TABLE 4

Risk factors for drug-induced torsades de pointes

Risk Factor	Mechanism of Increased Risk	Magnitude of Risk	Confounding Factors
Female sex	Sex hormonal regulation of repolarization especially by testosterone	Greater in females with 2- 3:1 female to male	Sex differences in density of ion channels and modulation of I_Kr
Bradycardia	Pause-dependent QT prolongation with typical short-long-short cycle	Typically with heart rates <60 bpm	Long-term atrioventricular block; hypothermia hypothyroidism
Electrolyte disturbances
Hypokalemia	Decreases I_Kr by enhanced inactivation or exaggerated competitive block of sodium Potentiation of drug blockade of residual I_Kr	Especially with serum potassium <3.5 mg/dl	Drug blockade enhanced with hypokalemia
Hypomagnesemia	Modulation of L-type calcium channel	Magnesium <1.5 mg/dl	Serum magnesium correlates poorly with intracellular levels
Recent conversion from atrial fibrillation especially with QT-prolonging drugs	Reduced heart rate after conversion to sinus QT remodeling in AF	1–3% incidence with QT-prolonging drugs
High drug concentrations and rapid infusion of QT-prolonging drugs	Dose- or concentration-dependent QT prolongation (except quinidine)	May increase QT by 50 ms at clinically prescribed doses	Renal impairment; reduced metabolism or inhibition of cytochromeP450 enzymes
Digitalis	Intracellular calcium overload with delayed afterdepolarizations and inhibition of KCNH2 trafficking	Rare and only with extreme toxicity
Subclinical (congenital)long QT syndrome	QT prolongation upon exposure to I_Kr-blocking drugs	<10% of cLQTS; mutations identified inKCNQ1, KCNH2,KCNE1, KCNE2, SCN5A	Responsible for incomplete penetrance in cLQTS
Ion channel polymorphisms	Minor effects at baseline but compounded with a QT-prolonging drug leading to torsades de pointes	Common polymorphisms identified: H558R SCN5A; R1047L KCNH2; D85N KCNE1; T8A and Q9E KCNE2	Non–ion-channel polymorphisms (see section VI.C for details)