Introduction

Myocarditis is a major inflammatory heart disease, primarily induced by viruses but can also be triggered by drugs and systemic immune-mediated diseases, leading to severe cardiac damage and acute heart failure.^1,2 Myocarditis affects people of all ages, and its clinical manifestations are diverse, making diagnosis challenging.³ Patients suspected of acute myocarditis are typically assessed in the emergency department with chest pain, shortness of breath, fatigue, palpitations, or syncope.⁴ According to large registry studies, chest pain is the predominant symptom of myocarditis (85%-95% of cases), followed by fever (about 65% of cases) and shortness of breath (19%-49% of cases).^5-8 Most myocarditis patients can spontaneously recover, but patients with persistent ventricular dysfunction have a 20% annual mortality rate.⁹ Therefore, accurately assessing the epidemiology of myocarditis is crucial for its prevention and treatment.

According to discharge records from 1990 to 2013, Global Burden of Disease (GBD) study estimated an annual incidence of approximately 22 cases of myocarditis per 100 000 patients worldwide.¹⁰ All data on myocarditis hospitalizations in the National Health Service (NHS) of England from 1998 to 2017 showed that during the 19 years, 12 927 hospitalizations with myocarditis as the primary diagnosis accounted for 0.04% (36.5/100 000) of all NHS hospitalizations, with about 2/3 of patients being male, and a median age of 33 years for males and 46 years for females, and a median hospital stay of 4.2 days. Over the study period, hospitalizations due to myocarditis increased by 88% (57% increase in all cardiac hospitalizations),¹¹ suggesting an added burden of hospitalizations from myocarditis. However, there is limited accurate information on the incidence and mortality trends of myocarditis for the entire Chinese population. A recent study based on GBD 2016 data reported an age-standardized incidence rate (ASIR) of 32.8 (per 100 000 individuals) for myocardial disease and myocarditis in China in 2016, an increase of 23.1% compared to 1990.¹² To our knowledge, there is currently no study that has applied age–period–cohort model to delineate the incidence and mortality trends of myocarditis in China. This study intended to use GBD 2019 data and age–period–cohort model to analyze the trends in the burden of myocarditis in China. This may lay the groundwork for public health policies, resource allocation, and the design of intervention plans.

Methods

Data Sources

All anonymous incidence and mortality data related to myocarditis in China during 1990-2019 were downloaded from the latest GBD database (GBD 2019, https://www.healthdata.org/gbd) from the Institute for Health Metrics and Evaluation. Global Burden of Disease has created a unique platform for comparing the severity of health losses caused by different diseases, injuries, and risk factors across different ages, sexes, and geographic locations. This study downloaded age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) data for myocarditis in China from GHDx (https://vizhub.healthdata.org/gbd-results/). Age-standardized incidence rate and ASMR are methods used to compare disease incidence and mortality rates among different populations or regions, taking into account variations in population age structure. These methods standardize the incidence or mortality rates of different age groups, enabling a more accurate comparison of disease incidence or mortality rates among different populations while eliminating differences caused by variations in age distribution. These standardized rates are typically expressed as the number of cases or deaths per 100 000 population per year.

Statistical Analysis

Joinpoint Regression Analysis

To evaluate trends in the disease burden attributable to myocarditis over time, we conducted Joinpoint regression analysis. The calculation method of this model used the least squares method to estimate changing patterns of disease rates, avoiding subjectivity of typical trend analysis on the basis of linear trends. The sum of squares of residuals between estimated and true values can be used to identify the inflection point of a shifting trend. We utilized Joinpoint software (version 4.9.1.0; National Cancer Institute, Rockville, Md, USA) to calculate the annual percentage change (APC) and average annual percentage change (AAPC), along with their corresponding 95% CI, to determine the trends in disease burden. We assessed the fluctuation trends in different sections by comparing APC/AAPC with 0 to determine statistical significance (P < .05). An APC/AAPC >0 indicates an upward trend, while the APC/AAPC <0 signifies a downward trend. If APC/AAPC equals 0, it suggests a stable trend (Supplementary Table 1 & 2).

Age–Period–Cohort Analysis

The age–period–cohort model was utilized to explain effects of age, period, and cohort on the incidence and mortality rates of myocarditis, with data analysis performed by APC online web tool (https://analystools.cancer.gov/apc/). We estimated rate ratios (RRs) of myocarditis incidence and mortality relative to a reference point for varying periods (period effects) and cohorts (cohort effects). The term “period effect,” which was used to describe changes in incidence and death rates brought on by artificial variables, such as the advancement of diagnostic technology, early screening and diagnosis, modifications to illness classification and registration, and advancements in therapy, was represented by the period RRs. Period effects can occur as a result of these artificial elements’ potential to change the incidence rate over time. Cohort effect was represented by cohort RR, which referred to the deviations in mortality rates between different generations resulting from changes in lifestyles or exposure to different risk factors. We calculated net drift, local drift, and longitudinal age curve of the incidence and mortality rates of myocarditis. Net drift represented the overall APC in age-adjusted incidence and mortality rates of myocarditis over time, which represented total linear trend of logarithmic incidence and mortality rates divided by period and cohort. Local drift indicated a particular logarithmic trend of myocarditis incidence and death rates divided by period and cohort, as well as APC in incidence and mortality rates of myocarditis for a certain age group over time. The reference cohort’s longitudinal age curve represented predicted age-specific ratios that had been period effects-adjusted.

We coded age, period, and cohort into data with continuous 5-year intervals. Age was divided into 17 groups. Due to the absence of relevant data in the GBD 2019 database for age groups below 15 years old, our study’s data start from 15 to 9 years, 20 to 24 years, and so on, up to 95+ years (where individuals aged 95 and above were grouped together). Period was divided into 6 groups (1990-1994, 1995-1999, ..., 2015-2019). Twenty-two birth cohorts (1895-1899, 1900-1904, ..., 1995-2000) were obtained based on age and period. The logarithmic linear model for the APC model is as follows:^13,14

Y = log(M) = µ + α(age)_i  + β (period)_j  + γ (cohort)_k  + Ɛ

where,M represents the incidence/mortality rate of myocarditis, μ and ε represent intercept error and random error, respectively. α_i represents the age group effect, and β and γ represent period and cohort effects.

GraphPad (Prism 9.1.0) and R software (version 3.5.1) were used to conduct the statistical analysis. P < .05 was considered as statistically significant.

Results

Trends in Age-Standardized Incidence Rate and Age-Standardized Mortality Rate of Myocarditis in China over Time

During 1990-2019, the ASIR of myocarditis in Chinese males and females remained relatively stable, with a slight decrease in 2006-2009, followed by stabilizing. The incidence was consistently higher in males than in females, and this trend remained consistent (Figure 1A).

During 1990-2019, ASMR of myocarditis in Chinese males and females elevated annually from 1990 to 2005, peaked in 2005 and then decreased annually. Age-standardized mortality rate was generally higher in males than in females (Figure 1B).

Joinpoint Regression Analysis of Age-Standardized Incidence Rate and Age-Standardized Mortality Rate of Myocarditis in Chinese Males and Females During 1990-2019

Table 1 showed AAPC of ASIR of myocarditis in both genders over the past 3 decades. The results showed that during 1990-2019, ASIR of myocarditis in Chinese males and females decreased by −0.202 (95% CI: −0.213 to −0.191) and −0.263 (95% CI: −0.27 to −0.256), respectively. Average annual percentage change of incidence rates was higher in males than in females. From 2006 to 2009, the incidence of myocarditis significantly decreased in both males (APC = −1.287, 95% CI: −1.391 to −1.183) and females (APC = −1.996, 95% CI: −2.062 to −1.93); however, the decreasing trend of incidence rates in both genders slowed down after 2009.

Table 2 showed the AAPC of ASMR of myocarditis in Chinese males and females over the past 3 decades. During 1990-2019, ASMR of myocarditis in Chinese males and females reduced by 0.233 (95% CI: −0.371 to −0.094) and 0.872 (95% CI: −1.112 to −0.631), respectively. From 1998 to 2005, ASMR in females substantially elevated (APC = 2.519), while from 2005 to 2019, they significantly decreased (APC = −2.341 from 2005 to 2014 and APC = −3.695 from 2014 to 2019). Similarly, from 1999 to 2005, the ASMR in males significantly increased (APC = 2.537), and from 2009 to 2019, they significantly decreased (APC = −1.49 from 2009 to 2015 and APC = −3.301 from 2015 to 2019).

Effects of Age, Period, and Cohort on Age-Standardized Incidence Rate and Age-Standardized Mortality Rate of Myocarditis in China

Discussion

This study investigated changes in myocarditis burden in China over the past 3 decades, focusing on gender and age. We found that during 1990-2019, myocarditis incidence in China remained stable, with no discernible decrease, while the mortality rate decreased annually from 2005 onward. This suggests that the burden of myocarditis in China is still high, and it is necessary for us to have a more comprehensive understanding of the differences in myocarditis by gender and age and to increase our focus on its prevention and treatment.

Regarding gender, this study showed that myocarditis incidence and mortality were generally higher in males than in females. This is highly consistent with the findings of Yu et al¹⁵ in their study on myocarditis burden in China. Moreover, several other studies have shown that incidence rate of myocarditis is significantly higher in males than in females, accounting for 71%-86% of total cases.^16,17 Additionally, this study demonstrates that from 2005 to 2019, the decline in ASMR for myocarditis in females was greater than in males, potentially due to the higher demand for healthcare services among women compared to men. This can be attributed to several factors. Firstly, women have specific health needs such as reproductive health, maternal care, family planning, and gynecological services, which require regular screening, consultations, and appropriate medical interventions, hence leading to a higher demand for healthcare services. Secondly, women often take on multiple roles within the family and community, including caring for children, the elderly, and other family members. These responsibilities prompt them to seek healthcare services, increasing their overall demand for healthcare. Moreover, there is a higher societal focus on women’s health issues, early detection of diseases, and health screenings. Awareness campaigns and educational initiatives about various health issues for women have also contributed to an increased understanding of health matters and reinforced their awareness to seek medical care. Furthermore, research also suggests that men are more prone to get severe myocarditis, whereas women are much less likely to pass away or need a heart transplant.¹⁸ In a mouse model experiment, CVB3, a predominant pathogen in viral myocarditis patients, induced a higher incidence and more severe clinical course of myocarditis in male mice.¹⁹ Testosterone promotes susceptibility to myocarditis in male mice, as castrated male mice are protected, and exogenous testosterone administration can restore susceptibility.²⁰ Treatment with male E2 provides a protective effect since ovariectomized female mice have higher myocarditis compared to intact female mice.²¹ The reason for this may be related to the ability of sex hormones to influence innate and adaptive immune responses. CVB3-infected male and female mice produce different T-cell responses, with males producing a pro-inflammatory response, while females produce an anti-inflammatory or immune-suppressive response.^22,23

To our knowledge, this study is the first to examine the trend of myocarditis in China using an age–period–cohort model. Age effects refer to changes in disease rates with age and are important determinants of disease occurrence. Myocarditis occurs in all age groups, with median age of onset being 30-45 years.^6,7,24 In the US COVID-19 Vaccine Adverse Event Reporting System, as of August 31, 2021, there were 1991 cases of myocarditis recorded, with a median age of 21 years.²⁵ However, this study found that myocarditis incidence and mortality in China elevated rapidly with age following adjusting for period and cohort biases using age–period–cohort model. Local drift curves also showed that individuals over 70 had a higher incidence and risk of death from myocarditis. Currently, the Chinese population is rapidly aging, and various diseases, especially cardiovascular diseases, are prevalent among the elderly.²⁶ Furthermore, it has been reported that female myocarditis patients often exhibit more severe disease manifestations (worsening of ventricular tachycardia, ventricular fibrillation) in old age.²⁷ These results indicate that the aging trend of the burden of myocarditis needs to be taken seriously, and further attention should be paid to myocarditis patients in the elderly population.

This study revealed a general trend toward a lessening influence of period and cohort effects on the incidence and death rates of myocarditis in China. Several factors, including measures to improve the timely diagnosis and treatment of myocarditis, may be a contributing factor to the decrease in the burden of myocarditis disease. The mortality rate is showing a downward trend, partly due to improvements in myocarditis treatment and an increase in the level of medical intervention.^28,29 Clinical signs and symptoms of myocarditis might range from minor chest pain to cardiogenic shock, and there are no specific diagnostic tests, making it difficult to diagnose clinically. Electrocardiography is used to test for myocarditis, but its sensitivity is only 47%.³⁰ Over the years, with the development of various diagnostic technologies, myocarditis patients have been more accurately identified, and diagnostic methods include clinical, laboratory, imaging, and histological parameters.^31,32 In recent years, utilization of cardiac magnetic resonance imaging for noninvasive assessment of suspected myocarditis patients has become more frequent,³³ with unique tissue characterization potential that can assess 3 markers of tissue damage, including intracellular and interstitial edema, congestion and capillary leak age, and necrosis and fibrosis.²⁸ We are better able to comprehend the actual prevalence and different patient types of myocarditis thanks to these new diagnostic tools and algorithms. Moreover, to increase the accessibility, affordability, and availability of medical care, the Chinese government is working to increase urbanization and basic health insurance. The improvement in medical technology and the abundance of medical resources may also be one of the reasons for the decreasing incidence and mortality rates of myocarditis.

Study Limitations

In spite of the progress, there are still several limitations. First off, biases resulting from missing data may be challenging to prevent, even though GBD 2019 has modified and adjusted data sources and collection evaluation methods to increase data quality. Due to different diagnostic criteria, statistical errors in the data appear to be unavoidable within the standards for including cases. Secondly, this study did not classify the burden of myocarditis according to etiology, such as viral myocarditis or immunotherapy-related myocarditis. Finally, we should also take other factors like environmental exposure, economic development level, and educational attainment into account in addition to the impacts of age, period, cohort, and gender.

Conclusion

In summary, the burden of myocarditis in China generally demonstrated a declining trend between 1990 and 2019, but the incidence rate remained high, posing a threat to people’s health and lives. In addition, the burden of myocarditis in male and elderly populations needs more attention. Therefore, relevant departments should take more proactive measures to reduce the burden of myocarditis, such as unifying diagnostic standards and exploring effective specific treatment methods.

Data Availability Statement

The datasets generated and analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Footnotes

Ethics Committee Approval: The Institutional Ethics Committee exempted the study, which did not require approval because the 2019 GBD data is publicly available. The study followed guidelines for accurate and transparent health assessment reporting.

Informed Consent: Not applicable.

Peer-review: Externally peer-reviewed.

Author Contributions: Concept – C.B., Y.W.; Design – L.S., C.B., Y.W., G.Y.; Supervision – G.Y., X.L.; Resource – X.L., Y.W., L.S.; Materials – Y.W.; Data Collection and/or Processing – C.B., Y.W., G.Y.; Analysis and/or Interpretation – X.L., G.Y., Y.W.; Literature Search – L.S., C.B., Y.W., G.Y.; Writing – C.B., Y.W.; Critical Review – C.B., Y.W., X.L., L.S., G.Y.

Declaration of Interests: The authors have no conflicts of interest to declare.

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