br Discussion br Conclusions br Conflicts of interest br
Conflicts of interest
Introduction Catecholaminergic polymorphic ventricular tachycardia (CPVT) is induced by emotional stress or exercise in patients without organic heart disease and may be polymorphic or bidirectional (Fig. 1) [1–3]. This ventricular arrhythmia sometimes degenerates into rapid polymorphic ventricular tachycardia and ventricular fibrillation (Fig. 1) and may lead to syncope or sudden death. The incidence of CPVT is reported to be as high as 1:10,000, but its real prevalence is unclear.
Clinical manifestations and prognosis The first clinical manifestations of CPVT are syncope or aborted sudden cardiac death during exercise or emotional stress and appear during the first or second decade of life [1–3]. CPVT differs from seizures, in that almost all syncopal events are associated with physical activity or emotional stress and do not occur during a resting state. The prognosis of CPVT is very poor. About 40% patients die within 10 years of diagnosis . Although prognosis in recent times could be better than previous reports, sudden death and severe sgk inhibitor damage are still reported in CPVT patients.
Diagnosis of CPVT CPVT patients usually have a normal resting ECG, or just a lower heart rate than is normal for their age . During exercise in these patients, monomorphic premature ventricular contractions (PVCs) increase, then polymorphic, or bidirectional PVC bigeminy appear, followed by bidirectional or polymorphic VT. Exercise induced supraventricular arrhythmias (atrial fibrillation, premature atrial contraction, and atrial tachycardia) are also common in the patients with CPVT . The diagnostic criteria of CPVT are as follows :
Mechanism of CPVT The major pathogenic mechanism of CPVT is thought to involve the malfunction of RyR2. RyR2 is a large tetrameric protein expressed on the sarcoplasmic reticulum (SR) membrane. RyR2 is anchored to calsequestrin (CASQ2) by satellite proteins such as calmodulin (CaM), FKBP12.6, (calstabin2), protein kinase A (PKA), phosphatase 1 (PP1), and phosphatase 2A (PP2A) bound to the cytoplasmic region and junction, and triadin (TRD) bound to the luminal side . A three-dimensional reconstruction of RyR2 bound to FKBP12.6 is shown in Fig. 2B. When RyR2 is bound to FKBP12.6, it forms a stable structure with closed pores, the domain 6 of RyR2 was found to protrude into the luminal side, when observed from the junctional face after the transmembrane assembly (TA) was rotated counterclockwise by about 4° . When unbound to FKBP12.6, RyR2 assumes an open state (Fig. 2A) . Several pathogenic hypotheses have been reported regarding the causes of CPVT . The first theory suggests the dissociation of FKBP12.6 from RyR2. The normal RyR2 channel is stabilized by FKBP12.6 and closes during diastole. With mutant RyR2, the binding affinity with FKBP12.6 is weakened, and phosphorylation of RyR2 by protein kinase A (PKA) results in dissociation of FKBP12.6 from RyR2, resulting in open channels which may leak Ca2+ during diastole (Fig. 3). The second hypothesis is a store overload-induced Ca2+ release (SOICR) theory . With normal RyR2, the resting and stress levels of free Ca2+ are below the SOICR level. However, with mutant RyR2, the SOICR threshold drops below the level of free Ca2+ in the SR. This may cause a spillover of Ca2+ from the SR (Fig. 4). The third hypothesis considers defective intramolecular domain interaction . RyR2 is stabilized by a tight zipping of the intramolecular structure. If a mutation interferes with this zipping structure, the intramolecular domain interaction is weakened, causing an unzipping of the interdomain structure and leads leaking of Ca2+ from the SR (Fig. 5). The fourth hypothesis suggests that the molecular and functional abnormalities are related to mutations in the CASQ2 gene . CASQ2 is a Ca2+ storage protein inside the SR. The functional storage capacity of CASQ2 or its reduced levels, may lead to increased levels of free Ca2+ inside the SR, leading to a Ca2+ leak during diastole (Fig. 6). It is also known that CASQ2 stabilizes binding of RyR2 with TRD and the junction.