Epidemiology of arrhythmogenic ventricular cardiomyopathy in China

Abstract Background Arrhythmogenic ventricular cardiomyopathy (AVC) is a common cause of ventricular arrhythmias and mortality, but limited data are available from large Asian cohorts. Our aim was to explore the current status of AVC and second, we examined the prevalence of ventricular tachycardia (VT), heart failure (HF) and mortality in patients with AVC in the Chinese population. Hypothesis At present, some studies have reported that the incidence of AVC is on the rise, which may be due to the increasing number of diagnostic methods for AVC. However, there is no epidemiological data on AVC in the Chinese population, so we speculate that the incidence of AVC in the Chinese population is increasing. Methods and Results We studied 15 888 adults from the Beijing Municipal Health Commission Information Center (BMHCIC) registry database in China from January 2010 to December 2020, and calculated the average annual percentage change (AAPC). Second, we determined the incidence of VT, HF and mortality in patients with AVC. Of the 10 318 men and 5570 women who were screened by cardiac magnetic resonance or examined by myocardial biopsy, there were a total of 256 newly diagnosed AVC patients (mean [SD]: 37.54[17.10]; 39.45% female). The incidence of AVC increased from 7.60 (3.12‐12.06) in 2010 to 19.62 (11.51‐27.75) per 1000 person‐years in 2020. Males had higher incidence of AVC than females. The AAPC for the rising incidence of AVC was 8.9 %. Males had similar VT prevalence (70.32% vs. 62.38%, p = 0.19) and mortality (1.94% vs. 1.98%, p = 0.98) but lower HF prevalence (42.58% vs. 60.40%, p = 0.006), when compared to females. Radiofrequency ablation (RFA) was more likely to be performed in males (p = 0.006). Conclusions The rising trend in AVC incidence was evident, with two‐fold increase by 2020. Males with AVC had similar VT prevalence and mortality rate, but HF prevalence were lower than females, perhaps impacted by RFA use.


| INTRODUCTION
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is primarily genetically determined heart disease characterized by cardiac fibrofatty replacement of the right ventricle. 1 Due to the increasing usage of imaging methods such as cardiac magnetic resonance imaging (cMRI), and improved genetic analyses in diagnosing ARVC, left ventricular fibrofatty replacement can be identified with a prevalence ranging from 10% to 50%, usually left-dominant forms of ARVC. 2,3AVC includes both kinds of diseases, with a higher risk of ventricular tachycardia (VT), heart failure (HF), and mortality. 4armacotherapy, such as angiotensin converting enzyme inhibitors (ACEI) and β-receptor antagonists, is the main treatment for AVC at present, 5 and catheter ablation 6 or implantable cardioverter defibrillator (ICD) is an option for VT treatment depending on the patient's estimated risk of sudden death, as well as their individual choice. 2If the disease is serious due to HF, cardiac resynchronization therapy-defibrillator (CRT-D) is considered.When a suitable donor is available, heart transplantation can be an option, but uptake is not high at present.The prevalence of AVC varied widely depending on the studied population and the available diagnostic methods.For example, the prevalence ranges from 1/1000 in northern Italy to 1/5000-10 000 in Germany and other parts of the world. 7,8However, few epidemiological studies are available on the incidence of AVC in the Chinese population.
We investigated the incidence of AVC in this retrospective study of 15 888 Chinese population investigated with at least one of the two protocols, which were cMRI and myocardial biopsy from 2010 to 2020.Second, we estimated the development of this disease with the trends estimation using annual percentage change (APC) and average annual percentage change (AAPC).Third, we explored the prevalence of VT (both sustained and nonsustained VT), HF, and mortality in the patients with AVC.

| Source of database
This registry study used the Beijing Municipal Health Commission Information Center (BMHCIC) database.BMHCIC is a mandatory health surveillance and supervision government agency requiring the medical information uploaded from all 153 hospitals/centers located in the overall Beijing area.The building of the data set was as previously described. 9The quality of the medical records was guaranteed through reviewing and analyzing the inspection results (https://www.phic.org.cn/).
The patients would receive ECG first and then they would be given echocardiography and angiography; also, signal-averaged ECG, cMRI and myocardial biopsy were finally performed to ascertain the diagnosis of AVC.Their genes would be examined if the patients agreed.The registry covered the demographics information including sex, age, ethnicity, registered date, registered center, contact information, variation of diseases, examination methods, and vital status during each hospitalization and outpatient visits.The study protocol conformed to the ethical guidelines of the Declaration of Helsinki and was approved by the Ethical committee of our institution.Informed consent was waived due to anonymized and unidentified information for the analysis.

| AVC and its complications (VT, HF, and mortality)
The diagnosis of AVC was established according to the 2010 diagnostic criteria 10,11  We selected the procedures of ICD implantment using codes 37.94002 or 37.94003; CRT with 00.51002; heart transplantation with 37.51001 and radiofrequency ablation (RFA) with 37.34001 and 37.34003 according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).

| Statistical analysis
The annual incidence of AVC was calculated with the number of newly diagnosed AVC cases divided by the population with cMRI or myocardial biopsy examinations in that referred year and expressed as per 1000 person-year.Prevalences of VT, HF, and mortality were calculated by dividing the events using the corresponding AVC number in that referred year.The occurrence of incident AVC cases with year was assumed to conform to Poisson distribution and the time trends was evaluated with Joinpoint 4.9.0.0 (https:// surveillance.cancer.gov/joinpoint/)with APC for each segment and AAPC for the whole trends. 14Joinpoint can be described as a turning point in a time series or trend, that is, a point of change from one trend to another, and can be used to describe the changing trend of some phenomena, such as the incidence, prevalence, and mortality of diseases, and to evaluate the effect of interventions and predict future trends.Incidence rate ratio (IRR) and 95% confidence interval (CI) of AVC cases with the potential effect of increased age and sex was calculated with the assumption of conforming to Poisson distribution.SPSS and Joinpoint software 4.9.0.0 were used for the calculation of the study.A p value < .05 was considered as statistically significant.

| Incidence of AVC from 2010 to 2020
From 2010 to 2020, 15 888 patients had at least one of the two examinations which were cMRI or myocardial biopsy in the registry and of these, 921 had repeated examinations of cMRI or myocardial biopsy for confirmation of diagnosis.
Of these, a total of 256 newly diagnosed AVC were identified for the current analysis (mean age 37.54 [SD:17.10]years;39.45% [N = 101] females).There were 3 athletes amongst them; 5 (1.95%) AVC were diagnosed after aborted SCD; 138 were diagnosed by cMRI; and 102 AVC were diagnosed by myocardial biopsy (16 patients were confirmed by both cMRI and biopsy).
Left ventricular dominated AVC were diagnosed in 32 (12.5%) patients, and both left and right ventricular involved AVC were diagnosed in 3 (1.17%)patients.Pathogenic mutation was seen in 89 of 125 patients with available genetic examination results, as shown in previous studies. 15e whole list of pathogenic mutations was unavailable for the current analysis.Baseline characteristics are shown in Table 1.
The incidence increased from 7.60 (3.12-12.06) in 2010 to 19.62 (11.51-27.75) in 2020 per 1000 person-years (Supporting Information: | 3 of 7 Table 1, Figure 1).The incidence of AVC maintained a high level at the age range of 10-39 years after adjustment of sex using Poisson distribution analysis as shown in Figure 2. The IRR of males to females was 0.74 (95% CI: 0.57-0.95)based on Poisson distribution analysis after adjustment of age.

| Prevalence of VT, HF, and mortality in AVC
Percentages of VT at first diagnosis was 67.19% (N = 172).Males had similar prevalence of VT to females (male vs. female: 109 [70.32%] vs. F I G U R E 2 Incidence rate ratio (95% CI) of arrhythmogenic ventricular cardiomyopathy with ageing after adjustment of sex.AVC, arrhythmogenic ventricular cardiomyopathy.
T A B L E 2 Temporal trends of incidence of arrhythmogenic ventricular cardiomyopathy.Note: Joinpoint 0 or 1 represents the number of turning point.
based on the patients' symptoms, signs, past history, and any clinical examinations, including 12-lead electrocardiogram (ECG), 24-hour Holter monitoring, echocardiography, angiography, signal-averaged ECG, cMRI, myocardial biopsy, and treatment methods.The involvement of left and/or right ventricles were confirmed by at least one of the following examination methods, which were cMRI or myocardial biopsy.The final diagnosis was then stored in BMHCIC using diagnostic codes (International Classification of Diseases, Tenth Revision, Clinical Modification; ICD-10-CM) of I42.802 and/or I42.806.Only those with right ICD codes and at least one of cMRI or myocardial biopsy examinations were used for this analysis.VT was diagnosed according to the established guidelines 12 with diagnosis confirmed by 12-lead ECG and 24-hour Holter monitoring and stored using ICD-10-CM codes I47.201, I47.202, I47.203, I47.204, I47.205, I47.206, I47.207, I47.210, and I47.212.Due to the rapid progression of ventricular fibrillation in patients, it is difficult to record the results, so ventricular fibrillation was not considered in this analysis.Meanwhile, premature ventricular contractions were not included in this study because most normal people have premature ventricular contractions.HF was diagnosed according to established guidelines, 13 with ICD-10-CM codes I 50.The first-time diagnosis with AVC or AVC-induced VT, and HF were considered as the date of onset for the condition.AVC, VT, and HF were assessed by independent cardiologists.