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  • serine protease inhibitors This Ca overload activates the fo


    This Ca2+ overload activates the forward mode of the Na+/Ca+ exchanger (NCX), increases the transient inward current (Iti), and induces ventricular arrhythmias due to delayed after depolarizations (DADs).
    Subtypes of CPVT Several subtypes of CPVT have been reported (Table 1). The most common type of CPVT is caused by an anomaly in the RyR2 gene (CPVT1) [9,10]. This accounts for more than 50% of CPVT cases. In our CPVT cohort, about 79% of the CPVT cases were related to an anomaly in the RyR2 gene. The inheritance of CPVT1 is autonomic dominant, and sudden death was observed in about 10% of these patients. There were no sex differences noted in this CPVT. The second most common type of CPVT is caused by a CASQ2 gene anomaly (CPVT2) [11,12]. The inheritance of CPVT2 is autosomal recessive, and the rate of sudden death is higher than that observed in CPVT1. However, autosomal serine protease inhibitors mutations of CASQ2 are also reported [13–15]. CPVT3 was reported in a family with showing a 7p22-p14 chromosome anomaly, but the gene responsible has not been identified yet [16]. Recently, calmodulin (CALM) [17] and triadin (TRD) [18] anomalies have been found to responsible for CPVT4 and CPVT5, respectively. CALM is a protein that involves the calcium dependent ICa inactivation of the L-type Ca channel. Further, CALM also stabilizes the RyR2 channel. Thus, a mutation in CALM may easily cause Ca2+ overload. TRD is a protein that connects CASQ to RyR2, and stabilizes the RyR2 channel. A mutation in TRD may also result in a diastolic leak of Ca2+ and Ca2+ overload in the myocytes. KCNJ2 encodes the cardiac inward rectifier K channel. A mutation in KCNJ2 causes the Andersen–Tawil syndrome (LQT7), and is also reported in patients with exercise induced bi-directional VT [19]. Whether or not this type of mutation should be included as a subtype of CPVT is a matter of controversy. Mutations in the ANK2 gene are well known as a cause of LQT4. Recently, a patient with an ANK2 mutation was reported to have bi-directional VT [20]. This may be another disease related to CPVT. A type of adult CPVT has also been reported [21,22]. In this disease, the patients are predominantly female, with CPVT onset at the age of around 40 years, and no sudden death is reported. We believe that this may not be a specific type of CPVT, but rather a mild form of the disease. In the Japanese CPVT registry, 78 patients (M:F=26:52, age=11.2±8.2 years) were enrolled. In this registry, only 6% of the cases were familial cases whereas 94% of the cases were sporadic (Fig. 7A). In this cohort, 56% of the patients had not undergone genetic testing. However, of the 46% patients who underwent genetic testing, 79% of the patients had an RyR2 gene anomaly, 6% had a CASQ2 gene anomaly, and in 15% of the patients the specific causative gene anomaly was unknown (Fig. 7B). The estimated RyR2 genotype percentage is reported to range from 35% [23] up to 65% [24,25], and the CASQ2 genotyped patients are estimated to account for approximately 3–5% [25]. The proportions of familial cases reported in other studies were 21.3% [26] and 30% [21]. The lower percentage of familial cases observed in our cohort may be because half of the registered cases are over 15 years old, at which time only information of familial history was taken without exercise or genetic testing. This may result in an apparently lower percentage of familial cases. Kawamura et al. have reported that RyR2 positive CPVT cases are more likely to have clinically diagnosed CPVT-affected family members with bidirectional VT, and sinus bradycardia [26].
    The mechanism of bidirectional VT Bidirectional VT is the most characteristic feature of CPVT. In the His–Purkinje system, DAD induced bigeminy may differ depending on whether they are induced by the right bundle branch or the left bundle branch. The right bundle branch (RBB) caused a DAD induced bigeminy at a pacing rate of 900ms (Fig. 8B), whereas the left bundle branch (LBB) induced a bigeminy at a pacing rate of 600ms (Fig. 8B) [27]. In these situations, the sinus rate exceeded the threshold of the RBB-DAD induced bigeminy rate, and the beat after the sinus beat may have been induced from the RBB, resulting in a LBB block (LBBB) type PVC. The coupling interval of the normal sinus beat to the LBBB type PVC exceeded the threshold of the LBB-DAD induced bigeminy, and the next beat arose from LBB, resulting in a RBB block (RBBB) type PVC. When the coupling interval of the LBBB type PVC and RBBB type PVC exceeded the threshold of the RBBDAD induced bigeminy, the next beat arose from the RBB followed by a beat from the LBB, one after the other (Fig. 8C) [27]. This computer simulation suggests a mechanism for the bidirectional VT.