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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.
Nonstandard abbreviations used: β-AR, β-adrenergic receptor; ATS, Andersen-Tawil syndrome; I^sub Kr^, rapidly activating delayed repolarizing cardiac potassium current; I^sub Ks^, slowly activating delayed repolarizing cardiac potassium current; I^sub Na^, cardiac sodium current; LQTS, long QT syndrome; QTc, heart rate-corrected QT (interval); RWS, Romano-Ward syndrome; TS, Timothy syndrome.
Background
The common form of long QT syndrome (LQTS), Romano-Ward syndrome (RWS), is a heterogeneous, autosomal dominant, genetic disease caused by mutations of ion channel genes involving the cell membranes of the cardiac myocytes. These channelopathies are associated with delayed ventricular repolarization and are clinically manifest by passing-out spells (syncope; see Glossary) and sudden death from ventricular arrhythmias, notably torsade de pointes (1). Clinically, LQTS is identified by abnormal QT interval prolongation on the ECG. The QT interval prolongation may arise from either a decrease in repolarizing cardiac membrane currents or an increase in depolarizing cardiac currents late in the cardiac cycle. Most commonly, QT interval prolongation is produced by delayed repolarization due to reductions in either the rapidly or the slowly activating delayed repolarizing cardiac potassium (K+) current, I^sub Kr^ or I^sub Ks^ (2). Less commonly, QT interval prolongation results from prolonged depolarization due to a small persistent inward "leak" in cardiac sodium (Na+) current, I^sub Na^ (3) (Figure 1A).
Patients with LQTS are usually identified by QT interval prolongation on the ECG during clinical evaluation of unexplained syncope, as part of a family study when 1 family member has been identified with the syndrome, or in the investigation of patients with congenital neural deafness. The first family with LQTS was reported in 1957 and was thought to be an autosomal recessive disorder (4), but in 1997 it was shown to result from a dominant, homozygous mutation involving the KvLQT1 gene...