Long QT syndrome – Bench to bedside

Figure 1. From the electrocardiogram (ECG) to cellular ion currents. Voltage-activated Na+ and K+ currents define the ventricular action potential and the QT interval of the ECG. A: Simulated ECG trace in normal conditions (black trace) and LQTS (red trace). The rapid upstroke of the ventricular action potential gives rise to the QRS complex. The duration of the QT interval is determined by the time of the ventricular repolarization. B: Simulated ventricular action potential in physiological situation (black trace), the rapidly activating and inactivating peak INa drives membrane depolarization; a very small sustained or late INaL is present. Two K+ currents, IKs and IKr, contribute mostly to the plateau phase and repolarization phase of the action potential, which restores the membrane resting potential. Simulated functional effect of loss of function of either IKs or IKr or gain of function of INaL on the ventricular action potential result in prolongation of ventricular action potential associated with LQT1, LQT2, and LQT3, respectively (red trace). Simulated action potential with early afterdepolarization events (green trace). C: Simulated normal time course and amplitude of IKs, IKr,…

Figure 2. Overall topology of KCNQ1, KCNH2, and SCN5A. A:KCNQ1 topology. Four KCNQ1 tetramerize to comprise the pore-forming α-subunit; each α-subunit contains 6 transmembrane segments, labeled as S1–S6. SF denotes the selectivity filter. Additionally, IKs macromolecular complex is illustrated, including β-subunit KCNE1, and associated scaffolding and signaling proteins. B:KCNH2, known as the human ether-a-go-go-related gene (hERG). Pore-forming α-subunit transmembrane segments are labeled S1–S6; SF denotes the selectivity filter topology. PAS denotes Per-Arnt-Sim domain, also referred to as “eag domain.” CNBHC denotes cyclic nucleotide-binding homology domain. Additionally, the β-subunit KCNE2 (MiRP1), which associates with KCNH2 α subunits resembling native cardiac IKr channels, is illustrated. C:SCN5A topology of α subunit with auxiliary SCN4B β subunit.