In December 2019, a novel viral infection arose in Wuhan, China, which then spread worldwide within several weeks. The infection was subsequently termed coronavirus disease-2019 (COVID- 19) and declared a pandemic by the World Health Organization by March 2020. Most infected patients are asymptomatic or mild symptomatic, but approximately 15-20% develop acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The effects of SARS-CoV-2 on the heart are variable, but cardiac damage confers a worse prognosis, whether in the presence or absence of pre-existing cardiovascular disease 1, 2 . Cardiac complications related to COVID-19 can be categorized into five types: a) cardiac injury (mainly due to ischemia or myocarditis); b) arrhythmia; c) new-onset or worsening of preexisting heart failure; d) thromboembolic disease; and e) cardiac abnormalities induced by medical treatment 3 .
In this setting, the electrocardiogram (ECG) is one of the leading tools to assess the extent of cardiac involvement in COVID-19 patients and the effect of medications, due to its wide accessibility, low cost, and the possibility of remote evaluation. Therefore, we proposed a review on the role of the ECG in the identification of cardiac involvement in and highlighted relevant clinical implications.
Overview Cardiac involvement in patients with COVID-19 is reflected in ECG alterations, such as ST changes, QT prolongation, conduction disturbances, and ventricular arrhythmias 4 . Therefore, patients presenting with cardiac symptoms and ECG changes should be carefully assessed in order to diagnose COVID-19 related cardiac complications such as myocarditis, brady-and tachyarrhythmias (Figure 1 ).
In the era of the COVID-19 pandemic, a high clinical suspicion should be maintained even in patients who present with atypical symptoms or signs. Furthermore, cardiovascular disease has been found to be associated with a worse prognosis [5] [6] [7] [8] . It should be stressed that the virus should not be considered as the cause of all cardiovascular complications, but may exacerbate or reveal underlying conditions 9, 10 . However, more studies are needed to further clarify the role of the cardiovascular system in the COVID-19 pandemic 11 .
Non-specific ECG findings reported in COVID-19 patients have been attributed to hypoxia or inflammatory damage. This includes a patient with SI, QIII, TIII pattern followed by a reversible but near-complete atrioventricular block, ST-segment elevation accompanied with multifocal ventricular tachycardia 4 , and flattening of the T-waves in the inferior leads with right axis deviation. The SIQIIITIII pattern was observed in another patient whose infection was complicated by pulmonary embolism 12 . It should be noted that the SIQIIITIII pattern suggests acute right ventricular overload. In a case series of patients with COVID-19 related complications, premature atrial complexes, lateral T wave inversions, and a QTc interval of 528 ms were noted in a patient who presented with decompensated heart failure 13 .
In a heart transplant recipient, sinus rhythm with new nonspecific T-wave inversions in the inferior and lateral precordial leads was seen 13 . In light of these published case reports and with the lack of further evidence, we propose that ST-T wave abnormalities, especially in the context of a cardiac-related clinical presentation, should lead to further investigations to exclude COVID-19 related cardiac complications during the current pandemic. ST-T wave abnormalities are useful especially when they develop during the course of a febrile disease and not to exclude but to demonstrate cardiac involvement, and especially without an evident context of cardiac-related clinical presentation. 
Cardiac arrhythmias have been reported in 16.7% of COVID-19 patients, while malignant arrhythmias have been reported in 11.5% of patients 1, 20 . In a recent study of 138 hospitalized patients with COVID-19, cardiac arrhythmias represented a leading complication and were more common among critically ill patients 20 . Another study found a higher incidence of arrhythmias in patients with severe disease than those with mild disease (44.4% versus 6.9%, p<0.001) 21 . There have also been reports of critically ill patients with COVID-J o u r n a l P r e -p r o o f Journal Pre-proof 19 experiencing cardiac arrest with pulseless electrical activity or ventricular arrhythmias during the recovery phase of their pulmonary condition 22 . Among 187 hospitalized patients with confirmed COVID-19, 5.9% of the patients experienced malignant arrhythmias, including ventricular tachycardia and fibrillation 1 . Additionally, critically ill COVID-19 patients with fever were observed to have a slower heart rate than expected 20, 23 . Bradycardia prolongs the QT interval and could facilitate Torsades de Pointes (TdP). Furthermore, QT prolongation secondary to antiviral therapies can also predispose patients to ventricular arrhythmias 24 . Although arrhythmias cannot be considered as a marker of COVID-19 infection, they can be a useful prognostic marker. Of note, patients with preexisting cardiovascular disease admitted to the intensive care unit for COVID-19-related illnesses may have a worse prognosis 20 .
Given the preliminary nature of the available literature, the difference in the incidence of arrhythmia amongst recovering critical patients, and patients with mild disease, has not yet been well delineated. As more data become available, an improved understanding of the pathophysiology and significance of arrhythmia in patients with COVID-19 will guide the recommendations for possible additional rhythm monitoring in an outpatient setting.
Proper ECG diagnosis of atrial fibrillation (AF) is important for COVID-19 patients.
It is not clear whether the presence of AF will alter the prognosis of COVID-19 patients.
However, there have been speculations on the mechanism of AF in COVID-19. For instance, hypoxemia caused by COVID-19 may bring about AF and could be refractory under impaired pulmonary function. A plausible mechanism of AF reduction is the inhibition of I K1 and I KACh channels 25 .
QT interval measurement J o u r n a l P r e -p r o o f
Leads II or V5-V6 are recommended for the measurement of the QT interval. The QT interval should always be corrected according to the heart rateemploy Bazett's formula for correction if the heart rate is less than 90 beats per minute or Fridericia's in the case of higher heart rates. The end of the T-wave should be taken as the intersection between the tangent extrapolated from the point of maximum downslope and the isoelectric line.
QT prolongation and subsequent ventricular arrhythmias have been associated with the use of hydroxychloroquine/chloroquine (HCQ/CQ), azithromycin (AZ), and antivirals such as lopinavir/ritonavir ( Table 1) , or in COVID-19 patients with pre-existing hepatic disease or renal failure [26] [27] [28] . Although cases of QT prolongation and TdP due to HCQ/CQ have been reported, data on QT prolongation due to HCQ/AZ are contradictory. Chang et al.
found that of 117 patients with COVID-19, only one patient experienced QT prolongation, in which case the medication was promptly discontinued 29 . However, in another cohort, 11% of patients developed QT prolongation, amongst which half of those patients had normal QT level at baseline 30 . This discrepancy can be explained by the heterogeneity of the patient cohort, such as the presence of comorbidities and varying disease severity. In the largest reported cohort of COVID-19 patients to date treated with HCQ/CQ ± AZ, no instances of TdP or arrhythmogenic death were reported. Although the use of these medications resulted in QT prolongation, clinicians seldom needed to discontinue therapy 31 . AZ is also known to have an increased risk of QT prolongation, TdP, and sudden cardiac death; however, the absolute risk is low 32, 33 . Table 2) . Taken together, they have the following points in common:
• Before considering any treatment, conduct a clinical history focused on a prior history of heart disease, syncope, sudden cardiac death, comorbidities, and generate a list of home medications.
• Identify and correct potentially modifiable risk factors for the prolongation of the QT interval ( Table 3) .
It should be noted that these guidance documents vary in their ECG-related recommendations. Some recommend that all patients receive a baseline and repeat ECG 36 , whereas others have reserved this recommendation for higher-risk populations 22, 38 .
The risk stratification of COVID-19 patients should be performed based on their preexisting diseases since their prognosis varies greatly based on their underlying comorbidities. High-risk patients should be monitored more closely, in particular through the use of an ECG, than those who are otherwise healthy (Figure 2) . We propose the following c) Patients on multiple drugs that may cause QT prolongation and an increased risk of malignant arrhythmias: It is important to note that combining more than one proarrhythmic medication is known to increase the risk of significant QT prolongation 45 . Therefore, medications should be reviewed, and unnecessary medications with QT-prolonging effects should be discontinued. Interestingly, amiodaroneas a medication that can potentially prolong the QT intervalhas been suggested as a possible inhibitor against the spreading of SARS-CoV-2 due to its ability to interfere with the endocytic pathway 46 Critically ill COVID-19 patients will likely be at a higher clinical risk of drug-induced arrhythmia, in which case ECG monitoring will more likely be indicated for supportive medical care. Patients with pre-existing structural heart disease pose a high risk of developing malignant arrhythmia; therefore, ECG should be assessed and monitored regularly before and during the initiation of COVID-19 related pharmacotherapy.
ECG monitoring is advisable especially when patients experience electrolyte disturbances and use concomitant QTc-prolonging drugs 47 . Therefore, ECG monitoring upholds a critical role in patient safety during the dose adjustment of medications used in the management of COVID-19. In an outpatient setting, mobile devices such as the KardiaMobile 6L (AliveCor, Mountain View, California) and the Apple Watch ECG (Apple, Cupertino, California) have shown to be effective in monitoring the QTc interval 48, 49 . In a recent study, the QTc interval in leads I and II from a handheld ECG device and 12-lead ECG were compared across 99 healthy volunteers, and 20 hospitalized patients in sinus rhythm treated with dofetilide or sotalol 50 . The handheld ECG device was accurate in the measurement of QTc interval for both patients with sinus rhythm and QT prolongation 50 . In cases with limited resources or quarantine, the Kardia6L systemwhich has received J o u r n a l P r e -p r o o f Journal Pre-proof expedited US Food and Drugs Administration clearancecould be used to deduce the risk status before initiation of drug therapy.
In the era of the SARS-CoV-2 pandemic, COVID-19 should be considered as a differential diagnosis for new or presumably new electrocardiographic abnormalities accompanied by a clinical presentation indicative of potential cardiac involvement. However, further studies with a systematic approach in the measurement of ECG parameters are needed to elucidate the potential role of ECG in myocardial injury diagnosis and risk stratification of COVID-19 patients. -Review and discontinue unnecessary QT-prolonging medications -For patients with a previous history of TdP or Long QT, the J o u r n a l P r e -p r o o f Journal Pre-proof use of potential COVID-19 therapies should be undertaken after expert consultation -For patients with no previous history or precipitating factors, it may be reasonable to proceed with antimicrobial drug without baseline or follow-up ECG if it would increase population risk of infection -Hospitalized patients or those not fulfilling the above criteria:
-ECG to assess QTc if not performed within the past 3 months; -If QTc ≥500 ms, reassess after correction of electrolyte abnormalities or discontinuation of other QT-prolonging drugs. Seek expert consultation if QTc remains ≥500 ms; -If QTc ≥470 ms for males or ≥480 ms for females by <500 ms, initiate antimicrobial drugs and consider repeat ECG in 48 hours; -In patients with clinically severe disease or taking multiple QT-prolonging medications, recheck QT after 48 hours of antimicrobial drug initiation; -If follow-up QTc increases ≥60 ms or is ≥500 ms, discontinue antimicrobial drugs and seek expert opinion 