key: cord-299082-s8bm40vy
authors: Wang, Yueying; Wang, Zhaojia; Tse, Gary; Zhang, Lin; Wan, Elaine Y.; Guo, Yutao; Lip, Gregory Y. H.; Li, Guangping; Lu, Zhibing; Liu, Tong
title: Cardiac arrhythmias in patients with COVID‐19
date: 2020-07-26
journal: J Arrhythm
DOI: 10.1002/joa3.12405
sha: 
doc_id: 299082
cord_uid: s8bm40vy

The emergence of coronavirus disease 2019 (COVID‐19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has become a major global public health concern. Although SARS‐CoV‐2 causes primarily respiratory problems, concurrent cardiac injury cannot be ignored since it may be an independent predictor for adverse outcomes. Cardiac arrhythmias are often observed in patients with COVID‐19, especially in severe cases, and more likely contribute to the high risk of adverse outcomes. Arrhythmias should be regarded as one of the main complications of COVID‐19. Mechanistically, a number of ion channels can be adversely affected in COVID‐19, leading to alterations in cardiac conduction and/or repolarization properties, as well as calcium handling, which can predispose to cardiac arrhythmogenesis. In addition, several antimicrobials that are currently used as potential therapeutic agents for COVID‐19, such as chloroquine, hydroxychloroquine and azithromycin, have uncertain benefit, and yet may induce electrocardiographic QT prolongation with potential ventricular pro‐arrhythmic effects. Continuous electrocardiogram monitoring, accurate and prompt recognition of arrhythmias are important. The present review focuses on cardiac arrhythmias in patients with COVID‐19, its underlying mechanisms, and proposed preventive and therapeutic strategies.

severity and fatal outcomes. [4] [5] [6] [7] A variety of pro-inflammatory mediators play a key role in the pathophysiology of cardiac complications in COVID- 19 . Previous work has identified that ARDS (20%), arrhythmias (17%), shock (9%), and acute cardiac injury (7%) are common compilations in COVID-19. 1 Therefore, a better understanding of cardiovascular effects in SARS-CoV-2 infection is essential to mitigate poor prognosis in patients with COVID- 19 . The aim of this study is to conduct a comprehensive review of published studies on the electrophysiological effects of COVID-19. This is followed by a discussion on the underlying mechanisms, with proposals of preventative and therapeutic strategies for treating cardiac arrhythmias in COVID-19 patients.

The clinical course of SARS-CoV-2 infection is mostly characterized by respiratory tract symptoms, including fever, cough, pharyngodynia, fatigue, and complications related to pneumonia, such as acute respiratory distress syndrome and shock. Nevertheless, a brief case reported by Inciardi et al 8 Several studies have proved that SARS-CoV-2 infection can induce cardiac injury. Previous studies defined cardiac injury as the serum levels of cardiac biomarkers (eg, troponin I) were above the 99th percentile upper reference limit. 1, 2, 9 Huang et al 2 first reported a 12% (5/41) incidence of acute cardiac injury in patients with COVID-19. A series of subsequently published studies confirmed the previous findings, the incidence of cardiac injury ranged from 7.2% to 28%. 1, 2, 6, 7, 10, 11 Moreover, the incidence of myocardial injury was higher in severe and critical cases, which ranged from 22% to 44%, 1, 2, 9, 12 compared to an incidence of approximately 2% to 4% 1, 2 in less severe cases. Death cases (28% to 89%) had a conspicuously higher risk of cardiac damage than survivors (1% to 15%). 5, 6, 9, 10, [12] [13] [14] [15] Several investigators have reported cardiac function and structural abnormalities in patients with SARS-CoV-2 infection, including acute heart failure (HF), 3,10,16 takotsubo syndrome, 17 ,18 viral myocarditis, 19 and acute myocardial infarction. 10 

Full-genome sequencing and phylogenic analysis indicated that SARS-CoV-2 has features typical of the coronavirus family and distinct classified in the beta-coronavirus, belongs to the same genus as human severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV).

In patients with SARS, tachycardia was the most common ECG abnormalities but usually self-limiting, the incidence ranged from 72% 22 ; bradycardia was relatively less common, ranged from 2% to 15%. [22] [23] [24] ST-T changes and cardiac arrhythmias such as branch block, atrial fibrillation (AF), premature beats, QT interval prolongation, or even sudden cardiac death (SCD) were also seen in SARS patients. 22 had arrhythmia, 14 in addition, cardiac arrhythmias were independently associated with an increased risk of in-hospital death (11.5%, vs 5.6% among those without arrhythmia; odds ratio, 1.95; 95% CI, 1.33-2.86). 31 Thus, arrhythmia should be regarded as one of the main complications of COVID-19, and proactive arrhythmia monitoring and management is needed.

COVID-19 patients have relatively increased fast heart rates (HR) ranging from 80 to 88 beats per minute (bpm) in sinus rhythm. 1, 5, 20, 32 HR in patients treated in the ICU was faster than whom admitted in the general ward. 1 Nonsurvivors showed significantly faster baseline heart rates on admission compared to survivors. 10 Another study documented heart rate in 17 COVID-19 patients, and tachycardia was found in three patients (17.6%), one of those was a severe case, and two were critical cases. 33 among them, atrial fibrillation in 12 patients, atrial flutter in 6 patients, and atrial tachycardia in 1 patient. 34 Atrial tachyarrhythmias were common among patients with COVID-19 who required admission to an intensive care unit and were often followed by hemodynamic deterioration.

In short, we have to pay attention to the tachycardias in the severe and critical COVID-19 patients. In addition to exacerbating the previous cardiomyopathy and conduction disorders, inducing arrhythmia events, SARS-CoV-2 may also induce electrophysiological abnormalities in patients with no previous history of heart disease under a variety of mechanisms.

Our recent work reported that the incidence of cardiac arrhythmias in COVID-19 patients ranged from 17% to 30%. 1,20 Among these, atrioventricular/ventricular block (11.8%) was the highest incidence in arrhythmia, and the ratio exceeded sinus tachycardia (7.5%), sinus bradycardia (8%), atrial arrhythmias (7%), and ventricular arrhythmias (4%). 20 Complete heart block and severe left ventricular dysfunction were developed in a Child with COVID-19 Infection. 35 Another case from Iran also reported transient complete heart block in a patient with COVID-19, 36 and a 21-year-old female patient' ECG showed nonspecific intraventricular conduction delay and multiple premature ventricular complexes. 19 

In our report, ST-T changes were the most common ECG abnormality in COVID-19 patients, accounting for about 41% (38/93). Five of these patients were diagnosed with acute myocardial infarction (AMI). 20 A recent case series showed 18 patients with COVID-19 who had ST segment elevation in ECG, 13 (72%) patients died in the hospital (acute ST segment elevation myocardial infarction: n = 4; noncoronary myocardial injury: n = 9). 21 A 61-year-old Hispanic male presented with a Brugada-type pattern ECG in right precordial leads, 2 days later he developed a brief episode of atrioventricular nodal reentrant tachycardia (AVNRT). 37 A patient finally died within 24 hours of the occurrence of multifocal ventricular tachycardia (VT) and ST segment elevation. 38 

Our study found a proportion of 13% (12/93) COVID-19 patients had prolonged QT interval, mean QT interval was 431 milliseconds (414-454 milliseconds). 20 QT prolongation has previously been described associated with various conditions (eg, inherited arrhythmia syndromes, myocarditis toxicity, metabolic disorders, certain drugs).

Several antimicrobials that are currently used as potential therapeutic agents for COVID-19 have uncertain benefit, and yet may induce electrocardiographic QT prolongation with potential ventricular pro-arrhythmic effects. These agents are chloroquine (CQ), hydroxychloroquine (HCQ), azithromycin, and lopinavir/ritonavir. 39 Recent evidence indicates significant QT prolongation in patients with COVID-19 receiving HCQ. 40 For example, Borba and colleagues 41 performed a parallel, double-blind, randomized clinical trial designed to assess the safety of CQ in dosages, they found that prolongation of QTc interval was observed in 4 of 36 patients (11.1%) in the low-dose group (ie, 450 mg twice daily on day 1 and once daily for 4 days) and 7 of 37 patients (18.9%) in the high-dose group (ie, 600 mg CQ twice daily for 10 days); in addition, 2 patients in the highdose group (2.7%) experienced ventricular tachycardia, 60% (3/5) patients in the high-dose group with underlying heart disease died. Moreover, the patients who received HCQ with concurrent treatment of azithromycin were at high risk of greater changes in QTc, 42 12% of them manifested critical QTc prolongation, and the combination caused greater prolongation than either drug alone. 43 Chorin et al 44 observed QTc prolongation from a baseline average of 435 ± 24 milliseconds to 463 ± 32 milliseconds (P < .001), which was observed 3.6 ± 1.6 days after administration of HCQ + azithromycin therapy. In a subset of those patients (9/84, 11%), QTc was severely prolonged to >500 milliseconds, a known ECG marker of high risk of malignant arrhythmia and sudden cardiac death. 44 A greater proportion of patients receiving HCQ+azithromycin experienced cardiac arrest (15.5%) and abnormal ECG findings (27.1%), as did those in the HCQ alone group (13.7% and 27.3%, respectively), compared with azithromycin alone (6.2% and 16.1%, respectively). 45 Certain antifungal drugs, glucocorticoids and certain antiarrhythmic drugs lead to prolonged QT intervals as well. If these medications are used, clinicians should monitor the patient for side effects, especially prolonged QTc interval by continuous ECG monitoring. 

A summary of the potential mechanisms by which cardiac arrhythmias occur in SARS-COV-2 infections is shown in Figure 1 . 50 We speculate that an analogous mechanism may operate in cardiomyocytes. Previous tissue visualization has revealed irregular shape of the myocardium, darkened cytoplasm, mild fibrosis, and mild hypertrophy of the myocardium. 51 the type of reactive oxygen species, thereby prolonging APD. 49, 63 In addition, TNF-α also reduced I CaL , intracellular calcium transients.

Moreover, TNF-α may reduce the expression of SERCA2a by inducing the level of DNA methyltransferase. 64 Therefore, TNF-α signaling is also an important inflammatory factor leading to arrhythmia.

Patients with COVID-19 often present with fever. In the patients with some underlying heart diseases, fever can trigger ventricular fibrillation. 65, 66 It may be related to ion channel mutations, such as SCN5A in Brugada syndrome. 64 Besides, abnormal sodium current also plays an important role. 67, 68 In addition, fever can cause tachyarrhythmias in individuals without inherited heart disease. Its presence may alter the efficacy of sodium channel blockers in terms of their antiarrhythmic effects. 69 SARS-COV-2 may induce myocardial injury by inhibiting the activity of ACE2. It is thought that ACE2 could be internalized and shed from the membrane surface diminishing function of ACE2 when SARS-COV-2 binding to ACE2 to enter cells. 68 The conversion of angiotensin II (Ang II) to Ang (1-7) may be reduced, which weakens the cardiovascular protection effect of Ang (1-7) through the Mas receptor. 70, 71 For example, Ang1-7 could change I CaL , Ito, expression of Kv4.3 potassium channel, and Ca 2+ channel to prevent AF ionic remodeling. 72 Besides, Ang II induces automatic activities by activating IP₃ receptors and Na⁺-Ca 2+ exchanger in guinea pig pulmonary vein myocardium. In addition, chronic Ang II exposure induces ROS production by NOX2 resulting in oxidative activation of CaMKII, further promotes SR-Ca 2+ leakage, thus increasing the possibility of delayed after depolarization (DAD). 73 Ang II induces membrane depolarization and activation of I CaL. 74 The accumulation of Ang II promotes myocardial fibrosis and cardiac remodeling. These will promote the occurrence of arrhythmias.

Many patients have disorders of coagulation and fibrinolytic system, showing hypercoagulability of blood, and even disseminated intravascular coagulation (DIC). 75 The effects of hypercoagulation on the myocardium, such as acute coronary syndrome, 76 will be ischemia and hypoxia, leading to cardiac electrophysiological abnormalities. It has been changed that Na + -Ca 2+ exchange, I K current, and phosphorylation of proteins in the sarcoplasmic reticulum. 77, 78 Next, early and late depolarization, inducing ectopic beats, and the APD changed. All these will promote the development of reentrant arrhythmias such as malignant ventricular arrhythmia. 64, 77 In addition, acute left atrial ischemia led to ATP-sensitive potassium current (IKATP) conductor-dependent shortened APD, as well as spontaneous focal discharges and reentry loops. 79 Chronic atrial ischemia/ infarction promoted atrial fibrillation by unprompted ectopy and sustained reentry. 80 Administration of certain drugs may affect the electrophysiological properties of the myocardium. For example, the recently controversial CQ and HCQ can cause prolongation of QT interval.

In sinoatrial node (SAN) myocytes, HCQ decreased spontaneous action potential firing rate and the "funny" current (I f ), and it also affected I CaL and I Kr . 81 These changes caused a delay in the depolarization, thus lowering the heart rate. 76, 82 In addition, azithromycin can also affect the occurrence of AP promoting arrhythmias in cardiomyocytes. It is reported that azithromycin can inhibit I CaL , I Na , and I Kr current, causing bradyarrhythmia. 83 However, azithromycin can increase I Na currents in cardiomyocytes with chronic (24 hour) exposure. 84 Moreover, azithromycin promoted the production of reactive oxygen species in cardiomyocytes, mitochondrial damage, 85 inducing cardiac dysfunction and eventually arrhythmia occurs.

Together, a number of ion channels can be adversely affected in COVID-19, leading to alterations in cardiac conduction and/or repolarization properties, as well as calcium handling, which can predispose to cardiac arrhythmogenesis.

Clinicians should be vigilant of potential rhythm disturbances in COVID- 19 . Palpitation has been reported as the initial symptom in 7% (10/137) of COVID-19 patients. 86 Around 4% of COVID-19 patients have a prior history of cardiac arrhythmias and may be particularly susceptible to further rhythm disorders. 87 

Outbreaks of COVID-19 threaten public health but the associated extrapulmonary manifestations and their prolonged consequences are often overlooked. Previous reports reveal that cardiac arrhythmias are one of the common complications associated with COVID-19, which may sometimes be life-threatening. We would suggest that front-line clinicians monitor cardiac rhythm as part of the routine care, and the data may shed light on whether COVID-19-related arrhythmic complications is an independent predictor of adverse outcomes. Early diagnosis and timely treatment to reduce mortality is of crucial importance. Herein, we summarize potential pharmacological and interventional strategies for dealing with such problem. Several medications are currently being tested for their antiviral actions, with potential side effects such as QT prolongation.

The authors declare no conflict of interest.

Not required. 

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