|Year : 2022 | Volume
| Issue : 1 | Page : 3-8
Clinical characteristics, outcomes, and genetic findings of patients with catecholaminergic polymorphic ventricular tachycardia in Hong Kong: A systematic review
Jeremy Man Ho Hui1, Yan Hiu Athena Lee1, Kyle Hui1, Jiandong Zhou2, Danish Iltaf Satti1, Cheuk To Chung1, Danny Radford3, Ishan Lakhani1, Amir Hossein Behnoush4, Leonardo Roever5, Khalid Bin Waleed6, Sharen Lee1, Gary Tse7
1 International Health Informatics Study Network, Cardiovascular Analytics Group, Hong Kong, China-UK Collaboration, China
2 Nuffield Department of Medicine, University of Oxford, Oxford, England, United Kingdom
3 International Health Informatics Study Network, Cardiovascular Analytics Group, Hong Kong, China-UK Collaboration; Kent and Medway Medical School, Canterbury, United Kingdom
4 International Health Informatics Study Network, Cardiovascular Analytics Group, Hong Kong, China-UK Collaboration; School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
5 Department of Clinical Research, Federal University of Uberlândia, Uberlândia, Brazil
6 International Health Informatics Study Network, Cardiovascular Analytics Group, Hong Kong, China-UK Collaboration; Department of Cardiology, St George's Hospital University of London, London, United Kingdom
7 Kent and Medway Medical School, Canterbury, United Kingdom; Department of Cardiology, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China
|Date of Submission||26-Jan-2022|
|Date of Decision||30-Mar-2022|
|Date of Acceptance||07-Apr-2022|
|Date of Web Publication||30-Jun-2022|
Dr. Sharen Lee
International Health Informatics Study Network, Cardiovascular Analytics Group, Hong Kong
Source of Support: None, Conflict of Interest: None
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare cardiac ion channelopathy. This was the first systematic review of published works on the clinical characteristics, outcomes, and genetic findings of patients with CPVT from Hong Kong. PubMed and Embase were searched electronically from their inception until February 2022. The Joanna Briggs Institute Critical Appraisal Checklist was used to critically appraise included studies. Studies written in English describing at least one patient with CPVT were included. Studies describing overlapping CPVT patients from previous reports were excluded. Two studies describing 17 patients with CPVT were included. All included studies were rated of acceptable quality. The largest case series evaluated 16 CPVT patients with a mean presentation age of 11 ± 4 years. Of these, 15 patients (93.8%) were symptomatic at initial presentation. Ten patients presented with both premature ventricular complexes (PVCs) and ventricular tachycardia/ventricular fibrillation (VT/VF), whereas one had PVCs without VT/VF. Among the 14 patients (87.5%) who underwent genetic testing, eight (57.1%) tested positive for the ryanodine receptor 2 (RyR2) gene. Over a mean follow-up duration of 116 ± 36 months, six patients (37.5%) had incident VT/VF. In a 5-year review of autopsy data retrieved from public mortuaries for 289 sudden cardiac death patients, one CPVT patient (0.03%) was identified. All patients with CPVT in Hong Kong presented at or below 19 years old, of whom a majority were initially symptomatic or had incident VT/VF events. Novel genetic variants in the RyR2 gene not reported beyond our locality were identified.
Keywords: Catecholaminergic polymorphic ventricular tachycardia, ryanodine receptor 2, sudden cardiac death
|How to cite this article:|
Ho Hui JM, Athena Lee YH, Hui K, Zhou J, Satti DI, Chung CT, Radford D, Lakhani I, Behnoush AH, Roever L, Waleed KB, Lee S, Tse G. Clinical characteristics, outcomes, and genetic findings of patients with catecholaminergic polymorphic ventricular tachycardia in Hong Kong: A systematic review. Ann Clin Cardiol 2022;4:3-8
|How to cite this URL:|
Ho Hui JM, Athena Lee YH, Hui K, Zhou J, Satti DI, Chung CT, Radford D, Lakhani I, Behnoush AH, Roever L, Waleed KB, Lee S, Tse G. Clinical characteristics, outcomes, and genetic findings of patients with catecholaminergic polymorphic ventricular tachycardia in Hong Kong: A systematic review. Ann Clin Cardiol [serial online] 2022 [cited 2022 Sep 29];4:3-8. Available from: http://www.onlineacc.org/text.asp?2022/4/1/3/349336
| Introduction|| |
Cardiac ion channelopathies increase a patient's susceptibility to developing spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF) and sudden cardiac death (SCD).,,,,, When compared to Brugada syndrome (BrS) or long QT syndrome (LQTS), catecholaminergic polymorphic VT (CPVT) is less prevalent in Asia., For example, in Hong Kong, the most prevalent cardiac ion channelopathy is BrS,, followed by LQTS, and CPVT. No cases of short QT syndrome were identified.
CPVT is typically caused by mutations in either the ryanodine receptor 2 (RyR2) or the calsequestrin 2 genes.,, It is usually precipitated by exercise or distress, resulting in bidirectional VT in the first two decades of life. Globally, population-based data on CPVT have mainly come from Western countries. The largest registry reported the characteristics of 237 patients., In a multi-national study from France, outcomes in 101 patients were reported, complementing a smaller registry by the same group. By contrast, data from Asia have mainly come from Japan, including a multi-centre registry of 78 patients, national study of 50 probands, and another study of 29 patients. Two studies from China have reported on six patients and 12 patients. This is the first systematic review of published works on the clinical characteristics, outcomes, and genetic findings of patients with CPVT from Hong Kong.
| Methods|| |
This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement.
PubMed and Embase were searched electronically to identify all studies describing patients with CPVT from all regions in Hong Kong without limitations. All databases were searched from their inception until February 2022. The search algorithm used was (“catecholaminergic polymorphic ventricular tachycardia” OR “CPVT”) AND “Hong Kong.” To maximize sensitivity, all search terms were combined with Boolean operators and searched as both keywords and MeSH terms. Reference lists of the included studies were manually searched to retrieve relevant studies.
At the title/abstract level, studies were first screened by at least two reviewers (JMHH, YHAL, GT). All identified studies were systematically assessed according to the inclusion and exclusion criteria. Any discrepancies were resolved by an independent reviewer (KH).
We included studies with data for at least one patient with CPVT. We considered only studies written in English. We excluded studies only describing overlapping CPVT patients from previous reports. Conference publications and studies without a description of the original patient with CPVT were excluded.
Data extraction – quality assessment
All the included studies were critically appraised by two independent reviewers (JMHH, YHAL) using The Joanna Briggs Institute Critical Appraisal Checklist. Predefined information about the included patients was extracted from the included studies by at least two independent reviewers (JMHH, YHAL, GT). Age, sex, family history of CPVT/SCD, symptoms, outcomes, and genetic findings were extracted.
| Results|| |
The systematic search identified eight non-duplicated studies. Full-texts of six studies were retrieved and assessed for inclusion eligibility, and two articles were included in this review [Figure 1]., All studies were assessed using The Joanna Briggs Institute Critical Appraisal Checklist. All included articles were deemed to be of acceptable quality for inclusion.
Clinical characteristics and outcomes of included patients
A total of 17 patients were included. The largest case series studied 16 patients (mean presentation age = 11 ± 4 years old; female = 50%) [Table 1]. Twelve patients fulfilled at least two criteria and four fulfilled one criterion of the 2013 Heart Rhythm Society (HRS)/European Heart Rhythm Association/Asia-Pacific HRS expert consensus statement [Table 2]. Fifteen patients (93.8%) were symptomatic at initial presentation to the hospitals. Ten patients had both premature ventricular complexes (PVCs) and VT/VF, whereas one had PVCs without VT/VF. The mean delay between initial presentation and diagnosis was 8 ± 10 months. All patients were prescribed beta-blockers (nadolol: n = 12, metoprolol: n = 5, atolol: n = 3, propranolol: n = 3, sotalol: n = 2), three received amiodarone, and two received verapamil. Eight patients had sympathectomy, three had implantable cardioverter defibrillators, and one had ablation. Over a mean follow-up duration of 116 ± 36 months, six patients (37.5%) had incident VT/VF.
|Table 2: Details on the diagnostic criteria met for individual catecholaminergic polymorphic ventricular tachycardia patients|
Click here to view
In a 5-year review of autopsy data retrieved from public mortuaries for 289 SCD patients, one CPVT patient (0.03%) was identified. He had a history of syncope, with negative autopsy and toxicology screening results.
In the case series of 16 patients, genetic tests were performed in 14 (87.5%) [Table 3], of whom eight (57.1%) tested positive for gene mutations. All mutations involved the RyR2 gene [Table 4]. These included c.14848G>A, c.12475C>A, c.7420A>G, c.11836G>A, c.14159T>C (RCV000182842.2), c.10046C>T,, c.7202G>A and c.14861C>G. In the review of autopsy data, another RyR2 variant, c.1509C>A, was identified.
|Table 4: Genetic testing in individual catecholaminergic polymorphic ventricular tachycardia patients|
Click here to view
| Discussion|| |
This is the first systematic review of published works on the clinical characteristics, outcomes, and genetic findings of patients with CPVT from Hong Kong. All patients presented at or below 19 years old, of whom a majority were initially symptomatic or had incident VT/VF events. Novel genetic variants in the RyR2 gene not reported beyond our locality were identified.
SCD is a problem of global importance, with congenital and acquired causes.,,, Of the congenital cardiac ion channelopathies, CPVT is characterized by exercise-induced bidirectional VT. When treatment is delayed, CPVT patients suffer from exceedingly high mortality rates. Several studies have examined the occurrence of adverse outcomes in CPVT cohorts such as syncope and SCD.,,, Patients who were initially symptomatic or younger at diagnosis, as seen in this study, have significantly higher risks of mortality and cardiac events. International registry studies on European and North American patients have reported a malignant arrhythmic phenotype of CPVT associated with significant delays between initial presentation and diagnosis of around six months., Similar findings were reported by our team in the largest CPVT study conducted in the region.
This study identified nine genetic variants. Of these, c.14848G>A, c.12475C>A, c.7420A>G, c.11836G>A, c.14159T>C (RCV000182842.2), c.10046C>T,, and c.7202G>A have been reported elsewhere. By contrast, c.14861C>G and c.1509C>A are novel RyR2 variants that give rise to changes in the A4954G and D503E amino acids, respectively. These mutations affect the cytoplasmic domain of the RyR2 gene and are expected to produce abnormalities in calcium handling, possible diastolic calcium leak, and triggered arrhythmogenesis. However, as RyR2 mutations can be associated with reduced conduction velocity in addition to disrupted calcium homeostasis,,, functional studies are needed to determine the precise mechanisms by which these structural changes can lead to the generation of electrophysiological substrate.
Several limitations should be noted for the present study. Firstly, as a systematic review, this study is inherently subjected to sampling bias. Nonetheless, included studies were assessed using standardized tools. Secondly, hospitals or clinics were not contacted for patients with CPVT. Finally, as some cases had no available data apart from the published descriptions, it was not possible to perform a meta-analysis.
| Conclusion|| |
All patients with CPVT in Hong Kong presented at or below 19 years old, of whom a majority were initially symptomatic or had incident VT/VF events. Novel genetic variants in the RyR2 gene not reported beyond our locality were identified. A national registry linking Hong Kong and mainland China as well as international cooperation are encouraged to improve risk stratification of this rare but devastating disease.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Rucinski C, Winbo A, Marcondes L, Earle N, Stiles M, Stiles R, et al.
A population-based registry of patients with inherited cardiac conditions and resuscitated cardiac arrest. J Am Coll Cardiol 2020;75:2698-707.
Li KH, Lee S, Yin C, Liu T, Ngarmukos T, Conte G, et al.
Brugada syndrome: A comprehensive review of pathophysiological mechanisms and risk stratification strategies. Int J Cardiol Heart Vasc 2020;26:100468.
Li Z, Chen P, Li C, Tan L, Xu J, Wang H, et al.
Genetic arrhythmias complicating patients with dilated cardiomyopathy. Heart Rhythm 2020;17:305-12.
Asatryan B, Schaller A, Seiler J, Servatius H, Noti F, Baldinger SH, et al.
Usefulness of genetic testing in sudden cardiac arrest survivors with or without previous clinical evidence of heart disease. Am J Cardiol 2019;123:2031-8.
Aiba T. Recent understanding of clinical sequencing and gene-based risk stratification in inherited primary arrhythmia syndrome. J Cardiol 2019;73:335-42.
Munroe PB, Addison S, Abrams DJ, Sebire NJ, Cartwright J, Donaldson I, et al.
Postmortem genetic testing for cardiac ion channelopathies in stillbirths. Circ Genom Precis Med 2018;11:e001817.
Skinner JR, Winbo A, Abrams D, Vohra J, Wilde AA. Channelopathies that lead to sudden cardiac death: Clinical and genetic aspects. Heart Lung Circ 2019;28:22-30.
Tse G, Zhou J, Lee S, Liu T, Bazoukis G, Mililis P, et al
. Incorporating latent variables using nonnegative matrix factorization improves risk stratification in Brugada syndrome. J Am Heart Assoc 2020;9:e012714.
Lee S, Zhou J, Li KH, Leung KS, Lakhani I, Liu T, et al.
Territory-wide cohort study of Brugada syndrome in Hong Kong: Predictors of long-term outcomes using random survival forests and non-negative matrix factorisation. Open Heart 2021;8:e001505.
Lee S, Wong WT, Wong IC, Mak C, Mok NS, Liu T, et al.
Ventricular tachyarrhythmia risk in paediatric/young vs. adult Brugada syndrome patients: A territory-wide study. Front Cardiovasc Med 2021;8:671666.
Tse G, Lee S, Zhou J, Liu T, Wong IC, Mak C, et al.
Territory-wide Chinese cohort of long QT syndrome: Random survival forest and Cox analyses. Front Cardiovasc Med 2021;8:608592.
Lee S, Zhou J, Jeevaratnam K, Wong WT, Wong IC, Mak C, et al.
Paediatric/young versus adult patients with long QT syndrome. Open Heart 2021;8:e001671.
Lee S, Zhou J, Jeevaratnam K, Lakhani I, Wong WT, Kei Wong IC, et al.
Arrhythmic outcomes in catecholaminergic polymorphic ventricular tachycardia. medRxiv 2021; [doi: 10.1101/2021.01.04.21249214].
Vemireddy LP, Aqeel A, Ying GW, Majlesi D, Woo V. A rare case of RYR2 mutation causing sudden cardiac arrest due to catecholaminergic polymorphic ventricular tachycardia. Cureus 2021;13:e13417.
Ng K, Titus EW, Lieve KV, Roston TM, Mazzanti A, Deiter FH, et al.
An international multicenter evaluation of inheritance patterns, arrhythmic risks, and underlying mechanisms of CASQ2-catecholaminergic polymorphic ventricular tachycardia. Circulation 2020;142:932-47.
Li Q, Guo R, Gao L, Cui L, Zhao Z, Yu X, et al.
CASQ2 variants in Chinese children with catecholaminergic polymorphic ventricular tachycardia. Mol Genet Genomic Med 2019;7:e949.
Behere SP, Weindling SN. Catecholaminergic polymorphic ventricular tachycardia: An exciting new era. Ann Pediatr Cardiol 2016;9:137-46.
Roston TM, Haji-Ghassemi O, LaPage MJ, Batra AS, Bar-Cohen Y, Anderson C, et al
. Catecholaminergic polymorphic ventricular tachycardia patients with multiple genetic variants in the PACES CPVT Registry. PLoS One 2018;13:e0205925.
Roston TM, Yuchi Z, Kannankeril PJ, Hathaway J, Vinocur JM, Etheridge SP, et al.
The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia: Findings from an international multicentre registry. Europace 2018;20:541-7.
Hayashi M, Denjoy I, Extramiana F, Maltret A, Buisson NR, Lupoglazoff JM, et al.
Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia. Circulation 2009;119:2426-34.
Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation 1995;91:1512-9.
Sumitomo N. Current topics in catecholaminergic polymorphic ventricular tachycardia. J Arrhythm 2016;32:344-51.
Kawamura M, Ohno S, Naiki N, Nagaoka I, Dochi K, Wang Q, et al
. Genetic background of catecholaminergic polymorphic ventricular tachycardia in Japan. Circ J 2013;77:1705-13.
Sumitomo N, Harada K, Nagashima M, Yasuda T, Nakamura Y, Aragaki Y, et al.
Catecholaminergic polymorphic ventricular tachycardia: Electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death. Heart 2003;89:66-70.
Jiang H, Li XM, Ge HY, Zhang Y, Liu HJ, Li MT. Investigation of catecholaminergic polymorphic ventricular tachycardia children in China: Clinical characteristics, delay to diagnosis, and misdiagnosis. Chin Med J (Engl) 2018;131:2864-5.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al.
The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021;372:n71.
Moola S, Munn Z, Sears K, Sfetcu R, Currie M, Lisy K, et al.
Conducting systematic reviews of association (etiology): The Joanna Briggs Institute's approach. Int J Evid Based Healthc 2015;13:163-9.
Mak CM, Mok NS, Shum HC, Siu WK, Chong YK, Lee HH, et al.
Sudden arrhythmia death syndrome in young victims: A five-year retrospective review and two-year prospective molecular autopsy study by next-generation sequencing and clinical evaluation of their first-degree relatives. Hong Kong Med J 2019;25:21-9.
Priori SG, Napolitano C, Memmi M, Colombi B, Drago F, Gasparini M, et al.
Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 2002;106:69-74.
Kawata H, Ohno S, Aiba T, Sakaguchi H, Miyazaki A, Sumitomo N, et al.
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) associated with ryanodine receptor (RyR2) gene mutations- long-term prognosis after initiation of medical treatment. Circ J 2016;80:1907-15.
Ozawa J, Ohno S, Fujii Y, Makiyama T, Suzuki H, Saitoh A, et al.
Differential diagnosis between catecholaminergic polymorphic ventricular tachycardia and long QT syndrome type 1- modified Schwartz score. Circ J 2018;82:2269-76.
Gallegos-Cortez A, Alonso-Ortiz N, Antunez-Argüellez E, Villarreal-Molina T, Totomoch-Serra A, Iturralde-Torres P, et al.
Catecholaminergic polymorphic ventricular tachycardia due to de novo RyR2 mutation: Recreational cycling as a trigger of lethal arrhythmias. Arch Med Sci 2020;16:466-70.
Seidelmann SB, Smith E, Subrahmanyan L, Dykas D, Abou Ziki MD, Azari B, et al.
Application of whole exome sequencing in the clinical diagnosis and management of inherited cardiovascular diseases in adults. Circ Cardiovasc Genet 2017;10:e001573.
Christiansen SL, Hertz CL, Ferrero-Miliani L, Dahl M, Weeke PE, LuCamp, et al.
Genetic investigation of 100 heart genes in sudden unexplained death victims in a forensic setting. Eur J Hum Genet 2016;24:1797-802.
Aizawa Y, Ueda K, Komura S, Washizuka T, Chinushi M, Inagaki N, et al.
A novel mutation in FKBP12.6 binding region of the human cardiac ryanodine receptor gene (R2401H) in a Japanese patient with catecholaminergic polymorphic ventricular tachycardia. Int J Cardiol 2005;99:343-5.
Pappone C, Micaglio E, Locati ET, Monasky MM. The omics of channelopathies and cardiomyopathies: What we know and how they are useful. Eur Heart J Suppl 2020;22:L105-9.
Pappone C, Ciconte G, Micaglio E, Monasky MM. Common modulators of Brugada syndrome phenotype do not affect SCN5A prognostic value. Eur Heart J 2021;42:1273-4.
Micaglio E, Monasky MM, Bernardini A, Mecarocci V, Borrelli V, Ciconte G, et al.
Clinical considerations for a family with dilated cardiomyopathy, sudden cardiac death, and a novel TTN frameshift mutation. Int J Mol Sci 2021;22:670.
Monasky MM, Micaglio E, Ciconte G, Pappone C. Brugada syndrome: Oligogenic or mendelian disease? Int J Mol Sci 2020;21:1687.
Napolitano C, Priori SG, Bloise R. Catecholaminergic polymorphic ventricular tachycardia. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Gripp KW, et al.
, editors. GeneReviews(®). Seattle (WA): University of Washington, Seattle; 1993.
Postma AV, Denjoy I, Kamblock J, Alders M, Lupoglazoff JM, Vaksmann G, et al.
Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients. J Med Genet 2005;42:863-70.
Bauce B, Rampazzo A, Basso C, Bagattin A, Daliento L, Tiso N, et al.
Screening for ryanodine receptor type 2 mutations in families with effort-induced polymorphic ventricular arrhythmias and sudden death: Early diagnosis of asymptomatic carriers. J Am Coll Cardiol 2002;40:341-9.
Roston TM, Vinocur JM, Maginot KR, Mohammed S, Salerno JC, Etheridge SP, et al.
Catecholaminergic polymorphic ventricular tachycardia in children: Analysis of therapeutic strategies and outcomes from an international multicenter registry. Circ Arrhythm Electrophysiol 2015;8:633-42.
Tse G. Mechanisms of cardiac arrhythmias. J Arrhythm 2016;32:75-81.
Saadeh K, Achercouk Z, Fazmin IT, Nantha Kumar N, Salvage SC, Edling CE, et al.
Protein expression profiles in murine ventricles modeling catecholaminergic polymorphic ventricular tachycardia: Effects of genotype and sex. Ann N Y Acad Sci 2020;1478:63-74.
Ning F, Luo L, Ahmad S, Valli H, Jeevaratnam K, Wang T, et al.
The RyR2-P2328S mutation downregulates Nav1.5 producing arrhythmic substrate in murine ventricles. Pflugers Arch 2016;468:655-65.
Zhang Y, Wu J, Jeevaratnam K, King JH, Guzadhur L, Ren X, et al.
Conduction slowing contributes to spontaneous ventricular arrhythmias in intrinsically active murine RyR2-P2328S hearts. J Cardiovasc Electrophysiol 2013;24:210-8.
[Table 1], [Table 2], [Table 3], [Table 4]