The Prevalence and Associated Death of Ventricular Arrhythmia and Sudden Cardiac Death in Hospitalized Patients With COVID-19: A Systematic Review and Meta-Analysis

Background Arrhythmia is a very common complication of coronavirus disease 2019 (COVID-19); however, the prevalence of ventricular arrhythmia and associated outcomes are not well-explored. Here, we conducted a systematic review and meta-analysis to determine the prevalence and associated death of ventricular arrhythmia and sudden cardiac death (SCD) in patients with COVID-19. Methods Databases of PubMed, Cochrane Library, Embase, and MdeRxiv were searched. Studies that could calculate the prevalence of ventricular arrhythmia/SCD during hospital admission or associated death in patients with COVID-19 were included. The study was registered with the PROSPERO (CRD42021271328). Results A total of 21 studies with 13,790 patients were included. The pooled prevalence of ventricular arrhythmia was 5% (95% CI: 4–6%), with a relatively high-SCD prevalence (1.8% in hospitalized COVID-19 and 10% in deceased cases of COVID-19). Subgroup analysis showed that ventricular arrhythmia was more common in patients with elevated cardiac troponin T [ES (effect size): 10%, 95% CI: −0.2 to 22%] and in European (ES: 20%, 95% CI: 11–29%) populations. Besides, ventricular arrhythmia was independently associated with an increased risk of death in patients with COVID-19 [odds ratio (OR) = 2.83; 95% CI: 1.78–4.51]. Conclusion Ventricular arrhythmia and SCD resulted as a common occurrence with a high prevalence in patients with COVID-19 admitted to the hospital. Furthermore, ventricular arrhythmia significantly contributed to an increased risk of death in hospitalized patients with COVID-19. Clinicians might be vigilant of ventricular arrhythmias for patients with COVID-19, especially for severe cases. Systematic Review Registration www.york.ac.uk/inst/crd, identifier: CRD42021271328.


INTRODUCTION
Coronavirus disease 2019 (COVID-19) is a serious lifethreatening disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which first occurred in November 2019 (1), and then rapidly spread throughout the rest of the world. As of July 31, 2021, more than 198 million individuals were diagnosed with cases of COVID-19, exceeding 420 thousand deaths. Although COVID-19 is characterized by substantial respiratory pathology, several extrapulmonary manifestations, such as thrombotic complications, myocardial dysfunction, and arrhythmia, acute kidney injury are also commonly found in patients afflicted with the virus (2)(3)(4).
Cardiac arrhythmias, such as new-onset atrial fibrillation, heart block, and ventricular arrhythmias, are prevalent in the patients with COVID-19. An early report study on 138 patients from Wuhan, China, showed that 17% of the hospitalized patients suffered from total arrhythmia (5). Our recent metaanalysis also showed that the atrial fibrillation reached 10% and was associated with increased death in COVID-19 (6). Ventricular arrhythmia is still the major leading cause of death from the cardiovascular diseases (7). According to a multicenter cohort from the US, 6% of 4,250 patients with COVID-19 had prolonged QTc interval (corrected QT; >500 ms) at admission (8). This result suggested that COVID-19 might significantly contribute to an increased risk of ventricular tachycardia as QTc prolongation is believed to predispose to the ventricular arrhythmias associated with sudden death in certain cardiac diseases. Although several studies have reported the increased risk of ventricular tachycardia among patients with COVID-19, the exact prevalence of ventricular tachycardia in patients with COVID-19 remains unknown. Moreover, a case series also reported ventricular tachycardia and ventricular fibrillation as the primary cause of death in hospitalized patients with COVID-19 without a prior history of the structural heart disease (9). However, it remains unclear whether COVID-19 associated the ventricular arrhythmias are independently linked to increased death in the patients with COVID-19.
Furthermore, sudden cardiac death (SCD) is the most devastating manifestation of ventricular arrhythmias that has emerged as one of the disturbing concerns associated with the infection of COVID-19. Thus, we conducted a systematic review and meta-analysis to determine the prevalence and associated death of ventricular arrhythmia and SCD in patients with COVID-19.

METHODS
This study has been registered with PROSPERO (International prospective register of systematic reviews. www.york.ac.uk/inst/crd)-registration number-CRD42021271328. Furthermore, we conducted the meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement (2020) (Supplementary Table 1).

Study Selection
All the results were organized by EndNote X9 software (Thomson Reuters, New York, NY, USA). After deleting the duplicate literature, the titles and abstracts were checked, and the relevant literature was preliminarily screened. Subsequently, full-texts of the relevant studies were searched to make sure they met the inclusion criteria. The inclusion criteria included the following: (1) studies that included adult patients diagnosed with COVID-19 based on the polymerase chain reaction tests; (2) studies that could calculate the prevalence of ventricular arrhythmia/SCD during hospital admission or reported the estimated effect between ventricular arrhythmia and death in patients with COVID-19.
If the same population was used in multiple studies, we selected the article with the most informative or the largest sample size. Studies that reported the effect of chloroquine/hydroxychloroquine and azithromycin in patients with COVID-19 were excluded because of the potential druginduced ventricular arrhythmias risk. Certain publication types without sufficient data (reviews, meta-analysis, cases, editorials, and comments) were also excluded.

Data Collection
The following information was independently abstracted by two researchers: the first author, publication year, country, time, study design, patient characteristics (sample size, age, and sex), number of ventricular arrhythmias, death, odds ratios (ORs), and the corresponding 95% CI and adjustments.

Quality Assessment
For studies that reported the prevalence, the Joanna Briggs Institute (JBI) critical appraisal checklist was used to assess the study quality, where 0 score represented a failure to meet the requirements; 1 represented the lack of detailed description, 2 score represented detailed and comprehensive description. For studies that reported the association between ventricular arrhythmia and death in patients with COVID-19, the Newcastle-Ottawa Scale (NOS) was applied. Studies with scores of NOS ≥ 7 and JBI ≥ 14 were considered as high-quality researches (10).

Statistical Analysis
RevMan software, version 5.3 (The Cochrane Collaboration 2014, Nordic Cochrane Center Copenhagen, Denmark) and Stata software (Version 14.0, Stata Corp LP, College Station, Texas, US) were both applied in our analysis. To explore the prevalence of ventricular arrhythmia and SCD in hospitalized patients with COVID-19, the exact binomial (Clopper-Pearson) method was used to calculate 95% CIs. Freeman-Tukey double arcsine transformation was used for standard estimates. To elucidate the outcome of ventricular arrhythmia and SCD in hospitalized patients with COVID-19, we pooled the ORs for each studies using the inverse variance method. We also estimated the adjusted ORs by calculating the natural logarithm of the OR (log [OR]) and its standard error (SElog [OR]), which is shown with 95% CIs. We evaluated the degree of heterogeneity using the I² test (25, 50, and 75% represent low, moderate, and high heterogeneity). We used the random effect model in our study to improve the reliability.
Subgroup analyses were performed to study possible factors influencing our results, including ventricular arrhythmia, region, cardiac injury, and population. To ensure the reliability of study outcomes, we carried out sensitivity analyses by omitting each study in turn. P < 0.05 was considered statistically significant.

Study Selection
The flow chart for the study selection process is shown in Figure 1. A total of 1,342 publications were identified following initial search (PubMed = 430; the Cochrane Library = 119; Embase = 405; MedRxiv = 388). After deleting 584 duplications and 680 irrelevant studies, the full-text assessment was performed on 78 studies. Subsequently, 57 articles were excluded due to the following reasons: (1) studies without insufficient data (n = 19); (2) certain publication types with no data (review = 11; case report = 3); (3) studies without appropriate population or exposure (n = 11); (4) studies that did not report target outcome (n = 13). Finally, 21 studies were included in the meta-analysis . All the excluded studies with reasons (n = 57) are shown in Supplementary Table 3.
All studies  scored between 16 and 20 on the Joanna Briggs Institute Critical Appraisal Checklist, which meant these articles took rigorous methodology. In addition, five studies (16,19,21,25,27) involved the association between ventricular arrhythmia and death in patients with COVID-19, with NOS scores > 7, thus were regarded as moderate high-quality studies (Supplementary Table 4).
Two articles reported the prevalence of SCD in hospitalized patients with COVID-19 (28,31). Article of Shao reported that the prevalence of SCD was 1.8% in the population with COVID-19 (28). Also, according to Yang et al. there was a higher SCD prevalence (10%) in the deceased population with COVID-19 (31).

Publication Bias
The potential publication bias for death was not performed due to the limited number of studies (N < 10).

DISCUSSION
In this study, we pooled data from 21 studies with 13,790 hospitalized patients with COVID-19, finding that: (i) the prevalence of ventricular arrhythmia in hospitalized patients with COVID-19 was 5%. Specifically, the premature ventricular complex, ventricular tachycardia, and ventricular fibrillation occurred in 13, 10, 1% in the hospitalized patients, respectively.
(ii) Ventricular arrhythmia was independently related to an increased risk of death in hospitalized patients with COVID-19. Overall, the ventricular arrhythmia and SCD were not uncommon and were associated with adverse outcomes in the hospitalized patients. To the best of our knowledge, this is the first meta-analysis that reported the prevalence of ventricular arrhythmia, SCD, and associated prognosis in the hospitalized patients with COVID-19. Cardiac arrhythmia was identified as one of the major complications of SARS-COV during the outbreak in China in 2003 (32). Tachycardia was the most common type of arrhythmia among the patients infected with SARS-COV and was independent of fever (33,34). Similarly, in hospitalized patients with COVID, arrhythmic events are not uncommon among the COVID-19 related cardiovascular complications. As we previously reported, atrial fibrillation is the most prevalent arrhythmia in hospitalized patients (6). Regarding ventricular arrhythmia, evidence from earliest cohorts from Wuhan, China, showed that ventricular arrhythmia occurred in 7% of patients (13/187) and that the rate of ventricular arrhythmia was almost doubled in patients with elevated troponin T levels on ICU admission (18), which is consistent with our results (Figure 3). However, the exact pathophysiology underlying ventricular arrhythmia in COVID-19 may be multifactorial and remains elusive.
First, as we previously described, cardiac injury or myocarditis commonly occurs due to the inhibited activity of angiotensinconverting enzyme 2 (ACE2) by SARS-COV2, which was found in 19% of hospitalized patients with COVID-19, and has been estimated to double among those with pre-existing cardiovascular and non-cardiovascular diseases (e.g., diabetes, hypertension, and cancers). These comorbidities might make their cardiomyocytes more vulnerable to be attacked by SARS-COV2 and thus causing a higher incidence of cardiac injury (35,36). This cardiac injury might contribute to the abnormalities in cardiac electrophysiology, eventually inducing ventricular  arrhythmia. This supposition is consistent with our subgroup analysis, which showed that the incident rate of ventricular arrhythmia increased with cardiac injury. Secondly, it is wellknown that COVID-19 is characterized by the dysregulated immune response and cytokine release syndrome. Numerous studies have shown an elevation of serum inflammatory markers, such as C-reactive protein, ferritin, erythrocyte sedimentation rate (37). It has also been identified as a predictor of severity and death in patients with COVID-19. On the other hand, various pro-inflammatory factors, such as C-reactive protein and tumor necrosis factor α, have also been shown to promote ventricular arrhythmia significantly (38). Third, thrombotic complications are the main extrapulmonary manifestations of COVID-19 (37). For example, autopsies performed at a single academic medical center revealed deep venous thrombosis in 7 out of 12 patients (58%) who were not suspected of venous thromboembolism  before death. Pulmonary embolism was the direct cause of death in four of these patients (39).
Limited studies reported the incidence of SCD in patients with COVID-19, our review showed it to be 1.8% in the all-hospitalized population with COVID-19 and 10% in the decreased patients. This incident rate is strikingly higher than that reported in the US in patients without COVID-19 (40). One study reported that the incidence of SCD was 14.9-110.8 per 100,000 in population with a non-COVID-19 in different regions (41). Nonetheless, the above results were consistent with several reports. For example, a cohort from Pennsylvania reported a 1.3% incidence of cardiac arrest amongst 700 urban patients admitted for COVID-19 (12). Furthermore, a multicenter cohort study in the US showed that 2.2% of non-ICU (intensive care unit) patients developed in-hospital sudden arrest (42). In the context of COVID-19, Acharya et al. showed the incidence of in-hospital sudden arrest for ICU patients was 15.4% in hospital patients (42). Yet, only ∼7% of the patients with COVID-19 survived to discharge after experiencing in-hospital sudden arrest according to their report (42). Currently, the reason for this high SCD or cardiac arrest rate is not fully evident, and both the cardiac (e.g., undetected ventricular fibrillation) or non-cardiac (e.g., missed pulmonary embolisms) factors might be responsible for this condition.
Our results also showed that ventricular arrhythmia was more likely to occur in American and European patients compared to Asian patients. This should be interpreted considering the limited sample size and differences in baseline characteristics. Notably, the hospitalized American and European patients were mostly older compared with Chinese patients (Table 1). Additionally, the prevalence of common comorbidities, such as obesity and diabetes, was also higher in American and European populations than in Asia. All the aforementioned risk factors might be contributing to a higher incidence rate of cardiac injury or severity of COVID-19 cases in American and European populations. Therefore, the regional difference should be validated by further studies.

Compassion With the Previous Study
Previous studies have proved that COVID-19 can significantly affect the cardiovascular system of the patient, leading to serious cardiovascular diseases (3,4,43). Also, the previous studies had revealed a positive relationship between arrhythmia and COVID-19 (4,24,43,44). Two meta-analyses studied the relationship between COVID-19 and ventricular arrhythmia. However, one of them focused on the patients after chloroquine or hydroxychloroquine treatment (45), while another explored the effect of COVID-19 on QTd, Tp-e/QTc ratio, and Tpe interval (46). In addition, two meta-analyses described the relationship between COVID-19 and all types of arrhythmias (47,48). Nevertheless, most of the included studies reported atrial fibrillation. Our meta-analysis extended the previous study and quantified'prevalence of ventricular arrhythmias and is associated with the clinical outcomes in hospitalized patients with COVID-19.

Clinical Implication
Considering the prevalence of the ventricular arrhythmias in patients with COVID-19, clinicians should be vigilant of ventricular arrhythmias in patients with COVID-19. Screening of high-risk groups for ventricular arrhythmias should be performed at admission. ECG monitoring at admission is suggested for those hospitalized patients who might be at higher risk for the cardiac arrhythmias, such as those with the cardiac injury, palpitations, dizziness, unexplained syncope, and prolonged QTc. In addition, although it is still being debated whether hydroxychloroquine and azithromycin are linked to increased risk of ventricular arrhythmia (49), hydroxychloroquine, and azithromycin can significantly prolong QT interval, which might lead to the ventricular arrhythmia (50,51). The non-pharmacological treatment (e.g., nutrition support) might also benefit (51). Therefore, these aforementioned treatments might be more carefully evaluated before application or avoided for patients with COVID-19 who were susceptible to ventricular arrhythmias.

Limitation
Our study has several limitations. First, a high degree of heterogeneity was observed in our results, which might be due to study design of the patients and baseline characteristics. For example, ventricular arrhythmia was monitored by a telemetry monitor in the study of Cho (14), while other studies used regular ECG or electrocardiography monitoring. Second, all the studies included hospitalized patients, which may overestimate the prevalence of the ventricular arrhythmia and its clinical impact on patients with COVID-19 compared with the community patients. Third, due to data restrictions, we could not explore the sex or age differences in the association between the ventricular arrhythmia and death. Third, as shown in Table 1, a number of patients receiving drugs tend to prolong the QT interval, which might overestimate the prevalence of the ventricular arrhythmia or SCD. Finally, considering the limited sample size, the incident rate related to the regional differences still needs to be validated by further studies.

CONCLUSION
Ventricular arrhythmia and SCD resulted as a common occurrence with a high prevalence in the hospitalized patients with COVID-19. Furthermore, the ventricular arrhythmia significantly contributed to an increased risk of death in hospitalized patients with COVID-19. Clinicians might be vigilant of ventricular arrhythmias for patients with COVID-19, especially for the severe cases.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

AUTHOR CONTRIBUTIONS
XL and PY were responsible for the entire project and revised the draft. ZT, KM, and ML performed the data extraction, statistical analysis, drafted the first version of the manuscript, and interpreting the data. All authors participated in the interpretation of the results and prepared the final version of the manuscript.