key: cord-0985125-36bxtlxh
authors: Guan, Hongquan; Liu, Jie; Ding, Jiaxing; Liu, Wei; Feng, Yu; Bao, Yintu; Li, Huili; Wang, Xuehua; Zhou, Zihua; Chen, Zhijian
title: Arrhythmias in patients with coronavirus disease 2019 (COVID-19) in Wuhan, China: Incidences and implications
date: 2021-01-24
journal: J Electrocardiol
DOI: 10.1016/j.jelectrocard.2021.01.012
sha: 38d46d9a85a5c622ea7465af1359ffcde616de87
doc_id: 985125
cord_uid: 36bxtlxh

BACKGROUND: Coronavirus disease 2019 (COVID-19) continues to impact populations around the globe. Information regarding the incidences and implications of arrhythmias in COVID-19 is limited. METHODS: A total of 463 patients with COVID-19 and who had at least one electrocardiogram recording from February 1 to March 19, 2020, in Wuhan Union Hospital were enrolled in the study. RESULTS: Arrhythmias occurred in 85 of 463 (18.4%) patients: atrial arrhythmias in 10.2%, junctional arrhythmias in 0.2%, ventricular arrhythmias in 3.5%, and conduction block in 7.3%. Compared with patients without arrhythmias, those with arrhythmias had higher mortality, both during the time from symptom onset (p < 0.001) and from admission to follow-up (p < 0.001). The frequencies of severe COVID-19 (44.7% vs. 21.2%; p < 0.001) and death (25.9% vs. 10.1%; p < 0.001) were higher in patients with arrhythmias than in those without arrhythmias. Atrial arrhythmias and ventricular arrhythmias could predict severity and mortality, their odds ratios (OR) were 4.45 (95% confidence interval [CI] 2.35 to 8.40), 5.80 (95% CI 1.89 to 17.76) respectively for severity, and were 3.51 (95% CI 1.74 to 7.08), 3.41 (95% CI 1.13 to 10.24) respectively for mortality. High levels of interleukin-6 (IL-6) and IL-10 were associated with the occurrence of arrhythmias (all p < 0.05). CONCLUSION: Arrhythmias were significantly associated with COVID-19 severity and mortality. Atrial arrhythmia was the most frequent arrhythmia type. IL-6 and IL-10 levels can predict the risk of arrhythmias in COVID-19 patients.

Introduction An outbreak of coronavirus disease 2019 , caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first reported in December 2019. [1] The number of deaths due to COVID-19 far exceeded the death toll of severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS). [2] [3] [4] Cardiovascular complications have been identified as common risk factors for disease severity and mortality in patients with COVID-19. [1, [5] [6] [7] [8] [9] The most common cardiovascular complications related to SARS-CoV-2 infection include arrhythmias, cardiac injury, myocarditis, and heart failure. [1] Arrhythmias were identified as aggravating factors in patients with COVID-19 and were more frequent among patients in intensive care units (ICU). [8] However, the prevalence of arrhythmia in patients with COVID-19 and their implications in COVID-19 severity and mortality remain unclear. In this study, we retrospectively investigated the prevalence and clinical relevance of different types of arrhythmias in COVID-19 patients.

2020, to March 19, 2020 , were enrolled in the study. COVID- 19 

The electronic medical records, including clinical charts, nursing records, laboratory findings, 12-lead ECGs, and ECG monitoring for all patients diagnosed with COVID-19, were reviewed by two trained cardiologists who worked in Wuhan Union Hospital West Campus.

Demographic, clinical, laboratory, and ECG data were collected using standardized data collection forms. Cases without available medical records or 12-lead ECG recordings were excluded.

paroxysmal supraventricular tachycardia), ventricular arrhythmias (premature ventricular beats, ventricular tachycardia, and ventricular fibrillation), and conduction block. Conduction block cases included incomplete right bundle branch block (RBBB), complete RBBB, complete left bundle branch block, left anterior fascicular block, left posterior fascicular block, first-degree atrial ventricular block (AVB), second-degree AVB, and third-degree AVB. We analyzed patients' clinical laboratory findings throughout the course of the disease.

The sampling points were the highest or lowest points of laboratory examination results, and the time point to judge the disease severity is consistent with the sampling point.

Categorical variables were expressed as percentages, and continuous variables were given as medians and interquartile range (IQR). Categorical variables were compared using the  2 test or Fisher's exact test, as appropriate. Continuous variables were analyzed using the Kolmogorov-Smirnov test for distribution normality; normally distributed data were compared using the t-test, and not normally distributed data were analyzed using the Mann-Whitney U test. Survival curves were plotted using the Kaplan-Meier method, and differences among groups were determined using the log-rank test. Multivariable analysis was conducted using binary logistic regression with disease severity and clinical outcomes as dependent variables. Statistical analyses were performed using SPSS version 22.0 (IBM), and a two-sided p <.05 was considered significant. To eliminate type I error, we adjusted p values using Bonferroni correction for multiple comparisons. 

In total, 470 patients with COVID- 19 The time between symptom onset or admission and end of follow-up did not differ significantly between the two groups . Several comorbidities were more frequent in patients with arrhythmias than in those without arrhythmias; these comorbidities included suggesting an association between arrhythmias and adverse COVID-19 outcomes.

Consistently, patients with arrhythmias were more likely to develop heart failure during hospitalization than did patients without arrhythmias (29 [34.12%] vs. 33 [8.73%]; p < 0.001).

Moreover, the all-cause mortality rate was higher in patients with arrhythmias than in those without arrhythmias (22 [25.9%] vs. 38 [10.1%]; p < 0.001). Survival analyses showed that arrhythmias were associated with a high mortality rate (p < 0.001; Figure 1A ). Furthermore, arrhythmias at admission were associated with an increased risk of death in patients with COVID-19 (p < 0.001; Figure 1B ). Table 2 The relationship between disease severity, clinical outcomes, and arrhythmias was evaluated by binary logistic regression analysis, and the results are presented in Table 3 and   Table 4 . Notably, atrial arrhythmias and ventricular arrhythmias were significantly associated with a high risk of severe COVID-19 and death during hospitalization. Regarding COVID-19 severity, the adjusted odds ratios (ORs) for atrial arrhythmias and ventricular arrhythmias respectively. As for death during hospitalization, the adjusted OR for atrial arrhythmias was 3.51 (95% CI, 1.74 to 7.08), and that for ventricular arrhythmias was 3.41 (95% CI, 1.13 to 10.24). We also performed binary logistic regression analysis to evaluate the clinical relevance of atrial and ventricular arrhythmia subtypes, including premature atrial beats Inflammatory cytokine analyses were performed in 328 patients. Patients were divided based on cytokine levels into the following groups: group 1 (normal), group 2 (less than two times elevated compared to the upper limit of normal), group 3 (two to four times elevated compared to the upper limit of normal), group 4 (more than four times elevated compared to the upper limit of normal). The relationship between cytokine levels and different types of arrhythmias is presented in Figure 2 . High levels of IL-10 were significantly associated with the incidence of arrhythmias. Atrial arrhythmias and ventricular arrhythmias were significantly more frequent in patients with elevated IL-10 levels than in those with physiological IL-10 levels ( Figure 2B-C) . Additionally, patients with a four times elevated level of IL-6 were more likely to experience atrial arrhythmias when compared with patients with a less than two times elevated level of IL-6 (all p < 0.05; Figure 2B ). 

In this retrospective study, we comprehensively analyzed the incidence and clinical relevance of different types of arrhythmias in patients with COVID-19. Previous studies reported that arrhythmias occurred in 4.3%~16.7% of patients infected with SARS-CoV-2. [8, 10] In line with these reports, we found that 18.4% of patients with COVID-19 experienced arrhythmias, with atrial arrhythmias being the most frequent. Previous studies showed that patients with pneumonia developed new-onset AF. [11] It can not be ruled out that pneumonia may affect the function of the adjacent atrium, causing atrial arrhythmias.

Mounting evidence shows a link between cardiac injury, hypoxemia, inflammation, and cardiac arrhythmias. SARS-CoV-1 has been shown to directly damage cardiomyocytes and the cardiac conduction system. [12] Arrhythmias have also been reported in patients diagnosed with SARS. The effects of SARS-CoV-2 and SARS-CoV-1 on the cardiovascular system may be similar because they are highly homologous. Thus, patients with COVID-19 may develop arrhythmias due to damage to the cardiac conduction system. COVID-19 is characterized by dyspnea, and hypoxemia was reported in 36.4% of COVID-19 cases. [13] [14] 

demonstrated that IL-6 and IL-10 were significantly elevated in patients with severe COVID-19. [17] Xu et al. [18] reported that tocilizumab, a monoclonal antibody targeting the IL-6 receptor, improved clinical symptoms in patients with COVID-19. Of note, it has been found that the release of inflammatory cytokines was correlated with lethal SARS-CoV-1. [19] Hence, inflammation is likely to contribute to deterioration and death in COVID-19 patients.

Our findings suggest that arrhythmias are significantly associated with critical illness and mortality in patients with COVID-19. Consistently, recent studies showed a higher incidence of arrhythmias in critically ill patients with COVID-19. [10, 20] In addition, a meta-analysis demonstrated that patients with COVID-19 experiencing arrhythmias had an increased risk of poor outcomes. [21] Here, we analyzed the effects of different types of arrhythmias and found atrial and ventricular arrhythmias to increase the risk of COVID-19 severity and mortality.

Patients with COVID-19 and who developed life-threatening arrhythmias, such as AT/AF or VT/VF, had unfavorable outcomes. Therefore, patients with COVID-19 should be closely monitored for arrhythmias and treated, if necessary. Many medications used to treat the symptoms caused by SARS-CoV-2 infection have been shown to affect cardiac electrophysiological activity. [22] Hence, arrhythmias should be taken into account for deciding OR, odds ratios. 95% CI, 95% confidence interval. PABs, premature atrial beats; AT/AF, atrial tachycardia/atrial fibrillation/atrial flutter; PVBs, premature ventricular beats; VT/AF, ventricular tachycardia/ventricular fibrillation. 

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