Genetics of acquired long QT syndrome

Abstract

The QT interval is the electrocardiographic manifestation of ventricular repolarization, is variable under physiologic conditions, and is measurably prolonged by many drugs. Rarely, however, individuals with normal base-line intervals may display exaggerated QT interval prolongation, and the potentially fatal polymorphic ventricular tachycardia torsade de pointes, with drugs or other environmental stressors such as heart block or heart failure. This review summarizes the molecular and cellular mechanisms underlying this acquired or drug-induced form of long QT syndrome, describes approaches to the analysis of a role for DNA variants in the mediation of individual susceptibility, and proposes that these concepts may be generalizable to common acquired arrhythmias.

Figure 1

Examples of acquired long QT syndrome. A common feature is a pause (often after an ectopic beat), indicated by a star, with deranged repolarization in the following cycle (red arrows). (A) Continuous recording from a 79-year-old man with advanced heart disease treated with the antiarrhythmic dofetilide. The abnormal QT interval is followed by 7 beats of polymorphic ventricular tachycardia (torsade de pointes). In this patient, torsade de pointes then precipitated sustained monomorphic ventricular tachycardia, due to underlying heart disease. (B) Torsade de pointes in a patient treated with the antipsychotic haloperidol. (C) Torsade de pointes in a patient with complete heart block. The blue arrows indicate nonconducted atrial depolarizations. (D) Markedly abnormal postpause repolarization in a patient with advanced heart failure. Such disordered repolarization may represent increased risk for torsade de pointes (7).

Figure 2

Computed action potentials, using the Luo-Rudy simulation (94) modified to include a transient outward current. This simulation incorporates physiologically realistic numerical models of individual ion currents and other electrogenic events (e.g., exchangers) and thereby allows in silico prediction of the effects of lesions in individual components on the whole physiologic system. A and B each show (from top to bottom) epicardial action potential, I_Kr and I_Ks during the epicardial action potential, midmyocardial action potential, I_Kr and I_Ks during the midmyocardial action potential, and an ECG signal computed from a 1-dimensional fiber consisting of endocardial, midmyocardial, and epicardial cells connected through resistive gap junctions (95). (A) Control. The numbered phases of the action potential are shown on the epicardial signal. Note the increase in I_Kr at the beginning of phase 3; as discussed in the text, this serves to enhance repolarization. The dotted lines indicate the ends of repolarization in the epicardial and midmyocardial cells and correspond roughly to the peak and end of the T wave, respectively. (B) 75% I_Kr blockade. Note that action potentials at both sites are prolonged, and the difference between them is exaggerated. The T wave abnormality in the computed ECG also reflects formation of EADs in endocardial cells (not shown).

Figure 3

Hypothesized molecular structure of the drug-binding site in the HERG channel. (A) The orientation of the channel pore, lined by S6 helices, is shown; drug access is via the intracellular face of the channel. Portions of 2 of the 4 subunits of the homotetrameric channel are shown, and the other 2 are omitted for clarity. The aromatic residues (tyrosine [Tyr] and phenylalanine [Phe]) that face the pore are thought to be high-affinity drug-binding sites. (B) Sequence comparisons between HERG and other potassium channels. With the exception of the closely related hEAG channel, the others have 1 or 2 prolines in S6 and 0 or 1 aromatic residues. As discussed in the text, these 2 features appear to determine the ease with which the HERG channel is blocked by a wide range of drugs. Adapted with permission from the Journal of Biological Chemistry (19).

Figure 4

Luo-Rudy simulations showing the concept of repolarization reserve. The blue line shows the effect of reducing I_Ks by 15%, as might be expected in a subtle congenital long QT syndrome mutation. The green line shows the expected prolongation of the control action potential resulting from 75% I_Kr blockade. The red line shows the effect of the same degree of drug blockade applied to the simulation with 15% I_Ks blockade. Not only is there marked exaggeration of action potential prolongation, but an EAD with a triggered upstroke is also generated; L-type calcium current generates the upstroke in this model.

Figure 5

Mechanisms of sudden death with HERG blockade. Drug blockade of the HERG channel (left) produces prolongation (blue) and an EAD (red) in the cardiac action potential. These changes, which are heterogeneous across the ventricular wall, generate QT interval prolongation and, through mechanisms described further in the text, torsade de pointes (right; upper panel). In this example, the arrhythmia degenerates to ventricular fibrillation (VF).