Hypothesis for the molecular physiology of the Romano-Ward long QT syndrome

OBJECTIVES. The aim of this review was to develop a hypothesis for the molecular pathophysiology of the inherited long QT syndrome. BACKGROUND. The pathophysiology of the long QT syndrome is unknown. An abnormality of the sympathetic nervous system has been suspected because of the slow heart rates observed and the common precipitation of syncope by adrenergic stimulation (exercise or fright). The characteristic QT prolongation and torsade de pointes arrhythmias suggest a potassium ion (K+) abnormality. Recent findings from molecular biology and genetic linkage analysis studies provide a basis for a new hypothesis that unifies these clinical manifestations. METHODS. Several recent studies regarding ras proteins were evaluated and correlated. Associations between ras proteins, G protein function and the known features of the long QT syndrome were identified. Based on these associations, a hypothesis for the molecular pathophysiology was developed. RESULTS. The Romano-Ward long QT phenotype is linked to the Harvey ras-1 gene on chromosome 11 in many, but not all, families. Ras genes exhibit G protein properties, acting as intermediaries in transmembrane signaling pathways including K+ and beta-adrenergic channels. Mutation of ras p21 protein significantly reduces the G protein function of the ras protein, thereby interfering with signal transduction. CONCLUSIONS. These various studies suggest that a mutation of the disease gene (not necessarily H-ras-1) alters the G protein function of the gene and interferes with delayed rectifier K+ and beta-receptor channel signaling. This hypothesis appears to explain and unify the several characteristic features of the long QT syndrome.

This article has been cited by other articles:

				S. S. Chugh, O. Senashova, A. Watts, P. T. Tran, Z. Zhou, Q. Gong, J. L. Titus, and S. J. Hayflick Postmortem molecular screening in unexplained sudden death J. Am. Coll. Cardiol., May 5, 2004; 43(9): 1625 - 1629. [Abstract] [Full Text] [PDF]

				H. Furushima, S. Niwano, M. Chinushi, K. Ohhira, A. Abe, and Y. Aizawa Relation between bradycardia dependent long QT syndrome and QT prolongation by disopyramide in humans Heart, January 1, 1998; 79(1): 56 - 58. [Abstract] [Full Text] [PDF]