RIGHT-VENTRICULAR OUTFLOW TRACT TACHYCARDIA DUE TO A SOMATIC-CELL MUTATION IN G-PROTEIN SUBUNIT(ALPHA-I2)

Idiopathic ventricular tachycardia is a generic term that describes th e various forms of ventricular arrhythmias that occur in patients with out structural heart disease and in the absence of the long QT syndrom e, Many of these tachycardias are focal in origin, localize to the rig ht ventricular outflow tract (RVOT), terminate in response to beta blo ckers, verapamil, vagal maneuvers, and adenosine, and are thought to r esult from cAMP-mediated triggered activity, DNA was prepared from bio psy samples obtained from myocardial tissue from a patient with adenos ine-insensitive idiopathic ventricular tachycardia arising from the RV OT, Genomic sequences of the inhibitory G protein G(alpha i2) were det ermined after amplification by PCR and subcloning, A point mutation (F 200L) in the GTP binding domain of the inhibitory G protein G(alpha i2 ) was identified in a biopsy sample from the arrhythmogenic focus. Thi s mutation was shown to increase intracellular cAMP concentration and inhibit suppression of cAMP by adenosine, No mutations were detected i n G(alpha i2) sequences from myocardial tissue sampled from regions re mote from the origin of tachycardia, or from peripheral lymphocytes, T hese findings suggest that somatic cell mutations in the cAMP-dependen t signal transduction pathway occurring during myocardial development may be responsible for some forms of idiopathic ventricular tachycardi a.