Electrical Mechanism of 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
Cellular and Ion Channel Mechanisms
The fundamental electrical abnormality underlying torsades de pointes involves disruption of ventricular myocyte repolarization through ion channel dysfunction 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 1
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
Transmural Dispersion: The Arrhythmogenic Substrate
The myocardium has physiological differences in repolarization across its layers, but pathological exaggeration of these differences creates the substrate for torsades 1:
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 1
Proarrhythmic states arise when medications or genetic mutations cause selective action potential prolongation in the M-cell region, leading to increased transmural repolarization gradients 1
This increased transmural gradient creates the conditions necessary for reentry 1
QT prolongation alone is insufficient to cause torsades—heterogeneity of repolarization is also necessary to produce an arrhythmogenic response 1
The Trigger Mechanism
The trigger for torsades is a premature ventricular contraction (PVC) that results from an early afterdepolarization generated during the abnormally prolonged repolarization phase 1:
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, 2
The characteristic "short-long-short" R-R interval sequence precedes torsades onset, with marked QT prolongation and T-U wave distortion in the last sinus beat terminating the long pause 1, 2, 3
This pause-dependent enhancement of the QT interval is a critical factor in torsades development 2
Perpetuation Through Reentry
Once triggered, the arrhythmia is sustained by a specific reentrant mechanism 1:
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
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
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
The common mechanism for initiation or termination of this bifurcation is development of functional conduction block between the anterior or posterior right ventricular free wall and the ventricular septum 1
The arrhythmia terminates when reentrant excitation is terminated 1
Dose-Response and Risk Relationships
The degree of electrical abnormality correlates with torsades risk 4:
QT prolongation is directly dose-related, with sotalol increasing QTc from baseline by an average of 25,40, and 50 msec at doses of 80,120, and 160 mg respectively 4
Torsades incidence increases dramatically with QTc >500 ms (1.3% incidence) to 3.4% at 500-525 ms, 5.6% at 525-550 ms, and 10.8% at QTc >550 ms 4
Each 10 ms increase in QTc contributes approximately 5-7% exponential increase in risk 2
Critical Clinical Caveats
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 5. The mechanism whereby different degrees of risk occur with similar QT prolongation is not well established 1.