Drug- and non-drug-associated QT interval prolongation

Abstract

Sudden cardiac death is among the most common causes of cardiovascular death in developed countries. The majority of sudden cardiac deaths are caused by acute ventricular arrhythmia following repolarization disturbances. An important risk factor for repolarization disturbances is use of QT prolonging drugs, probably partly explained by gene-drug interactions. In this review, we will summarize QT interval physiology, known risk factors for QT prolongation, including drugs and the contribution of pharmacogenetics. The long QT syndrome can be congenital or acquired. The congenital long QT syndrome is caused by mutations in ion channel subunits or regulatory protein coding genes and is a rare monogenic disorder with a mendelian pattern of inheritance. Apart from that, several common genetic variants that are associated with QT interval duration have been identified. Acquired QT prolongation is more prevalent than the congenital form. Several risk factors have been identified with use of QT prolonging drugs as the most frequent cause. Most drugs that prolong the QT interval act by blocking hERG-encoded potassium channels, although some drugs mainly modify sodium channels. Both pharmacodynamic as well as pharmacokinetic mechanisms may be responsible for QT prolongation. Pharmacokinetic interactions often involve drugs that are metabolized by cytochrome P450 enzymes. Pharmacodynamic gene-drug interactions are due to genetic variants that potentiate the QT prolonging effect of drugs. QT prolongation, often due to use of QT prolonging drugs, is a major public health issue. Recently, common genetic variants associated with QT prolongation have been identified. Few pharmacogenetic studies have been performed to establish the genetic background of acquired QT prolongation but additional studies in this newly developing field are warranted.

Figure 1

Corrected QT interval using Bazett's formula. Source: Al-Khatib [10]

Figure 2

The cardiac action potential. A) action potential showing the five phases of cardiac depolarization and repolarization with ion current directions during activation of the different ion channels; B) ECG. Phase 0: Rapid depolarization is caused by a large inward current of sodium ions (INa). Repolarization consists of three phases [–3]: Phase 1: Rapid repolarization phase is caused by inactivation of I_Na and the transient efflux of potassium ions (I_t0); Phase 2: Plateau phase, which is a reflection of a balance between the influx of calcium ions through l-type calcium channels (I_Ca) and outward repolarizing potassium currents (I_K); Phase 3: Late repolarization phase results from the efflux of potassium (I_Kr, I_Ku, I_Ks). Phase 4: Resting potential is maintained by the inward rectifier potassium current (I_K1). I_Ca = calcium current; I_K = potassium current; I_K1 = inwardly rectifying potassium current; I_Na = depolarizing sodium current; I_t0 = transient outward potassium current; I_Kr = rapidly activating delayed rectifier potassium current; I_Ks = slowly activating delayed rectifier potassium current; I_Ku = ultra rapidly activating delayed rectifier potassium current. Source: Titier et al. [64]

Figure 3

Mechanisms of sudden cardiac death with hERG blockade. Drug blockade of the hERG channel (left) can result in QT interval prolongation (middle) and torsade de pointes (right; upper panel), which can develop into to ventricular fibrillation (VF) (right; lower panel). Source: Roden et al. [65]