Catecholaminergic polymorphic ventricular tachycardia: differences in inheritance and implications for patients, families and future studies

Sudden cardiac arrest (SCA) in young and otherwise healthy individuals remains an intriguing occurrence that warrants indepth evaluation. In the past decades, the origin of these cardiac arrests has finally been elucidated in many SCA victims. For example, longQT syndrome (LQTS), Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT) were found to coincide with these cases. 2 CPVT is the subject of the paper by Shimamoto and colleagues from multiple centres in Japan. CPVT is one of the rare arrhythmia syndromes, its prevalence is estimated to be approximately 1 in 10 000 individuals, and it associates with bidirectional and polymorphic ventricular tachycardia (VT), ventricular fibrillation (VF), and subsequent syncope and SCA, most often occurring in children, adolescents, and young adults. The hallmark of CPVT is the adrenergic triggering of these arrhythmias and associated symptoms in otherwise healthy individuals without overt structural heart disease and with a normal baseline ECG. Importantly, like other arrhythmia syndromes, CPVT may be inheritable, and may thus affect whole families with a propensity to SCA. In CPVT, genetic testing has a very high yield, and in most indisputable CPVT cases, a pathogenic or likely pathogenic variant in either the cardiac ryanodine receptor gene (RYR2) is identified, or, in less cases, a (usually homozygous) pathogenic or likely pathogenic variant in the cardiac calsequestrin gene (CASQ2). A critical similarity between these two genes and their resultant proteins is that both are pivotal for calcium homeostasis in the cardiac sarcoplasmatic reticulum. The unifying pathophysiological mechanism is the occurrence of spontaneous diastolic calcium release from the ventricular sarcoplasmatic reticulum, resulting in a propensity for delayed afterdepolarisations and triggering of polymorphic ventricular ectopy and VT/VF, especially during adrenergic circumstances. Although several other genes related to CPVT have been uncovered, the absence of a genetic underpinning of a proposed CPVT case currently even questions whether the patient actually has CPVT or is affected by another disease entity, in particular when a very classic phenotype including bidirectional couplets or VT is absent. Moreover, like other arrhythmia syndromes, the calling of likely or presumed pathogenic variants in CPVT is challenging. Because CPVT is of such a rare occurrence and has significant mortality rates, the indepth evaluation of CPVT is clearly hampered already by the number of available individuals. Multicentre initiatives and (inter)national collaboration are therefore key to study this syndrome in more detail and to gain the necessary insights to treat and advise these patients and their relatives more accurately. One such question among clinicians and scientists is the suggestion that de novo genetic variants (ie, not inherited from the individual’s parents but newly occurring in that particular individual) display a more extreme phenotype compared with inherited or familial variants. One explanation for this scenario would be that when de novo variants indeed display an extreme phenotype, the patient may be recognised early, and may not get to parenthood, while less extreme phenotypes will present later and after the stage the patient may have had children which then may result in familial CPVT. In this scientific spectrum, Shimamoto and colleagues started their study with 346 Japanese patients, probands, suspected for CPVT who had RYR2 investigated. They subsequently excluded 176 patients who did not have a likely pathogenic or pathogenic RYR2 variant, and another 88 who either did not receive a final CPVT diagnosis, had complex (eg, multiple) genetic variants or in whom the trio genetic analysis (ie, the proband and both parents) was not performed. As such they included 82 patients with CPVT in their study, 58 (70%) with de novo and 24 (30%) with familial (putative) pathogenic RYR2 variants. In their analysis, it appeared that patients with de novo variants indeed displayed a worse phenotype, with SCA occurring at younger age compared with those with familial variants (see their table 2 and figure 4: at the age of 5 years, 17% of de novo cases experienced an SCA compared with 0% for familial cases, at the age of 10 years this was 36% vs 8%, and at the age of 15 years 50% vs 37%). In addition, there appeared to be a difference in the location of these variants, de novo variants more often occurred in the Cterminus domain of RYR2 as opposed to Nterminus domain variants, compared with the familial variants which displayed the opposite distribution (Nterminus>Cterminus). A further study of the familial cases showed that there was a trend towards an earlier occurrence of SCA when the RYR2positive parent also experienced an SCA, and that RYR2positive siblings of the proband experienced less cardiac events and developed symptoms several years later compared with the proband. There are several aspects for discussion from this study. As mentioned earlier, it appears again that collaborative efforts can be crucial to come to appreciable results in rare arrhythmia syndromes (see figure 1 for an overview). The compiling of data from these centres of excellence in Japan reached novel results and simultaneously also shows that the numbers of finally included cases are still very low, which subsequently hampers several definite conclusions. Still, this is a unique in trio study of RYR2associated CPVT. As opposed to other arrhythmia syndromes such as, for example, LQTS, in CPVT there appears a much higher burden of de novo variants compared with familial variants (70 vs 30%—while in LQTS de novo variants are only sporadically observed), although in earlier CPVT studies there was not such a clear dominance of de novo variants as compared with familial variants. Still, in previous studies, the suggested extreme pathogenicity of many de novo variants has actually been questioned, although this may not be as specifically true for CPVT. As explained earlier, there probably is a survival bias towards de novo variants in CPVT due to the high and very early cardiac event rate in CPVT probands as compared with other arrhythmia syndromes. Although in LQTS cardiac events may also occur from infancy onward in familial cases, the penetrance of LQTS appears to be lower. In arrhythmia syndromes like LQTS, there is an important role for common genetic variations that determines LQTS susceptibility. In CPVT, such role for common genetic variations is certainly suspected, as suggested, for example, by the variable cardiac event rates Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Cardiovascular Sciences, Amsterdam, Netherlands