Long QT syndrome: from channels to cardiac arrhythmias

Abstract

Long QT syndrome, a rare genetic disorder associated with life-threatening arrhythmias, has provided a wealth of information about fundamental mechanisms underlying human cardiac electrophysiology that has come about because of truly collaborative interactions between clinical and basic scientists. Our understanding of the mechanisms that control the critical plateau and repolarization phases of the human ventricular action potential has been raised to new levels through these studies, which have clarified the manner in which both potassium and sodium channels regulate this critical period of electrical activity.

Figure 1

(A) An illustrative example of a single cardiac cycle detected as spatial and temporal electrical gradients on the ECG. The P wave is generated by the spread of excitation through the atria. The QRS complex represents ventricular activation and is followed by the T wave, which reflects ventricular repolarization gradients. (B) Schematic representation of the KCNH2 (HERG) potassium channel α subunit, involving the N-terminal part (NH₃⁺), 6 membrane-spanning segments with the pore region located from segment S5 to segment S6, and the C-terminal portion (COO^–). Mutation locations are indicated by blue dots. Fourteen different mutations were located in 13 locations within the pore region. Reproduced with permission from Circulation (28).

Figure 2

Kaplan-Meier cumulative probability of first cardiac events from birth through age 40 years for subjects with mutations in pore (n = 34), N-terminal (n = 54), and C-terminal (n = 91) regions of the KCNH2 (HERG) channel. The curves are significantly different (P < 0.0001, log-rank), mainly because of the high first-event rate in subjects with pore mutations. Reproduced with permission from Circulation (28).

Figure 3

Three major cardiac ion channel currents (I_Na, I_Kr, and I_Ks) and respective genes responsible for generation of portions of the ventricular action potential (AP).