Electrocardiographic features of patients with COVID-19: One year of unexpected manifestations

Published:October 14, 2021DOI:https://doi.org/10.1016/j.ejim.2021.10.006

      Keywords

      1. Introduction

      Coronavirus Disease 2019 (COVID-19) is the clinical manifestation of infection with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) [
      • Cheng Z.J.
      • Shan J.
      2019 Novel coronavirus: where we are and what we know.
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      • Angeli F.
      • Zappa M.
      • Reboldi G.
      • Trapasso M.
      • Cavallini C.
      • Spanevello A.
      • Verdecchia P.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection: one year later.
      ]. COVID-19 is frequently characterized by symptoms and signs of respiratory tract infection which may progress to pneumonia, acute respiratory distress syndrome (ARDS) and shock. [
      • Cheng Z.J.
      • Shan J.
      2019 Novel coronavirus: where we are and what we know.
      ,
      • Yang W.
      • Cao Q.
      • Qin L.
      • Wang X.
      • Cheng Z.
      • Pan A.
      • Dai J.
      • Sun Q.
      • Zhao F.
      • Qu J.
      • et al.
      Clinical characteristics and imaging manifestations of the 2019 novel coronavirus disease (COVID-19):A multi-center study in Wenzhou city, Zhejiang, China.
      ,
      • Brussow H.
      The Novel Coronavirus - A Snapshot of Current Knowledge.
      ] Thus, much of the focus has been on the respiratory system.
      Nonetheless, COVID-19 can also cause a variety of cardiovascular complications including myocardial injury, myocarditis, acute myocardial infarction, stress cardiomyopathy, heart failure, dysrhythmias, and thromboembolic events [
      • Long B.
      • Brady W.J.
      • Koyfman A.
      • Gottlieb M.
      Cardiovascular complications in COVID-19.
      ,
      • Sandoval Y.
      • Januzzi J.L.
      • Jaffe A.S.
      Cardiac Troponin for Assessment of Myocardial Injury in COVID-19: JACC Review Topic of the Week.
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • Xiang J.
      • Wang Y.
      • Song B.
      • Gu X.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ]. In this context, standard electrocardiography (ECG) showed to be a crucial test in the diagnosis of cardiac complications in patients with SARS-CoV-2. A study of 756 patients hospitalized with COVID-19 in New York, documented a range of COVID-19-related ECG findings including atrial fibrillation (5.6%), atrial and ventricular premature beats (7.7% and 3.4%, respectively), right bundle branch block (7.8%), left bundle branch block (1.5%), T-wave inversion (10.5%), and nonspecific repolarization abnormalities (29.0%) [
      • McCullough S.A.
      • Goyal P.
      • Krishnan U.
      • Choi J.J.
      • Safford M.M.
      • Okin P.M.
      Electrocardiographic Findings in Coronavirus Disease-19: Insights on Mortality and Underlying Myocardial Processes.
      ]. These manifestations are believed to be the result of several pathogenetic mechanisms including cytokine and Angiotensin II storms, activation of coagulation cascade, hypoxic injury, endothelial and myocardial injuries, and atherosclerotic plaque destabilization and rupture [
      • Long B.
      • Brady W.J.
      • Koyfman A.
      • Gottlieb M.
      Cardiovascular complications in COVID-19.
      ,
      • Angeli F.
      • Marazzato J.
      • Verdecchia P.
      • Balestrino A.
      • Bruschi C.
      • Ceriana P.
      • Chiovato L.
      • Dalla Vecchia L.A.
      • De Ponti R.
      • Fanfulla F.
      • et al.
      Joint effect of heart failure and coronary artery disease on the risk of death during hospitalization for COVID-19.
      ,
      • Long B.
      • Brady W.J.
      • Bridwell R.E.
      • Ramzy M.
      • Montrief T.
      • Singh M.
      • Gottlieb M.
      Electrocardiographic manifestations of COVID-19.
      ,
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection.
      ].
      Several evidences of uncommon ECG manifestations of COVID-19 have been recently accrued. A paper from our group [
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • Feci D.
      • Reboldi G.
      • Fabbri L.M.
      • Verdecchia P.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ] published in the 2020 August issue of the European Journal of Internal Medicine [
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • Feci D.
      • Reboldi G.
      • Fabbri L.M.
      • Verdecchia P.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ] was one of the first studies to report a wide spectrum of unexpected ECG features of COVID-19 which exhibited a late onset and mostly occurred after recovery from the acute phase. In patients hospitalized for COVID-19 pneumonia, we found a 6% incidence of atrial fibrillation, a 2% incidence of brady-tachy syndrome, a 2% incidence of persistent ST-T changes not associated with increase in troponin I levels nor pericardial effusion, and a 12% incidence of ST-T changes associated with acute pericarditis [
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • Feci D.
      • Reboldi G.
      • Fabbri L.M.
      • Verdecchia P.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ].
      The main aim of this narrative review was to explore incidence and pathogenesis of ECG features of COVID-19, with particularly emphasis to “unexpected” manifestations.
      Our review was performed according to standard methods. [
      • Haynes R.B.
      • Kastner M.
      • Wilczynski N.L.
      • Hedges T.
      Developing optimal search strategies for detecting clinically sound and relevant causation studies in EMBASE.
      ] We searched for eligible studies or case reports using research methodology filters [
      • Wong S.S.
      • Wilczynski N.L.
      • Haynes R.B.
      • Hedges T.
      Developing optimal search strategies for detecting clinically relevant qualitative studies in MEDLINE.
      ]. We used PubMed, Scopus, and Web of Science for literature searches. The following search terms were used: “ECG”, “electrocardiography”, “EKG”, “COVID-19″, “SARS-CoV-2″, and “coronavirus”.

      2. “Typical” ECG features of COVID-19 complications

      At the beginning of the pandemic, much attention has been focused on ECG features of “common” cardiovascular complications of SARS-CoV-2 infections [
      • Zheng Y.Y.
      • Ma Y.T.
      • Zhang J.Y.
      • Xie X.
      COVID-19 and the cardiovascular system.
      ,
      • Akhmerov A.
      • Marban E.
      COVID-19 and the Heart.
      ,
      • Clerkin K.J.
      • Fried J.A.
      • Raikhelkar J.
      • Sayer G.
      • Griffin J.M.
      • Masoumi A.
      • Jain S.S.
      • Burkhoff D.
      • Kumaraiah D.
      • Rabbani L.
      • et al.
      Coronavirus Disease 2019 (COVID-19) and Cardiovascular Disease.
      • Fried J.A.
      • Ramasubbu K.
      • Bhatt R.
      • Topkara V.K.
      • Clerkin K.J.
      • Horn E.
      • Rabbani L.
      • Brodie D.
      • Jain S.S.
      • Kirtane A.
      • et al.
      The Variety of Cardiovascular Presentations of COVID-19.
      ]. Several reports described “typical” features of COVID-19 complications including arrhythmias, ischemic ST-T abnormalities (spanning from acute coronary syndromes to Takotsubo syndrome), pulmonary embolism, acute heart failure, and myocarditis [
      • Zheng Y.Y.
      • Ma Y.T.
      • Zhang J.Y.
      • Xie X.
      COVID-19 and the cardiovascular system.
      • Fried J.A.
      • Ramasubbu K.
      • Bhatt R.
      • Topkara V.K.
      • Clerkin K.J.
      • Horn E.
      • Rabbani L.
      • Brodie D.
      • Jain S.S.
      • Kirtane A.
      • et al.
      The Variety of Cardiovascular Presentations of COVID-19.
      ]. Remarkably, ECG abnormalities are common, being present up to 93% of critically ill patients [
      • Bertini M.
      • Ferrari R.
      • Guardigli G.
      • Malagu M.
      • Vitali F.
      • Zucchetti O.
      • D'Aniello E.
      • Volta C.A.
      • Cimaglia P.
      • Piovaccari G.
      • et al.
      Electrocardiographic features of 431 consecutive, critically ill COVID-19 patients: an insight into the mechanisms of cardiac involvement.
      ]. For these conditions, interpretation of the ECG is unchanged from the non-COVID-19 patient [
      • Long B.
      • Brady W.J.
      • Bridwell R.E.
      • Ramzy M.
      • Montrief T.
      • Singh M.
      • Gottlieb M.
      Electrocardiographic manifestations of COVID-19.
      ].

      2.1 Sinus tachycardia

      It is the most common ECG manifestation overall in patients with COVID-19. It may reflect several underlying mechanisms including intrinsic sinus node hyperactivity, autonomic dysfunction and a hyperadrenergic state (fever, hypovolemia, hypoxia, pain, anxiety, and hypoperfusion) [
      • Olshansky B.
      • Sullivan R.M.
      Inappropriate sinus tachycardia.
      ]. Nonetheless, inflammatory cytokines released by patients with COVID-19 may affect the function of myocardial ion channels and perpetuate the sinus tachycardia [
      • Lazzerini P.E.
      • Laghi-Pasini F.
      • Boutjdir M.
      • Capecchi P.L.
      Cardioimmunology of arrhythmias: the role of autoimmune and inflammatory cardiac channelopathies.
      ]. As in the general population, other etiologies of sinus tachycardia should be considered (i.e. pulmonary embolism) [
      • Desai A.D.
      • Boursiquot B.C.
      • Melki L.
      • Wan E.Y.
      Management of Arrhythmias Associated with COVID-19.
      ].

      2.2 Atrial arrhythmias

      Atrial arrhythmias are the most commonly reported features in patients with COVID-19. Specifically, atrial fibrillation is commonly observed among COVID-19 patients (as detected in 19% to 21% of all cases) [
      • Gopinathannair R.
      • Merchant F.M.
      • Lakkireddy D.R.
      • Etheridge S.P.
      • Feigofsky S.
      • Han J.K.
      • Kabra R.
      • Natale A.
      • Poe S.
      • Saha S.A.
      • et al.
      COVID-19 and cardiac arrhythmias: a global perspective on arrhythmia characteristics and management strategies.
      ,
      • Inciardi R.M.
      • Adamo M.
      • Lupi L.
      • Cani D.S.
      • Di Pasquale M.
      • Tomasoni D.
      • Italia L.
      • Zaccone G.
      • Tedino C.
      • Fabbricatore D.
      • et al.
      Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy.
      ].
      The etiology of atrial arrhythmias remains to be fully elucidated. However, a reduction in angiotensin-converting enzyme 2 (ACE2) receptor availability, CD147- and sialic acid-spike protein interaction, enhanced inflammatory signaling, direct viral endothelial damage, metabolic derangements, electrolytes and acid-base balance abnormalities in the acute phase of COVID-19 have been suggested as putative mechanisms [
      • Gawalko M.
      • Kaplon-Cieslicka A.
      • Hohl M.
      • Dobrev D.
      • Linz D.
      COVID-19 associated atrial fibrillation: Incidence, putative mechanisms and potential clinical implications.
      ].
      For atrial fibrillation, it is worth mentioning that epicardial fat has been linked to atrial electrical remodeling and the progression of atrial fibrillation [
      • Friedman D.J.
      • Wang N.
      • Meigs J.B.
      • Hoffmann U.
      • Massaro J.M.
      • Fox C.S.
      • Magnani J.W.
      Pericardial fat is associated with atrial conduction: the Framingham Heart Study.
      ,
      • Thanassoulis G.
      • Massaro J.M.
      • O'Donnell C.J.
      • Hoffmann U.
      • Levy D.
      • Ellinor P.T.
      • Wang T.J.
      • Schnabel R.B.
      • Vasan R.S.
      • Fox C.S.
      • et al.
      Pericardial fat is associated with prevalent atrial fibrillation: the Framingham Heart Study.
      ]. Although it is likely that atrial fibrillation may be related to COVID-19 infection (systemic hyperinflammation, fever, hypoxia, adrenergic tone), the involvement of epicardial adipocytes (as demonstrated by ECG signs of pericarditis and development of pericardial effusion) during SARS-CoV-2 infection could predispose to the development of atrial fibrillation [
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • Feci D.
      • Reboldi G.
      • Fabbri L.M.
      • Verdecchia P.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ].

      2.3 Ventricular arrhythmias

      These arrhythmias may occur among COVID-19 patients with myocarditis, metabolic abnormalities, or treated with QT interval prolonging medications [
      • Long B.
      • Brady W.J.
      • Koyfman A.
      • Gottlieb M.
      Cardiovascular complications in COVID-19.
      ,
      • Long B.
      • Brady W.J.
      • Bridwell R.E.
      • Ramzy M.
      • Montrief T.
      • Singh M.
      • Gottlieb M.
      Electrocardiographic manifestations of COVID-19.
      ,
      • Kang Y.
      • Chen T.
      • Mui D.
      • Ferrari V.
      • Jagasia D.
      • Scherrer-Crosbie M.
      • Chen Y.
      • Han Y.
      Cardiovascular manifestations and treatment considerations in COVID-19.
      ].
      Abrams and co-workers reviewed demographics, laboratory and cardiac tests, medications, and cardiac rhythm proximate to death or initiation of comfort care for patients hospitalized with a positive SARS-CoV-2 reverse-transcriptase polymerase chain reaction in three New York City hospitals between March 1 and April 3, 2020. They documented that the last cardiac rhythm recorded was ventricular tachycardia or fibrillation in 5.3% of all cases [
      • Abrams M.P.
      • Wan E.Y.
      • Waase M.P.
      • Morrow J.P.
      • Dizon J.M.
      • Yarmohammadi H.
      • Berman J.P.
      • Rubin G.A.
      • Kushnir A.
      • Poterucha T.J.
      • et al.
      Clinical and cardiac characteristics of COVID-19 mortalities in a diverse New York City Cohort.
      ].
      Furthermore, life threatening ventricular arrhythmias are reported to be more common in patients with elevated serum levels of cardiac troponins [
      • Kang Y.
      • Chen T.
      • Mui D.
      • Ferrari V.
      • Jagasia D.
      • Scherrer-Crosbie M.
      • Chen Y.
      • Han Y.
      Cardiovascular manifestations and treatment considerations in COVID-19.
      ,
      • Guo T.
      • Fan Y.
      • Chen M.
      • Wu X.
      • Zhang L.
      • He T.
      • Wang H.
      • Wan J.
      • Wang X.
      • Lu Z.
      Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19).
      ].

      2.4 Myocardial ischemia and injury

      A plethora of ischemic and myocardial injuries manifestations have been documented among hospitalized patients with COVID-19 [
      • Long B.
      • Brady W.J.
      • Koyfman A.
      • Gottlieb M.
      Cardiovascular complications in COVID-19.
      ,
      • Guo T.
      • Fan Y.
      • Chen M.
      • Wu X.
      • Zhang L.
      • He T.
      • Wang H.
      • Wan J.
      • Wang X.
      • Lu Z.
      Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19).
      • Doyen D.
      • Moceri P.
      • Ducreux D.
      • Dellamonica J.
      Myocarditis in a patient with COVID-19: a cause of raised troponin and ECG changes.
      ].
      In a retrospective observational study including patients with COVID-19 admitted at the Wuhan Asia General hospital, ST-T abnormalities (40%) were the most common ECG feature [
      • Li Y.
      • Liu T.
      • Tse G.
      • Wu M.
      • Jiang J.
      • Liu M.
      • Tao L.
      Electrocardiograhic characteristics in patients with coronavirus infection: A single-center observational study.
      ].
      Of note, myocardial injury during the acute phase of COVID-19 demonstrates ST segment deviations (both elevation or depression), pathological Q waves, and T wave inversion at standard ECG [
      • Bertini M.
      • Ferrari R.
      • Guardigli G.
      • Malagu M.
      • Vitali F.
      • Zucchetti O.
      • D'Aniello E.
      • Volta C.A.
      • Cimaglia P.
      • Piovaccari G.
      • et al.
      Electrocardiographic features of 431 consecutive, critically ill COVID-19 patients: an insight into the mechanisms of cardiac involvement.
      ,
      • Mehraeen E.
      • Seyed Alinaghi S.A.
      • Nowroozi A.
      • Dadras O.
      • Alilou S.
      • Shobeiri P.
      • Behnezhad F.
      • Karimi A.
      A systematic review of ECG findings in patients with COVID-19.
      ,
      • Ajmal M.
      • Butt K.
      • Moukabary T.
      COVID-19 Disease and its Electrocardiographic Manifestations: Our Experience.
      • Siripanthong B.
      • Nazarian S.
      • Muser D.
      • Deo R.
      • Santangeli P.
      • Khanji M.Y.
      • Cooper L.T.
      • Chahal C.A.A.
      Recognizing COVID-19-related myocarditis: The possible pathophysiology and proposed guideline for diagnosis and management.
      ]. Although the distinction between a ST-elevation myocardial infarction and myocarditis remains difficult, diagnosis of acute myocardial infarction is suggested with focal ST-segment elevations; conversely, myocardial injury demonstrates diffuse or widespread ST-segment elevation [
      • Bangalore S.
      • Sharma A.
      • Slotwiner A.
      • Yatskar L.
      • Harari R.
      • Shah B.
      • Ibrahim H.
      • Friedman G.H.
      • Thompson C.
      • Alviar C.L.
      • et al.
      ST-Segment Elevation in Patients with Covid-19 - A Case Series.
      ].
      It has been proposed that mechanisms of SARS-CoV-2 myocardial injury may be explained by a combination of direct cell injury and T-lymphocyte-mediated cytoxicity [
      • Buckley B.J.R.
      • Harrison S.L.
      • Fazio-Eynullayeva E.
      • Underhill P.
      • Lane D.A.
      • Lip G.Y.H.
      Prevalence and clinical outcomes of myocarditis and pericarditis in 718,365 COVID-19 patients.
      ,
      • Tavazzi G.
      • Pellegrini C.
      • Maurelli M.
      • Belliato M.
      • Sciutti F.
      • Bottazzi A.
      • Sepe P.A.
      • Resasco T.
      • Camporotondo R.
      • Bruno R.
      • et al.
      Myocardial localization of coronavirus in COVID-19 cardiogenic shock.
      ].

      2.5 Pulmonary embolism

      A high prevalence of venous thromboembolism (VTE) is reported during hospitalization for COVID-19 [
      • Jevnikar M.
      • Sanchez O.
      • Humbert M.
      • Parent F.
      Prevalence of pulmonary embolism in patients with COVID-19 at the time of hospital admission and role for pre-test probability scores and home treatment.
      ]. The most common ECG finding in the setting of a pulmonary embolism is sinus tachycardia [
      • Ullman E.
      • Brady W.J.
      • Perron A.D.
      • Chan T.
      • Mattu A.
      Electrocardiographic manifestations of pulmonary embolism.
      ]. This associated ECG condition is also confirmed among COVID-19 patients [
      • Long B.
      • Brady W.J.
      • Bridwell R.E.
      • Ramzy M.
      • Montrief T.
      • Singh M.
      • Gottlieb M.
      Electrocardiographic manifestations of COVID-19.
      ,
      • Kho J.
      • Ioannou A.
      • Van den Abbeele K.
      • Mandal A.K.J.
      • Missouris C.G.
      Pulmonary embolism in COVID-19: Clinical characteristics and cardiac implications.
      ]. The S1Q3T3 sign (prominent S wave in lead I, Q wave and inverted T wave in lead III) is a classic sign of acute cor pulmonale (acute pressure and volume overload of the right ventricle because of pulmonary hypertension) with increased right ventricular strain [
      • Chan T.C.
      • Vilke G.M.
      • Pollack M.
      • Brady W.J.
      Electrocardiographic manifestations: pulmonary embolism.
      ].
      Nonetheless, a single center, retrospective observational cohort study of COVID-19 patients diagnosed with pulmonary embolism showed that the S1Q3T3 sign was present in less than 10% of cases and that non-specific ST-T abnormalities or T wave changes were the most common ECG findings of pulmonary embolism [
      • Kho J.
      • Ioannou A.
      • Van den Abbeele K.
      • Mandal A.K.J.
      • Missouris C.G.
      Pulmonary embolism in COVID-19: Clinical characteristics and cardiac implications.
      ].

      3. “Unexpected” ECG features of COVID-19

      Evidences on unexpected ECG features of COVID-19 have been recently accrued, showing that uncertainties still overshadow our clinical knowledge in the field [
      • Long B.
      • Brady W.J.
      • Bridwell R.E.
      • Ramzy M.
      • Montrief T.
      • Singh M.
      • Gottlieb M.
      Electrocardiographic manifestations of COVID-19.
      ,
      • Mehraeen E.
      • Seyed Alinaghi S.A.
      • Nowroozi A.
      • Dadras O.
      • Alilou S.
      • Shobeiri P.
      • Behnezhad F.
      • Karimi A.
      A systematic review of ECG findings in patients with COVID-19.
      ].
      Interestingly, in our previous report of ECG features of patients with COVID-19 pneumonia, we documented that the development of ECG abnormalities during hospitalization was unrelated to the severity of respiratory function [
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • Feci D.
      • Reboldi G.
      • Fabbri L.M.
      • Verdecchia P.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ]. Moreover, abnormal serum levels of high sensitivity troponin I were recorded in the 38% of cases and ECG abnormalities showed a late onset from hospitalization and initiation of COVID-19 symptoms. The average time for development of ECG abnormalities was 20 and 30 days from admission and onset of symptoms, respectively [
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • Feci D.
      • Reboldi G.
      • Fabbri L.M.
      • Verdecchia P.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ]. Notably, a large proportion of patients (54%) experienced ECG abnormalities immediately before the scheduled discharge from hospital and after 2 consecutive negative nasopharyngeal swabs [
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • Feci D.
      • Reboldi G.
      • Fabbri L.M.
      • Verdecchia P.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ].

      3.1 Right ventricular strain

      COVID-19 patients with acute respiratory failure may present QRS complex axis deviation with right ventricular strain (prominent R waves in leads V1 and V2, ST segment depression or T wave inversion in leads II, III, aVF, V1,V2, V3, and V4) [
      • Elias P.
      • Poterucha T.J.
      • Jain S.S.
      • Sayer G.
      • Raikhelkar J.
      • Fried J.
      • Clerkin K.
      • Griffin J.
      • DeFilippis E.M.
      • Gupta A.
      • et al.
      The Prognostic Value of Electrocardiogram at Presentation to Emergency Department in Patients With COVID-19.
      ]. Of note, right ventricular strain seems to be associated with an increased risk of death or need of mechanical ventilation during hospitalization [
      • Elias P.
      • Poterucha T.J.
      • Jain S.S.
      • Sayer G.
      • Raikhelkar J.
      • Fried J.
      • Clerkin K.
      • Griffin J.
      • DeFilippis E.M.
      • Gupta A.
      • et al.
      The Prognostic Value of Electrocardiogram at Presentation to Emergency Department in Patients With COVID-19.
      ,
      • Barman H.A.
      • Atici A.
      • Sahin I.
      • Dogan O.
      • Okur O.
      • Tugrul S.
      • Avci I.
      • Yildirmak M.T.
      • Gungor B.
      • Dogan S.M.
      Prognostic value of right ventricular strain pattern on ECG in COVID-19 patients.
      ].

      3.2 Brady-arrhythmias and atrioventricular blocks

      Incidence of bradicardias, atrioventricular blocks, and brady-tachy syndromes is not well characterized among COVID-19 patients [
      • Long B.
      • Brady W.J.
      • Bridwell R.E.
      • Ramzy M.
      • Montrief T.
      • Singh M.
      • Gottlieb M.
      Electrocardiographic manifestations of COVID-19.
      ,
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • Feci D.
      • Reboldi G.
      • Fabbri L.M.
      • Verdecchia P.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ,
      • He J.
      • Wu B.
      • Chen Y.
      • Tang J.
      • Liu Q.
      • Zhou S.
      • Chen C.
      • Qin Q.
      • Huang K.
      • Lv J.
      • et al.
      Characteristic Electrocardiographic Manifestations in Patients With COVID-19.
      ].
      To date, these ECG manifestations are considered as disease-caused deterioration [
      • He J.
      • Wu B.
      • Chen Y.
      • Tang J.
      • Liu Q.
      • Zhou S.
      • Chen C.
      • Qin Q.
      • Huang K.
      • Lv J.
      • et al.
      Characteristic Electrocardiographic Manifestations in Patients With COVID-19.
      ].
      However, a recent case series by Dagher and co-workers [
      • Dagher L.
      • Wanna B.
      • Mikdadi G.
      • Young M.
      • Sohns C.
      • Marrouche N.F.
      High-degree atrioventricular block in COVID-19 hospitalized patients.
      ] described four cases of COVID-19 patients who developed a transient high-degree atrioventricular block during the course of their hospitalization, not requiring permanent pacing [
      • Dagher L.
      • Wanna B.
      • Mikdadi G.
      • Young M.
      • Sohns C.
      • Marrouche N.F.
      High-degree atrioventricular block in COVID-19 hospitalized patients.
      ]. Similar findings were also reported in our cohort [
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • Feci D.
      • Reboldi G.
      • Fabbri L.M.
      • Verdecchia P.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ] and by Eneizat Mahdawi and co-workers in a case series of heart blocks [
      • Eneizat Mahdawi T.
      • Wang H.
      • Haddadin F.I.
      • Al-Qaysi D.
      • Wylie J.V.
      Heart block in patients with coronavirus disease 2019: A case series of 3 patients infected with SARS-CoV-2.
      ].

      3.3 ECG features of pericardial disease

      Postmortem studies have identified pericarditis in about 20% of the COVID-19 cases [
      • Basso C.
      • Leone O.
      • Rizzo S.
      • De Gaspari M.
      • van der Wal A.C.
      • Aubry M.C.
      • Bois M.C.
      • Lin P.T.
      • Maleszewski J.J.
      • Stone J.R.
      Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study.
      ,
      • Hanley B.
      • Naresh K.N.
      • Roufosse C.
      • Nicholson A.G.
      • Weir J.
      • Cooke G.S.
      • Thursz M.
      • Manousou P.
      • Corbett R.
      • Goldin R.
      • et al.
      Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study.
      ] and several case reports reported acute pericarditis in patients with SARS-CoV-2 infection with typical ECG signs (diffuse ST elevation and PR depression) [
      • Furqan M.M.
      • Verma B.R.
      • Cremer P.C.
      • Imazio M.
      • Klein A.L.
      Pericardial Diseases in COVID19: a Contemporary Review.
      • Kumar R.
      • Kumar J.
      • Daly C.
      • Edroos S.A.
      Acute pericarditis as a primary presentation of COVID-19.
      ].
      Data from 63,822 COVID patients attending 50 Spanish emergency department during the COVID outbreak were used to analyze the frequency of (myo)pericarditis [
      • Miro O.
      • Llorens P.
      • Jimenez S.
      • Pinera P.
      • Burillo-Putze G.
      • Martin A.
      • Martin-Sanchez F.J.
      • Gonzalez Del Castillo J.
      • Spanish n.
      Investigators in Emergency Situations TeAm, Frequency of five unusual presentations in patients with COVID-19: results of the UMC-19-S1.
      ]. Compared with general emergency department population, COVID patients developed more frequently (myo)pericarditis (odds ratio [OR]: 1.45, 95% confidence interval [CI]: 1.07–1.97) [
      • Miro O.
      • Llorens P.
      • Jimenez S.
      • Pinera P.
      • Burillo-Putze G.
      • Martin A.
      • Martin-Sanchez F.J.
      • Gonzalez Del Castillo J.
      • Spanish n.
      Investigators in Emergency Situations TeAm, Frequency of five unusual presentations in patients with COVID-19: results of the UMC-19-S1.
      ]. Similarly, in a retrospective cohort study involving 718,365 patients with COVID-19, 10,706 (1.5%) patients developed new-onset pericarditis with a 6-months all-cause mortality of 15.5% (vs 6.7% in matched controls, OR: 2.55, 95% CI: 2.24 2.91) [
      • Buckley B.J.R.
      • Harrison S.L.
      • Fazio-Eynullayeva E.
      • Underhill P.
      • Lane D.A.
      • Lip G.Y.H.
      Prevalence and clinical outcomes of myocarditis and pericarditis in 718,365 COVID-19 patients.
      ].
      In our study cohort [
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • Feci D.
      • Reboldi G.
      • Fabbri L.M.
      • Verdecchia P.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ], ECG signs of acute pericarditis were the most common ECG manifestations of COVID-19. Notably, we diagnosed acute pericarditis by ECG evidence of new widespread concave ST elevation and PR depression throughout most of the limb (I, II, III, aVL, aVF) and precordial (V2-V6) leads, reciprocal ST depression, and PR elevation in aVR, and a ST segment/T wave ratio> 0.25 [
      • Adler Y.
      • Charron P.
      • Imazio M.
      • Badano L.
      • Baron-Esquivias G.
      • Bogaert J.
      • Brucato A.
      • Gueret P.
      • Klingel K.
      • Lionis C.
      • et al.
      2015 ESC Guidelines for the diagnosis and management of pericardial diseases: The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC)Endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS).
      ]. We also noted late persistence of ECG signs of acute pericarditis (Fig. 1). Similar findings were documented by Soewono [
      • Soewono K.Y.
      • Raney 3rd, K.C.
      • Sidhu M.S.
      Pericarditis with pericardial effusion as a delayed complication of COVID-19.
      ] and Eiros and co-workers [

      Eiros, R., Pericarditis and myocarditis long after SARS-CoV-2 infection: a cross-sectional descriptive study in health-care workers. https://www.medrxiv.org/content/10.1101/2020.07.12.20151316v1, 2020.

      ]. Specifically, Soewono et al. described the case of a 30-year-old man with diagnosis of acute pericarditis 6 weeks after respiratory symptoms and a positive test for SARS-CoV-2 infection [
      • Soewono K.Y.
      • Raney 3rd, K.C.
      • Sidhu M.S.
      Pericarditis with pericardial effusion as a delayed complication of COVID-19.
      ]. Eiros et al. studied 139 health-care workers with confirmed past SARS-CoV-2 infection. Participants underwent clinical assessment, electrocardiography, laboratory tests including immune cell profiling and cardiac magnetic resonance (CMR). Overall, 14% of the total participants fulfilled the pericarditis criteria at week 10 [

      Eiros, R., Pericarditis and myocarditis long after SARS-CoV-2 infection: a cross-sectional descriptive study in health-care workers. https://www.medrxiv.org/content/10.1101/2020.07.12.20151316v1, 2020.

      ].
      Fig. 1
      Fig. 1A 79-year-old white woman who developed during hospitalization COVID-19 pneumonia, chest pain with ECG signs of acute pericarditis and significant pericardial effusion
      [
      • Angeli F.
      • Spanevello A.
      • De Ponti R.
      • Visca D.
      • Marazzato J.
      • Palmiotto G.
      • Feci D.
      • Reboldi G.
      • Fabbri L.M.
      • Verdecchia P.
      Electrocardiographic features of patients with COVID-19 pneumonia.
      ]
      . After 1 month after discharge from hospital, the patient was asymptomatic and the echocardiographic examination documented complete regression of pericardial effusion (upper panel). However, standard ECG revealed the persistence of signs of pericarditis (lower panel).
      To date, the exact pathophysiological mechanism of pericardial involvement is not fully understood. As proposed mechanisms, systemic inflammatory reaction (with cytokine storm), and endothelial damage induced by COVID-19 may lead to pericardial involvement [
      • Furqan M.M.
      • Verma B.R.
      • Cremer P.C.
      • Imazio M.
      • Klein A.L.
      Pericardial Diseases in COVID19: a Contemporary Review.
      ]. Furthermore, COVID-19 induced pericarditis might reflect the expression of ACE2 receptors in epicardial adipocites (mediating the cell entry of SARS-CoV-2) [
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection.
      ,
      • Patel V.B.
      • Basu R.
      • Oudit G.Y.
      ACE2/Ang 1-7 axis: A critical regulator of epicardial adipose tissue inflammation and cardiac dysfunction in obesity.
      ,
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection.
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      COVID-19: ACE2centric Infective Disease?.
      ], and possibly triggering local inflammation [
      • Verdecchia P.
      • Reboldi G.
      • Cavallini C.
      • Mazzotta G.
      • Angeli F.
      [ACE-inhibitors, angiotensin receptor blockers and severe acute respiratory syndrome caused by coronavirus].
      ,
      • Angeli F.
      • Reboldi G.
      • Verdecchia P.
      Ageing, ACE2 deficiency and bad outcome in COVID-19.
      ,
      • Angeli F.
      • Masnaghetti S.
      • Visca D.
      • Rossoni A.
      • Taddeo S.
      • Biagini F.
      • Verdecchia P.
      Severity of COVID-19: The importance of being hypertensive.
      ,
      • Angeli F.
      • Reboldi G.
      • Verdecchia P.
      SARS-CoV-2 infection and ACE2 inhibition.
      ,
      • Angeli F.
      • Spanevello A.
      • Reboldi G.
      • Visca D.
      • Verdecchia P.
      SARS-CoV-2 vaccines: Lights and shadows.
      ,
      • Angeli F.
      • Verdecchia P.
      • Reboldi G.
      RAAS Inhibitors and Risk of Covid-19.
      ,
      • Verdecchia P.
      • Cavallini C.
      • Spanevello A.
      • Angeli F.
      COVID-19: ACE2centric Infective Disease?.
      • Verdecchia P.
      • Angeli F.
      • Reboldi G.
      Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and coronavirus.
      ].

      3.4 Brugada-like pattern

      Two case reports documented Brugada patterns in patients with COVID-19 [
      • Vidovich M.I.
      Transient Brugada-Like Electrocardiographic Pattern in a Patient With COVID-19.
      ,
      • Chang D.
      • Saleh M.
      • Garcia-Bengo Y.
      • Choi E.
      • Epstein L.
      • Willner J.
      COVID-19 Infection Unmasking Brugada Syndrome.
      ]. In the first report [
      • Vidovich M.I.
      Transient Brugada-Like Electrocardiographic Pattern in a Patient With COVID-19.
      ], standard ECG revealed a Brugada-like pattern in a 61-year-old man presented with fever, shortness of breath, and chest pain (with coronary angiography demonstrating normal coronary arteries).
      In the second, a 49-year-old Bangladeshi man without significant medical history and positive for COVID-19 showed a Brugada syndrome, with the combination of the Brugada ECG pattern and clinical symptoms [
      • Chang D.
      • Saleh M.
      • Garcia-Bengo Y.
      • Choi E.
      • Epstein L.
      • Willner J.
      COVID-19 Infection Unmasking Brugada Syndrome.
      ].

      4. Conclusions

      COVID-19 impacts the cardiovascular system, causing a variety of cardiac complications and leading to a range of ECG abnormalities [
      • Dherange P.
      • Lang J.
      • Qian P.
      • Oberfeld B.
      • Sauer W.H.
      • Koplan B.
      • Tedrow U.
      Arrhythmias and COVID-19: A Review.
      ,
      • Lazzeri C.
      • Bonizzoli M.
      • Batacchi S.
      • Cianchi G.
      • Franci A.
      • Fulceri G.E.
      • Peris A.
      Cardiac Involvment in COVID-19-Related Acute Respiratory Distress Syndrome.
      ] (Fig. 2). Cardiac injury is found in 7%−17% of COVID-19 patients, and it is associated with a higher risk of mortality [
      • Shi S.
      • Qin M.
      • Shen B.
      • Cai Y.
      • Liu T.
      • Yang F.
      • Gong W.
      • Liu X.
      • Liang J.
      • Zhao Q.
      • et al.
      Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China.
      ,
      • Wang D.
      • Hu B.
      • Hu C.
      • Zhu F.
      • Liu X.
      • Zhang J.
      • Wang B.
      • Xiang H.
      • Cheng Z.
      • Xiong Y.
      • et al.
      Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
      • Zhou F.
      • Yu T.
      • Du R.
      • Fan G.
      • Liu Y.
      • Liu Z.
      • Xiang J.
      • Wang Y.
      • Song B.
      • Gu X.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      ]. Therefore, clinicians must be aware of the ECG manifestations of COVID-19.
      Fig. 2
      Fig. 2Main mechanisms of cardiac involvement during SARS-CoV-2 infection (including direct injury and indirect damage). See text for details. Legend: AII = angiotensin II; ACE2 = angiotensin converting enzyme 2 receptor; ARDS = Acute respiratory distress syndrome; GI = gastrointestinal.
      As the body of academic literature is expanding, it is also mandatory to understand uncommon ECG manifestations of COVID-19. Some patients with pericarditis may not have chest pain even with myocarditis coexists. On the other hand, several patients with acute pericarditis develop significant pericardial effusion necessitating pericardial drainage [
      • Asif T.
      • Kassab K.
      • Iskander F.
      • Alyousef T.
      Acute Pericarditis and Cardiac Tamponade in a Patient with COVID-19: A Therapeutic Challenge.
      ,
      • Blagojevic N.R.
      • Bosnjakovic D.
      • Vukomanovic V.
      • Arsenovic S.
      • Lazic J.S.
      • Tadic M.
      Acute pericarditis and severe acute respiratory syndrome coronavirus 2: Case report.
      ,
      • Fox K.
      • Prokup J.A.
      • Butson K.
      • Jordan K.
      Acute Effusive Pericarditis: A Late Complication of COVID-19.
      ,
      • Walker C.
      • Peyko V.
      • Farrell C.
      • Awad-Spirtos J.
      • Adamo M.
      • Scrocco J.
      Pericardial effusion and cardiac tamponade requiring pericardial window in an otherwise healthy 30-year-old patient with COVID-19: a case report.
      ].
      It's now well established that several uncommon ECG manifestations of SARS-CoV-2 infection are associated with an increased risk of adverse outcome [
      • Long B.
      • Brady W.J.
      • Bridwell R.E.
      • Ramzy M.
      • Montrief T.
      • Singh M.
      • Gottlieb M.
      Electrocardiographic manifestations of COVID-19.
      ,
      • Mehraeen E.
      • Seyed Alinaghi S.A.
      • Nowroozi A.
      • Dadras O.
      • Alilou S.
      • Shobeiri P.
      • Behnezhad F.
      • Karimi A.
      A systematic review of ECG findings in patients with COVID-19.
      ,
      • Bergamaschi L.
      • D'Angelo E.C.
      • Paolisso P.
      • Toniolo S.
      • Fabrizio M.
      • Angeli F.
      • Donati F.
      • Magnani I.
      • Rinaldi A.
      • Bartoli L.
      • et al.
      The value of ECG changes in risk stratification of COVID-19 patients.
      ]. These conditions require an early diagnosis, a proper workup and specific management strategies based on organ involvement.

      Declaration of Competing Interest

      None of the authors of this study has financial or other reasons that could lead to a conflict of interest.

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