ARVCD Linked to Mutations of RyR2 Gene

Mutations of the RyR2 gene cause effort-induced polymorphic ventricular arrhythmias (PVA) associated with mild alterations of the right ventricle or with normal hearts [12-16]. The RyR2 receptor is involved in the calcium release from the sarcoplas-mic reticulum. Mutations of this gene cause malfunction of the receptor resulting in intracellular calcium overload [17, 18]. The calcium overload may induce both cellular injury that triggers apop-tosis and electrical instability due to after-depolarization potentials.

Ventricular arrhythmias are usually induced during exercise testing and the heart rate threshold at which they appear is different in each subject. This heart rate can be quite low, even below 100 bpm, and these subjects are particularly at risk of sudden death, since it is common to reach this rate in normal life. Beta-blockers have a role in raising the heart rate threshold, thus they have a preventive effect on the onset of arrhythmias. Bauce et al. studied eight families with RyR2 mutations [14] (Fig. 3.2). A total of 43 subjects were found to carry a RyR2 mutation; among these, 28 (65%, 13 males and 15 females; mean age 28±12 years) presented with effort-induced arrhythmic symptoms or signs (PVA in 26 cases and isolated syncopal episodes in 2) (Fig. 3.3). Among the 26 subjects with PVA during exercise, 15 presented with polymorphic ventricular complexes, either isolated or in couplets, whereas in ten subjects, PVA progressed to nonsustained ventricular tachycardia (VT). In one patient a sustained VT was induced. PVA were re-

Ca+ overload RyR2

Intercellular junctions defects Desmoplakin Plakoglobin Plakophilin-2 Desmoglein-2 Desmocollin-2

Myocites necrosis

Fibro-fatty substitution

Myocardial fibrosis

TGFbeta 3

Fig. 3.2 • Pedigrees of two families carrying RyR2 mutation. Note that in family 125 no subjects had polymorphic ventricular arrhythmias,thus sudden death was the only clinical manifestation. Reproduced from [14]
Fig. 3.3 • Electrocardiographic monitoring during an exercise test in a 22-year-old male with RyR2 mutation and a family history of sudden death. As the effort increases, premature polymorphic ventricular arrhythmias appear

lated to the increased heart rate with exercise, and each subject seemed to have a reproducible heart rate threshold at which the PVA appeared. The average sinus rate at the onset of arrhythmias was 127 ±14 bpm, and in all subjects PVA disappeared during the first minute of recovery. In two families sharing the same RyR2 mutation, exercise testing did not induce polymorphic ventricular arrhythmias in any subject. In these families syncope and sudden death were the only clinical manifestations of the disease. No patient had documented PVA or syncopal episodes before the age of 11 years. The comparison between arrhythmic and nonarrhyth-mic subjects carrying RyR2 mutations did not show any statistically significant difference regarding gender and age. In nine subjects arrhythmic symptoms were not present at the first visit and appeared during follow-up.

The twelve-lead ECG showed normal sinus rhythm, normal atrioventricular conduction, and normal QT interval in all mutation carriers. The signal-averaged ECG showed late potentials in five subjects (12%), whereas the 24-h ambulatory ECG revealed sporadic monomorphic ventricular complexes in four subjects (9%). In 17 (39%) gene mutation carriers, the 2D echocardiogram showed kinetic alterations of the RV, whereas mild structural abnormalities as trabecular thickening and/or highly reflective moderator band were found in 26 affected subjects (60%). Left ventricular volume and kinetics were normal in all subjects. In the nine subjects who underwent EP study, ventricular arrhythmias were not induced, even during isoproterenol infusion.

Beta-blocker therapy was administered to the 26 patients with exercise-induced PVA and the exercise test showed the disappearance of PVA in 17 (65%). In the remaining subjects, arrhythmias were triggered at a higher work load; thus, the antiarrhyth-mic drug dosage was increased. At the same time, patients were strongly advised to avoid strenuous physical activity. During follow-up (mean 6.5 years, range 6 months to 14 years), no patient on antiar-rhythmic therapy had syncopal episodes or died suddenly.

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