Cardiac Conduction Defect

A number sign (#) is used with this entry because cardiac conduction defect and familial sudden death have been demonstrated to have various genetic and nongenetic causes.

Variation in the AKAP10 gene (604694) has been associated with heart rate and heart rate variability, markers that predict an increased risk of sudden cardiac death.

Clinical Features

Green et al. (1969) described a family in which sudden death occurred in at least 10 persons in 3 generations at an average age of 21 years (range 4-44). No clinical abnormalities were detectable in members of the family, including one who died suddenly. An abnormality of the conduction system was postulated but not definitely demonstrated. Gault et al. (1972) described a 10-year-old girl with 'alternating bidirection tachycardia.' Autopsy showed fatty and mononuclear cell infiltration in the atrioventricular conduction system and the main left bundle branch. A similar arrhythmia was documented in an 18-year-old sister. Autopsy showed no gross cardiac abnormality but the conduction system was not studied. A brother, aged 21 years, and the mother, aged 45, also had ventricular bigeminal rhythm and the maternal grandmother and a maternal uncle had died suddenly. Cardiac irregularity was known to have been present in the grandmother. Lynch et al. (1973) described a kindred in which many persons in several generations had a progressive atrioventricular conduction defect. Prolonged AV conduction had its onset usually in the 30s with loss of R waves in the right precordial leads. Arrhythmia occurred only as a late manifestation. Syncopal attacks were the main symptom. Progression from first- to third-degree block was usually slow, but in a few persons a relatively fulminant course with death in 2 or 3 years was observed. Since the disorder appears to be limited to the conduction system, prognosis with artificial pacemaker should be excellent. The authors found several reports that may concern the same disorder.

Strasberg et al. (1983) described a mother and daughter with paroxysmal torsade de pointes. Both had structurally normal hearts and a normal QT interval. Both were successfully treated with propranolol during their limited follow-up.

Brookfield et al. (1988) described a family rather similar to that of Green et al. (1969). A 15.5-year-old boy died suddenly after completing a 100-yard swim. He had had 4 syncopal episodes over a 3-year period, all occurring after strenuous exercise; extensive studies, including cardiac catheterization and electrophysiologic studies, revealed no abnormality. The patient's 12-year-old brother had died suddenly while swimming about 16 months before the proband's death. A maternal uncle had died at age 18, and 2 brothers of the maternal grandfather had died at ages 17 and 15. The great grandmother had died at age 35. All of these were sudden deaths. The mother and the maternal grandfather, presumed carriers, were normal by physical examination, electrocardiogram, and 2D echocardiogram, except for induction of ventricular ectopic beats and polymorphic nonsustained (325 beats) ventricular tachycardia with some procedures. The patient had been placed on 40 mg of nadolol, a beta-adrenergic blocker, 1 year before death. Also, the patient developed right bundle branch block after infusion of isoproterenol. Autopsy showed right ventricular septal hypertrophy with displacement of the conduction bundle. Thus, this family may fall in the category of asymmetric septal hypertrophy (192600).

Chambers et al. (1995) described familial sudden death syndrome with an abnormal signal-averaged electrocardiogram (Simson, 1981) as a potential marker. No structural heart disease or 12-lead electrocardiographic abnormalities were found in the individuals studied. The proposita was a 50-year-old white woman who developed ventricular fibrillation without a history of previous medical problems. The heart was unremarkable at autopsy. The 16-year-old daughter of her brother died suddenly while swimming, and no anatomic cause of death was found. Her paternal grandmother died suddenly at age 40 while working in her kitchen. Her 53-year-old brother, the father of the 16-year-old niece, had a history of palpitations and 2 episodes of syncope resulting in injury. Another of his daughters had 2 cardiac arrests at ages 13 and 19, both while swimming, and was successfully resuscitated each time. A brother of these 2 girls and a nephew of the proposita drowned at age 3 years in what was thought to be an accidental drowning. The 2 surviving family members with a clinical history of arrhythmic events had abnormal signal-averaged electrocardiograms and inducible ventricular arrhythmias during electrophysiologic studies. Chambers et al. (1995) raised the question of whether an abnormal signal-averaged electrocardiogram may be a marker for the sudden death trait.

Clinical Management

In animals with heart failure and in patients with inherited forms of exercise-induced sudden cardiac death, depletion of the channel-stabilizing protein calstabin-2 (FKBP12.6; 600620) from the ryanodine receptor-calcium release channel (RYR2; 180902) complex causes an intracellular calcium leak that can trigger fatal cardiac arrhythmias. Wehrens et al. (2004) found that a derivative of 1,4-benzothiazepine increased the affinity of calstabin-2 for RYR2, which stabilized the closed state of RYR2 and prevented the calcium leak that triggers arrhythmias. Wehrens et al. (2004) postulated that enhancing the binding of calstabin-2 to RYR2 may be a therapeutic strategy for common ventricular arrhythmias.

Molecular Genetics

Tingley et al. (2007) characterized the cardiac cycle and AKAP10 I646V genotype (604694.0001) of 122 participants in the Heart and Soul Study who had stable coronary heart disease and found that the 646V variant was associated with markers of low vagus nerve sensitivity, e.g., fast heart rate and low heart rate variability; the authors noted that these markers predict an increased risk of sudden cardiac death. Kammerer et al. (2003) had reported an association between this variant and reduced longevity (see 152430).