1 Cardiac Electrophysiology Unit, Cardiovascular Analytics Group, Laboratory of Cardiovascular Physiology, 999077 Hong Kong, China
2 School of Data Science, City University of Hong Kong, 999077 Hong Kong, China
3 Faculty of Health and Medical Sciences, University of Surrey, GU2 7XH Guildford, UK
4 State Key Laboratory of Agrobiotechnology (CUHK), School of Life Sciences, Chinese University of Hong Kong, 999077 Hong Kong, China
5 Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, 300211 Tianjin, China
§joint first authors.
Academic Editor: Konstantinos P. Letsas
Abstract
Background: This study examined the clinical characteristics, genetic
basis, healthcare utilisation and costs of catecholaminergic ventricular
tachycardia (CPVT) patients from a Chinese city. Methods: This was a
territory-wide retrospective cohort study of consecutive CPVT patients at public
hospitals or clinics in Hong Kong. Healthcare resource utilisation for accident
and emergency (A&E), inpatient and outpatient attendances were analysed over 19
years (2001–2019) followed by calculations of annualised costs (in USD).
Results: Sixteen patients with a median presentation age (interquartile
range (IQR) of 11 (9–14) years old) were included. Fifteen patients (93.8%)
were initially symptomatic. Ten patients had both premature ventricular complexes
(PVCs) and ventricular tachycardia/fibrillation (VT/VF). One patient had PVCs without VT/VF. Genetic tests were
performed on 14 patients (87.5%). Eight (57.1%) tested positive for the ryanodine receptor 2 (RyR2)
gene. Seven variants have been described elsewhere (c.14848G
Keywords
- CPVT
- HCRU
- tachycardia
- genetics
Cardiac ion channelopathies predispose to the development of spontaneous ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death (SCD) [1, 2, 3, 4, 5, 6]. Of these, catecholaminergic ventricular tachycardia (CPVT) is a less prevalent condition compared to Brugada syndrome (BrS) in Asia [7, 8]. It is typically caused by mutations in either ryanodine receptor 2 (RyR2) [9], or calsequestrin 2 (CASQ2) [10, 11], but other genes such as calmodulin (CALM) have been implicated [12, 13, 14]. CPVT is usually precipitated by exercise or distress, which results in bidirectional VT, typically presenting in the first two decades of life [15]. Globally, population-based data on CPVT have mainly come from Western countries. The largest registry created by the Pediatric and Congenital Electrophysiology Society of the United States has reported the characteristics of 237 patients [16, 17]. In another multi-national study including mainly patients from France, outcomes in 101 patients were reported [18], complementing smaller registry and case series studies by the same group [19, 20]. Another study reported specifically that 21 CPVT patients carried mutations in the CALM genes [12].
By contrast, data from Asia have been relatively sparse. A multi-centre Japanese registry of 78 patients found that 94% of the cases were sporadic with only 6% of the cases being familial [21]. In a national study from Japan, it was found that 30 gene mutation carriers were found for 3 genes in 50 probands [22]. Another Japanese study reported on the findings of 29 patients [23]. To corroborate, two studies from China have reported on six patients [11] and 12 patients [24]. Moreover, few studies have studied the economic burden of CPVT patients on the healthcare systems. In this study, we investigated the clinical characteristics, genetic basis, arrhythmic outcomes, healthcare utilisation and costs of CPVT patients from Hong Kong.
This study was part of a wider study on cardiac arrhythmias that was approved by The Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee. The cohort included consecutive patients diagnosed with CPVT between January 1st, 1997 to December 31st, 2018 in public hospitals or clinics of Hong Kong Hospital Authority [25]. Our team has previously used this system for conducting disease-based epidemiological or clinical studies for both prevalent and rare conditions [26], including Brugada syndrome [27] and long QT syndrome [28, 29]. This cohort, including clinical characteristics and genetic basis of this cohort have already been published by our team as a preprint [30] with subsequent publication of the anonymised dataset (https://zenodo.org/record/5636292). In the original study, centralised electronic health records were reviewed for patient identification and data extraction. The diagnosis was made initially by the case physicians. They were confirmed by G.T. through the review of case notes, documented ECGs, diagnostic test results, and genetic reports in reference to the 2013 HRS/EHRA/APHRS expert consensus statement (Supplementary Table 1). Diagnosis of CPVT was established based on the exercise treadmill test, adrenaline challenge test, or genetic testing by the participating institution at the time of entry. In this study, only deidentified data obtained from the administrative database were analysed.
The baseline clinical data extracted from the electronic health records include: (1) sex; (2) age of first characteristic ECG presentation and last follow-up; (3) follow-up duration; (4) family history of SCD and the specific ion channelopathy; (5) syncope manifestation and its frequency; (6) presentation of sustained VT/VF and its frequency; (7) performance of electrophysiological study (EPS), 24-hours Holter study, ion channelopathy-specific genetic testing of the RYR2 gene, and the respective results; (8) performance of echocardiogram; (9) presence of other arrhythmias; (10) implantation of implantable cardioverter-defibrillator (ICD); (11) occurrence, cause and age of death; (12) period between the initial presentation of characteristic ECG and the first post-diagnosis VT/VF episode; (13) initial disease manifestation (asymptomatic, syncope, VT/VF). In the present study, symptoms refer to syncope or VT/VF, thus asymptomatic indicates freedom from either presentation. Other arrhythmias include sick sinus syndrome, bradycardia, atrioventricular block, atrial tachyarrhythmias, and supraventricular tachyarrhythmias. Positive EPS is defined as the induction of spontaneous VT/VF that either sustained a minimum of 30 seconds or produced hemodynamic collapse. VT/VF in the present study is defined as ventricular tachyarrhythmia at a heart rate greater than 100 beats per minute sustained for at least 30 seconds.
The following automated measurements were extracted from baseline ECGs: (1) heart rate; (2) P wave duration (PWD) and PR interval; (3) QRS duration; (4) QT and QTc interval; (5) P, QRS and T wave axis; (6) amplitude of R and S wave from leads V5 and V1 respectively; (7) presence of 1st degree atrioventricular block, defined as PR-interval greater than 200 ms; (8) presence of interventricular delay, defined as QRS-interval greater or equal to 110 ms. Baseline ECG is the documented ECG taken at or the earliest after the initial characteristic ECG presentation. All ECG parameters, except for the amplitude of R- and S-wave from leads V5 and V1 respectively, were averaged across the 12 leads.
Categorical variables were compared using Fisher’s exact test and reported as
total number (percentage), whilst discrete and continuous variables were compared
by Kruskal-Wallis one-way ANOVA and expressed as mean
Healthcare resource utilisation for accident and emergency (A&E), inpatient and outpatient attendances were analysed over a 19-year period (2001–2019). The costs for these attendances were calculated using unit costs published by the local government and then annualised. These costs were first calculated in the local currency (Hong Kong Dollars) and converted to US Dollars.
The clinical characteristics of this cohort have been analysed and published by
our team as a preprint [30]. A total of 16 consecutive patients were included.
They have a median (interquartile range) age of presentation of 11 (9 to 14 years
old) and 50% were female. All patients presented at or below the age of 19 years
old (Table 1). Twelve patients fulfilled at least two criteria and four patients
fulfilled one criterion of the 2013 HRS/EHRA/APHRS expert consensus statement
(Supplementary Table 1). All patients were Han Chinese. Of the whole
cohort, 15 (93.8%) were initially symptomatic and five patients experienced
VT/VF/SCD prior to diagnosis. Ten patients had both PVCs and VT/VF, whereas one
patient had PVCs without VT/VF. In addition, 14 patients experienced initial
syncope. Moreover, cardiac MRI was performed on five patients, however no
abnormalities were identified. Interestingly, some patients were asymptomatic,
though the documentations did not reveal if they were family members of probands.
The median delay between initial presentation and diagnosis was 4.5 (Q1–Q3:
0.8–8.5) months. Genetic tests were performed on 14 patients (87.5%), of which
8 patients (57.1%) tested positive for gene mutations. All mutations involved
the RyR2 gene (Supplementary Table 2). The c.14861C
| Variable | All CPVT patients (n = 16) | p-value |
| Clinical characteristics | ||
| Female | 8 (50.0) | 0.302 |
| Presentation age (years) | 10.8 |
0.478 |
| Diagnosis age (years) | 11.4 |
0.489 |
| Current age (years) | 20.5 |
0.729 |
| Follow-up duration (months) | 116.3 |
0.904 |
| Family history of CPVT/SCD | 3 (18.8) | 0.137 |
| Initial symptomatic | 15 (93.8) | 0.424 |
| Initial syncope | 14 (87.5) | 0.696 |
| Initial VT/VF/SCD | 5 (31.3) | 0.330 |
| PVC | 11 (68.8) | 0.330 |
| VT/VF | 10 (62.5) | 0.016 |
| VT/VF post-presentation | 7 (43.8) | - |
| Genetic test | 14 (87.5) | 0.696 |
| Positive genetic test | 8 (57.1) | 0.207 |
| Exercise tolerance test | 15 (93.8) | 0.424 |
| Positive exercise tolerance test | 13 (92.9) | 0.231 |
| EPS | 2 (12.5) | 0.696 |
| Positive EPS | 2 (100) | 1.000 |
| ICD | 3 (18.8) | 0.013 |
| Holter study | 14 (87.5) | 0.696 |
| Arrhythmia in Holter study | 6 (46.2) | 0.053 |
| Echocardiogram | 15 (93.8) | 0.182 |
| Abnormal echocardiogram | 1 (6.7) | 0.464 |
| Cardiac MRI performed | 5 (31.3) | 0.889 |
| Abnormal cardiac MRI | 0 (0) | 1.000 |
| EEG | 8 (50) | 0.039 |
| Positive EEG | 0 (0) | 1.000 |
| Baseline ECG characteristics | ||
| Heart rate | 81 |
0.323 |
| P-wave duration | 94 |
0.881 |
| PR interval | 163 |
0.955 |
| QRS interval | 90 |
0.757 |
| QT interval | 369 |
0.874 |
| QTc interval | 424 |
0.836 |
| P axis | 40 |
0.338 |
| QRS axis | 67 |
0.203 |
| T axis | 43 |
0.919 |
| 1st degree AV block | 1 (6.3) | 0.182 |
| Interventricular delay | 2 (12.5) | 0.551 |
| Categorical and continuous variables were compared between groups using Fisher’s
exact test or t-test, respectively. Bolded text indicate p | ||
For the whole cohort, the total number of attendances for A&E, inpatient and
outpatient settings were 86, 145 and 1251, respectively. These corresponded to
costs of
| Attendence type | Attendances | Costs ($) | Annualised costs ($/year) |
| Accident & Emergency | 5 (3–7) | 711 (395–1146) | 66 (40–95) |
| Inpatient | 7 (5–12), 232 (57–757) days | 151,754 (37,679–496,022) | 10,521 (5240–66,887) |
| Outpatient | 70 (44–111) | 10,583 (6630–14,895) | 791 (546–1105) |
| Median (25th to 75th percentile) values are presented. Costs are shown in US dollars. | |||
This is the first territory-wide cohort study of CPVT in Hong Kong. There are
several major findings for the present study: (1) All patients presented before
the age of 19, (2) the yield of genetic testing was 57%, identifying RyR2
mutants, of which c.14861C
Sudden cardiac death is an important clinical problem globally, with congenital
and acquired causes [31, 32, 33, 34]. Of the congenital cardiac ion channelopathies, CPVT
is characterised by exercise-induced bidirectional VT. International registry
studies on European and North American patients have reported that there is a
malignant arrhythmic phenotype associated with this disease with significant
delays between initial presentation and subsequent diagnosis of around six months
[17, 35]. By contrast, the epidemiology and characteristics of studies in Asia
are limited. Locally in Hong Kong, the burden of CPVT is low [36]. A previous
study examined a cohort of sudden arrhythmic death syndrome in young patients,
which only identified two cases of CPVT [37]. In this study, we reported the
findings of 16 patients, confirming a highly arrhythmic phenotype, with 10
patients with VT/VF at presentation or on follow-up. Regarding the genetic basis,
this study identified eight variants. Of these, c.14848G
The major strengths of the present study include (1) comprehensive linkage of electronic health records within the public system of the city, with the availability of attendances at different hospitals; (2) costs were estimated using unit costs over long follow-up periods.
Several limitations should be noted for the present study. First, the retrospective nature of the study is inherently subjected to selection and information bias. However, consultations were performed at least annually for most patients, hence the patients were closely followed-up. Secondly, the predictive value of predictors is limited by the relatively small sample size as CPVT is the rarest out of the different ion channelopathies in our city. Furthermore, the family history of patients was not documented in detail, thus it is unclear if the asymptomatic patients were simply family members of probands. In addition, further stratification of patients based on their arrhythmic presentation would be more user-friendly, such as the absence of catecholaminergic arrhythmias versus the presence of catecholamine-induced PVCs, couplets, non-sustained VT or sustained VT/VF. However, due to the relatively small sample size, the extent of patient stratification is limited. Finally, Cox regression was attempted but because of the low number of patients, significant clinical or electrocardiographic predictors for arrhythmic outcomes could not be identified and the modifier effects by anti-arrhythmic agents could not be assessed. Recent work has examined the effects of different beta blockers on arrhythmogenicity in a large cohort of CPVT patients. This should be evaluated further in our cohort in a prospective setting.
All CPVT patients presented before the age of 19. Clinical and electrocardiographic findings are important predictors of arrhythmic outcomes. A nonparametric machine learning survival analysis achieved high accuracy to predict the probabilities of incident VT/VF.
None.
CTC—statistical analysis, cost analysis, manuscript drafting, manuscript revision; SL and GT—study conception, data acquisition, database building, statistical analysis, manuscript drafting, manuscript revision; KJ, JZ, OHIC, TTLL, KSKL, WTW, TL—data interpretation, statistical analysis, manuscript revision.
This study was part of a wider study on cardiac arrhythmias that was approved by The Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (Approval number: 2019.361). The need for informed consent was waived by the committee owing to the retrospective nature of this study. Copyright permissions and informed consent have been obtained from all authors involved in this manuscript.
Not applicable.
This research received no external funding.
The authors declare no conflict of interest. Gary Tse, Tong Liu, and Sharen Lee are serving as the Guest Editors of this journal. We declare that Gary Tse, Tong Liu, and Sharen Lee have no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Konstantinos P. Letsas.
Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/j.rcm2308276.
References
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