The arrhythmogenic substrate of the long QT syndrome: genetic basis, pathology, and pathophysiologic mechanisms

The Long QT syndrome (LQTS) is a relatively rare disorder. It has a major clinical impact as affected individuals are prone to syncope and sudden arrhythmogenic cardiac death. The LQTS comprises three groups of patients. The Jervell-Lange-Nielsen syndrome is characterized by an autosomal recessive pattern of inheritance and congenital neural deafness. The Romano-Ward syndrome shows an autosomal dominant pattern of inheritance and normal hearing. Patients with the sporadic form of LQTS have no evidence of familial transmission and have normal hearing. Imbalance of sympathetic cardiac innervation with predominance of the left stellate ganglion and an intrinsic myocardial defect leading to early afterdepolarization are the two pathogenetic mechanisms of LQTS discussed today. More recently a genetic basis for the Romano-Ward LQTS has been reported. The genetic linkage to the Harvey ras-1 gene provides the basis for a new hypothesis that an impairment of guanine nucleotide binding proteins is responsible for symptoms observed in LQTS. This paper discusses the genetic basis, pathology and pathophysiology of LQTS and tries to unify the different theories.