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Observational Study
. 2018 Mar 1;20(3):541-547.
doi: 10.1093/europace/euw389.

The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia: findings from an international multicentre registry

Thomas M Roston  1 , Zhiguang Yuchi  1 , Prince J Kannankeril  2 , Julie Hathaway  3 , Jeffrey M Vinocur  4 , Susan P Etheridge  5 , James E Potts  1 , Kathleen R Maginot  6 , Jack C Salerno  7 , Mitchell I Cohen  8 , Robert M Hamilton  9 , Andreas Pflaumer  10 , Saira Mohammed  1 , Lynn Kimlicka  1 , Ronald J Kanter  11 , Martin J LaPage  12 , Kathryn K Collins  13 , Roman A Gebauer  14 , Joel D Temple  15 , Anjan S Batra  16 , Christopher Erickson  17 , Maria Miszczak-Knecht  18 , Peter Kubuš  19 , Yaniv Bar-Cohen  20 , Michal Kantoch  21 , Vincent C Thomas  17 , Gabriele Hessling  22 , Chris Anderson  23 , Ming-Lon Young  24 , Sally H J Choi  1 , Michel Cabrera Ortega  25 , Yung R Lau  26 , Christopher L Johnsrude  27 , Anne Fournier  28 , Filip Van Petegem  1 , Shubhayan Sanatani  1
Affiliations
Observational Study

The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia: findings from an international multicentre registry

Thomas M Roston et al. Europace. .

Abstract

Aims: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy characterized by ventricular arrhythmia during exertion or stress. Mutations in RYR2-coded Ryanodine Receptor-2 (RyR2) and CASQ2-coded Calsequestrin-2 (CASQ2) genes underlie CPVT1 and CPVT2, respectively. However, prognostic markers are scarce. We sought to better characterize the phenotypic and genotypic spectrum of CPVT, and utilize molecular modelling to help account for clinical phenotypes.

Methods and results: This is a Pediatric and Congenital Electrophysiology Society multicentre, retrospective cohort study of CPVT patients diagnosed at <19 years of age and their first-degree relatives. Genetic testing was undertaken in 194 of 236 subjects (82%) during 3.5 (1.4-5.3) years of follow-up. The majority (60%) had RyR2-associated CPVT1. Variant locations were predicted based on a 3D structural model of RyR2. Specific residues appear to have key structural importance, supported by an association between cardiac arrest and mutations in the intersubunit interface of the N-terminus, and the S4-S5 linker and helices S5 and S6 of the RyR2 C-terminus. In approximately one quarter of symptomatic patients, cardiac events were precipitated by only normal wakeful activities.

Conclusion: This large, multicentre study identifies contemporary challenges related to the diagnosis and prognostication of CPVT patients. Structural modelling of RyR2 can improve our understanding severe CPVT phenotypes. Wakeful rest, rather than exertion, often precipitated life-threatening cardiac events.

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Figures

Figure 1
Figure 1
Plot of the percentage of variants found in hotspot areas on RyR2 thought to underlie most cases of CPVT in comparison to hotspot localization of RyR2 variants identified in the present study.
Figure 2
Figure 2
Plot of the percentage of variants by RyR2 region.
Figure 3
Figure 3
Circumstances immediately preceding all life-threatening events defined as syncope and/or cardiac arrest.
Figure 4
Figure 4
(A) Homology model of human RyR2. The protein is shown in cartoon form, with the disease hotspots highlighted in colours (hotspot 1: blue, hotspot 2: red; hotspot 3: green; hotspot 4: light blue). View is from the ‘side,’ parallel to the membrane. Only two out of four subunits are shown for clarity. Positions for CPVT-associated variants are highlighted, with atoms shown in Van der Waals representation (purple: associated with cardiac arrest, black: all others). (B) Close-up of the transmembrane region of the RyR2. This region forms the bulk of disease hotspot 4. The following subregions are highlighted: pore-forming region (red), additional transmembrane (cyan), and C-terminal cytosolic extension to the pore (green). Positions of CPVT-associated variants associated with cardiac arrest are highlighted in purple, and all others in black. The S5 and S6 helices and the S4–S5 linker are labelled.
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References

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