Long QT Syndrome pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Mechanism of arrhythmia generation

All forms of the long QT syndrome involve an abnormal repolarization of the heart. The abnormal repolarization causes differences in the "refractoriness" of the myocytes. After-depolarizations (which occur more commonly in LQTS) can be propagated to neighboring cells due to the differences in the refractory periods, leading to re-entrant ventricular arrhythmias.

It is believed that the so-called early after-depolarizations (EADs) that are seen in LQTS are due to re-opening of L-type calcium channels during the plateau phase of the cardiac action potential. Since adrenergic stimulation can increase the activity of these channels, this is an explanation for why the risk of sudden death in individuals with LQTS is increased during increased adrenergic states (ie exercise, excitement) -- especially since repolarization is impaired. Normally during adrenergic states, repolarizing currents will also be enhanced to shorten the action potential. In the absence of this shortening and the presence of increased L-type calcium current, EADs may arise.

The so-called delayed after-depolarizations (DADs) are thought to be due to an increased Ca²⁺ filling of the sarcoplasmic reticulum. This overload may cause spontaneous Ca²⁺ release during repolarization, causing the released Ca²⁺ to exit the cell through the 3Na⁺/Ca²⁺-exchanger which results in a net depolarizing current.

Genetics

The two most common types of LQTS are genetic and drug-induced. Genetic LQTS can arise from mutation to one of several genes. These mutations tend to prolong the duration of the ventricular action potential (APD), thus lengthening the QT interval. LQTS can be inherited in an autosomal dominant or an autosomal recessive fashion. The autosomal recessive forms of LQTS tend to have a more severephenotype, with some variants having associated syndactyly (LQT8) or congenital neural deafness (LQT1). A number of specific genes loci have been identified that are associated with LQTS.

Associated syndromes

A number of syndromes are associated with LQTS.

Jervell and Lange-Nielsen syndrome

The Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive form of LQTS with associated congenital deafness. It is caused specifically by mutation of the KCNE1 and KCNQ1 genes

In untreated individuals with JLNS, about 50 percent die by the age of 15 years due to ventricular arrhythmias.

Romano-Ward syndrome

Romano-Ward syndrome is an autosomal dominant form of LQTS that is not associated with deafness.