coincides with transient bifurcation of the predominantly single rotating scroll into two simultaneous scrolls involving both ventricles separately 1, 3, 6

Each 10 ms increase in QTc contributes approximately 5-7% exponential increase in risk 8
Not all QT-prolonging drugs carry equal torsadogenic risk—some drugs prolong QT without significantly affecting transmural dispersion of repolarization, suggesting lower arrhythmic potential despite measurable QT changes 10