Ventricular Tachycardia, Familial

A number sign (#) is used with this entry because of the finding that somatic mutation in the gene encoding the G protein subunit alpha-i2 (GNAI1; 139360) is responsible in at least 1 case. This raises the possibility that familial cases may be caused by mutation in this or related genes. Stress-induced polymorphic ventricular tachycardia (VTSIP; 604772), also known as catecholaminergic polymorphic ventricular tachycardia, has been found to be caused by mutation in the gene encoding the cardiac ryanodine receptor gene (RYR2; 180902).

Rubin et al. (1992) reported a kindred in which members in 4 successive generations suffered from paroxysmal ventricular tachycardia. They suggested that this is the first report of an autosomal dominant ventricular tachycardia not associated with cardiomyopathy, metabolic disorder, or repolarization abnormality. In generation 2, 4 of 7 sibs sustained sudden cardiac death. In generation 3, 5 of 10 sibs had documented ventricular tachycardia and 1 of the 5 had sudden cardiac death. In generation 4, 4 of 12 sibs had ventricular tachycardia and 1 of them died suddenly. All the children in generation 5, all prepubertal, were asymptomatic and had normal cardiac investigations. No systemic abnormalities were found in 2 affected fourth-generation family members studied in great detail. The ventricular tachycardia detected in these sibs on 24-hour ambulatory monitoring had a similar right bundle branch block, with left axis deviation pattern. Rubin et al. (1992) reviewed the reasons to think that reentry and triggered automaticity were not likely mechanisms, leaving abnormal automaticity as the likely cause.

Familial ventricular tachycardia is usually attributable to recognized conditions such as arrhythmogenic right ventricular dysplasia, hypertrophic cardiomyopathy, familial cardiomyopathy, or one of the long QT syndromes. There are families with ventricular tachycardia in which no recognized underlying condition has been identified. The features of the disorder are variable from family to family. Fisher et al. (1999) described a family in which members developed ventricular arrhythmias during sinus tachycardia, whether induced by exercise, isoproterenol infusion, or emotion. Their QT intervals were normal at rest and during exercise. In this family, Fisher et al. (1999) reported a 25-year period of apparently effective medical therapy. The affected members appeared to have catecholamine hypersensitivity as the basis of their ventricular arrhythmias. Guided therapy using serial exercise-pharmacologic testing provided reliable protection for this familial ventricular arrhythmia.

Idiopathic ventricular tachycardia is a generic term that describes the various forms of ventricular arrhythmias that occur in patients without structural heart disease and in the absence of long QT syndrome. Many of these tachycardias are focal in origin, localize to the right ventricular outflow tract (RVOT), terminate in response to beta-blockers, verapamil, vagal maneuvers, and adenosine, and are thought to result from cAMP-mediated triggered activity. Lerman et al. (1998) studied a patient with adrenergically mediated idiopathic RVOT ventricular tachycardia that was unresponsive to adenosine and vagal maneuvers. The subject was a 58-year-old man who developed sustained monomorphic ventricular tachycardia during an intense argument. Because of insensitivity of the tachycardia to adenosine, Lerman et al. (1998) investigated the possibility that a mutation in the inhibitory branch of the cAMP signal transduction pathway could have elevated intracellular cAMP and facilitated the spontaneous initiation of ventricular tachycardia. They succeeded in identifying a point mutation in the GNAI2 gene (139360.0004) from the arrhythmogenic focus biopsied in this patient. Both stable and transient transfection of CHO-K1 cells with the mutant gene showed that this mutation increased the stimulated levels of cAMP and prevented adenosine suppression of cAMP. No mutations were detected in myocardial tissue sampled from regions remote from the origin of the tachycardia, or in peripheral lymphocytes.