The prediction of clinical severity grading of catecholaminergic polymorphic ventricular tachycardia by RyR2 gene mutation: a systematic review_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

HE Ruyuan , ZHANG Jingxuan , DING Song ,  GENG Qing

Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, P. R. China;

Corresponding?author：

GENG Qing, Email: gengqingwhu@whu.edu.cn

Keywords：

Catecholaminergic polymorphic ventricular tachycardia; RyR2 gene mutation; implantable cardioverter defibrillator; left cardiac sympathetic denervation; systematic review

DOI：

10.7507/1007-4848.202503088

Video：

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Objective To explore the genetic mutation characteristics, clinical manifestations, and treatment outcomes of catecholaminergic polymorphic ventricular tachycardia (CPVT), and to construct a quantitative scoring system for the severity of CPVT. The correlation between the mutations in different structural domains of the RyR2 gene and clinical manifestations and prognosis was analyzed. Methods By searching the PubMed and Web of Science databases for CPVT-related case reports published up to December 2024, data such as patient age, clinical manifestations, gene mutation sites, and treatment responses were collected. The quality of the literature was assessed using the CARE guidelines. The χ² test was used to compare the severity and treatment response differences among different RyR2 structural domain mutation groups, and an innovative quantitative scoring system based on symptoms and efficacy was established. Results A total of 80 articles were included, with 102 patients in total. The quality of the literature was reliable. The age of the patients ranged from 1 to 84 years, with a higher proportion of children under 10 years old (25.5%). Female patients (54.9%) outnumbered males (45.1%). For CPVT patients, a quantitative scoring system was developed, with a total score of 2 to 10 points. Among them, 2 to 4 points were classified as mild, 5 to 7 points as moderate, and 8 to 10 points as severe. The results showed that severe patients often had a history of cardiac arrest and were resistant to treatment. Out of the 102 CPVT patients, RyR2 gene mutations accounted for 53.9% (55/102) of patients. Among them, the proportion of severe patients with N-terminal structural domain mutations was significantly higher than other regions, indicating that the RyR2 gene mutation structural domain has a significant impact on the severity of CPVT (χ²=17.530, P=0.008). The proportion of patients with mutations in the central hinge region who were ineffective with β-blockers reached 42.9% (3/7), which was significantly higher than other regions. Left cardiac sympathectomy was performed in 24 cases, and postoperative symptoms were almost completely controlled, significantly better than the drug treatment group.Conclusion Mutations in the N-terminal structural domain of the RyR2 gene are significantly correlated with the severity of CPVT. Left cardiac sympathectomy has gradually become an effective intervention for refractory cases. The scoring system proposed in this study can provide a basis for clinical stratified treatment. In the future, there is a need to expand the sample size to verify mutation-specific treatment strategies.

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2. Mariani MV, Pierucci N, Fanisio F, et al. Inherited arrhythmias in the pediatric population: An updated overview. Medicina (Kaunas), 2024, 60(1): 94.
3. Napolitano C, Mazzanti A, Bloise R, et al. Catecholaminergic polymorphic ventricular tachycardia. In: Adam MP, Feldman J, Mirzaa GM, et al. GeneReviews?. Seattle (WA): University of Washington, 1993.
4. Lahat H, Pras E, Olender T, et al. A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel. Am J Hum Genet, 2001, 69(6): 1378-1384.
5. Liu N, Colombi B, Memmi M, et al. Arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia: insights from a RyR2 R4496C knock-in mouse model. Circ Res, 2006, 99(3): 292-298.
6. Jiang D, Xiao B, Yang D, et al. RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR). Proc Natl Acad Sci U S A, 2004, 101(35): 13062-13067.
7. Wleklinski MJ, Kannankeril PJ, Knollmann BC. Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia. J Physiol, 2020, 598(14): 2817-2834.
8. Song J, Luo Y, Jiang Y, et al. Advances in the molecular genetics of catecholaminergic polymorphic ventricular tachycardia. Front Pharmacol, 2021, 12: 718208.
9. Devalla HD, Gelinas R, Aburawi EH, et al. TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT. EMBO Mol Med, 2016, 8(12): 1390-1408.
10. Hayashi M, Denjoy I, Extramiana F, et al. Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia. Circulation, 2009, 119(18): 2426-2434.
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12. De Ferrari GM, Dusi V, Spazzolini C, et al. Clinical management of catecholaminergic polymorphic ventricular tachycardia: The role of left cardiac sympathetic denervation. Circulation, 2015, 131(25): 2185-2193.
13. Roses-Noguer F, Jarman JW, Clague JR, et al. Outcomes of defibrillator therapy in catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm, 2014, 11(1): 58-66.
14. Perez PR, Hylind RJ, Roston TM, et al. Gene therapy for catecholaminergic polymorphic ventricular tachycardia. Heart Lung Circ, 2023, 32(7): 790-797.
15. Priori SG, Wilde AA, Horie M, et al. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm, 2013, 10(12): e85-e108.
16. Abdullah NM, Ali A. RYR2 receptor gene mutation associated with catecholaminergic polymorphic ventricular tachycardia in children: a case report & literature review. Transl Pediatr, 2024, 13(2): 359-369.
17. Acharya S, Devkota P, Shrestha R, et al. Catecholaminergic polymorphic ventricular tachycardia presented as generalized tonic-clonic seizure: a case report. Cureus, 2022, 14(8): e27806.
18. Ahmed A, Phillips JR. Teenage pregnancy with catecholaminergic polymorphic ventricular tachycardia and documented ICD discharges. Clin Case Rep, 2016, 4(4): 361-365.
19. Aizawa Y, Komura S, Okada S, et al. Distinct U wave changes in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). Int Heart J, 2006, 47(3): 381-389.
20. Akilzhanova A, Guelly C, Nuralinov O, et al. RYR2 sequencing reveals novel missense mutations in a Kazakh idiopathic ventricular tachycardia study cohort. PLoS One, 2014, 9(6): e101059.
21. Akinci G, Topaloglu H, Akinci B, et al. Spectrum of clinical manifestations in two young Turkish patients with congenital generalized lipodystrophy type 4. Eur J Med Genet, 2016, 59(6-7): 320-324.
22. Annor AK, May SA, Fenton AM, et al. Recurrent cardiac arrest with negative stress test: an unusual presentation of catecholaminergic polymorphic ventricular tachycardia. JACC Case Rep, 2020, 2(8): 1178-1181.
23. Arad M, Glikson M, El-Ani D, et al. A family with recurrent sudden death and no clinical clue. Ann Noninvasive Electrocardiol, 2012, 17(4): 387-393.
24. Atik SU, Alp FE, Dedeoglu R, et al. A rare cause of sudden cardiac arrest: catecholaminergic polymorphic ventricular tachycardia. Turk Pediatri Ars, 2018, 53(2): 124-128.
25. Azevedo AI, Dias A, Teixeira M, et al. Catecholaminergic polymorphic ventricular tachycardia: a rare cause of recurrent syncope. Oxf Med Case Reports, 2015, 2015(10): 337-342.
26. Bellamy D, Nuthall G, Dalziel S, et al. Catecholaminergic polymorphic ventricular tachycardia: the cardiac arrest where epinephrine is contraindicated. Pediatr Crit Care Med, 2019, 20(3): 262-268.
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Latest ArticlesThe prediction of clinical severity grading of catecholaminergic polymorphic ventricular tachycardia by RyR2 gene mutation: a systematic review

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