COVID-19 Coronavirus Disease 2019 and Cardiac Arrhythmias Antoni Martínez-Rubio, Soledad Ascoeta, Fadwa Taibi and Josep Guindo Soldevila Department of Cardiology, Parc Taulí University Hospital and Institut d’Investigació i Innovació I3PT, Universitat Autònoma de Barcelona, Sabadell, Barcelona, Spain Abstract The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a very contagious virus, has led to the coronavirus disease 2019 (COVID-19) pandemic. The clinical manifestations of this virus in humans vary widely, from asymptomatic to severe, with diverse symptomatology and even death. The substantial transmission from asymptomatic people has facilitated the widespread transmission of SARS-CoV-2, hampering public health initiatives to identify and isolate infected people during the pre-symptomatic contagious period. COVID-19 is associated with cardiac complications that can progress from mild to life-threatening. The aim of this article is to analyse the present knowledge of COVID-19 and cardiac involvement, the development of arrhythmia risk and its treatment. Keywords Anti-arrhythmic drug, arrhythmia, coronavirus, COVID-19, infection, SARS-CoV-2, sudden death Disclosure: The authors have no conflicts of interest to declare. Received: 24 May 2020 Accepted: 4 August 2020 Citation: European Cardiology Review 2020;15:e66. DOI: https://doi.org/10.15420/ecr.2020.23 Correspondence: Antoni Martínez-Rubio, Parc Taulí University Hospital (Autonomous University of Barcelona), Department of Cardiology, Parc Taulí 1, E-08208 Sabadell, Barcelona, Spain. E: amartinezrubio@icloud.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non- commercial purposes, provided the original work is cited correctly. In the last months of 2019 and the beginning of 2020, a novel disease SARS-CoV-2 is known to bind to cells via the membrane-bound glycoprotein appeared, caused by severe acute respiratory syndrome coronavirus 2 angiotensin-converting enzyme 2 (ACE2).1 Thus, the role of the ACE2 (SARS-CoV-2), a very contagious virus, which causes coronavirus molecule has been the subject of attention, given that it has a very broad disease 2019 (COVID-19). The clinical manifestations of this virus in expression in humans (e.g. type II pneumocytes, myocardium and humans vary widely from asymptomatic to severe, with diverse endothelium). At this time, it is unclear if the use of ACE inhibitors or symptomatology and even death. The substantial transmission from angiotensin receptor blockers (ARB) influences receptor expression, asymptomatic people has facilitated the widespread transmission of thereby affecting the propensity or severity of SARS-CoV-2 infection. SARS-CoV-2 and contributed to its pandemic potential, thereby However, in a case-population study from seven Spanish hospitals, hampering public health initiatives to identify and isolate infected analysing data from 1,139 cases (aged 18 years or older with a PCR- people and the estimation of overall infectivity in the general population. confirmed diagnosis of COVID-19 requiring admission) and 11,390 Thus, containment measures aimed solely at isolating symptomatic population controls, renin–angiotensin–aldosterone system inhibitors did individuals are inadequate. Specifically, potentially exposed people not increase the risk of COVID-19 requiring admission to hospital, including during the pre-symptomatic contagious period need to be identified fatal cases and those admitted to intensive care units, suggesting that they and isolated for fast interruption of the transmission process. COVID-19 and should not be discontinued to prevent a severe case of COVID-19.4 is associated with cardiac complications that can progress from mild to Major societies have recommended continuation of ACE inhibitor or ARB life-threatening. The aim of this review is to analyse the present therapy in patients with a previous indication for these drugs.5,6 knowledge of COVID-19 regarding arrhythmia risk and its treatment. Symptomatology Basic Virology Data The largest (n=72,314) published registry of COVID-19 patients reported The Coronaviridae constitute a family of enveloped, single-stranded, high-level details for putative (47%) and confirmed (63%) COVID-19 positive-sense, RNA viruses with a characteristic crown, or corona, of cases.7 In this population, predominantly identified by the presence of electron density seen on transmission electron microscopy. The lifecycle symptoms (approximately 99%), age plays a major role in the infection of SARS-CoV-2 is presumed to be similar to SARS-CoV-1 and other rate and also in the prognosis and <2% of cases occurred in individuals coronaviruses.1 SARS-CoV-2 spreads primarily through small respiratory <19 years of age. Of confirmed cases, most (81%) were mild, 14% were droplets from infected individuals that can travel approximately 1–2 m. severe with significant pulmonary infiltrates or signs of respiratory Live virus has also been isolated and cultured from faecal specimens, compromise, and 5% were critical with respiratory failure (e.g. raising the possibility of orofaecal transmission, although clinical mechanical ventilation), shock or multiorgan system failure. The evidence for this mode of transmission is lacking.2 The virus can exist in estimated case fatality rate was <1% in patients <50 years; 1.3% in nature on surfaces from hours to several days.3 Several aspects of SARS- those aged 50–59 years; 3.6% for 60–69 years, 8% for 70–79 years, and CoV-2 remain unknown and are under intensive investigation globally. 14.8% in those aged ≥80 years.7 © RADCLIFFE CARDIOLOGY 2020 Access at: www.ECRjournal.com COVID-19 Figure 1: Pathophysiological Mechanisms of Cardiovascular Effects in Coronavirus Disease 2019 Infection COVID-19 infection Heart (myocytes) Respiratory system (type II pneumocytes) Vascular system (pericytes and endothelial cells) Cell Electrical conduction Respiratory Systemic inflammation Micro and macrovascular damage abnormalities failure Cytokine release (IL6, IL7, CXCL10) dysfunction Fulminant Hypoxaemia Plaque rupture Hypercoagulability myocarditis Sympathetic surge Arrhythmia Acute coronary syndrome Drug COVID-19 = coronavirus disease 2019; IL = interleukin. The most common symptoms are fever in up to 90%, followed by cough, SARS-CoV-2 infection can affect the cardiac structures via various fatigue, sputum production and shortness of breath.8 Less common mechanisms of injury (Figure 1), such as by direct damage to the symptoms include headache, myalgia, sore throat, nausea, vomiting, and myocytes and the vascular cells, and also indirectly by cytokine diarrhoea, but anosmia and dysgeusia have also been described. Blood expression after systemic inflammation. The infection provokes a abnormalities include lymphopenia, elevations in D-dimer, lactate disarray of the coagulation and fibrinolytic system, with a clinical picture dehydrogenase, transaminases and C-reactive protein (CRP), and consistent with disseminated intravascular thrombosis. Therefore, interleukin (IL)-6, ferritin and others.8–12 empiric anticoagulation is being used in some centres. In addition, an oxygen supply/demand mismatch or severe hypoxia caused by Development of acute respiratory disease syndrome (ARDS), along with respiratory failure may modulate the cardiac affects, which may include acute cardiac injury, have been described as independent predictors of myocarditis, acute coronary syndrome (ACS; type 2 MI) and arrhythmia, death.13 Importantly, hypoxaemic respiratory failure is the leading cause which might lead to acute or chronic heart failure.12–19 of death in COVID-19, contributing to 60% of deaths.14 Furthermore, the arrhythmia occurrence (e.g. AF with fast ventricular Cardiac Involvement response) may facilitate ischaemia, which can also cause arrhythmias The reported rate of cardiac injury varies between studies, from 7% to (e.g. VF). In addition, some cardiotoxic drugs or drugs affecting the 28% of hospitalised patients, and is related to worse outcomes, electrical properties of the heart may facilitate proarrhythmia (e.g. including intensive care unit (ICU) admission and death.9,10,12–15 drugs prolonging the QT interval may facilitate torsades de pointes Importantly, early cardiac injury has been reported, even in the absence tachycardia). Thus, patients with SARS-CoV-2 infection may have heart of respiratory symptoms and signs of interstitial pneumonia.16 The rhythm disturbances due to a variety of mechanisms, which are mortality rate for those hospitalised with subsequent evidence of interrelated and inter-facilitated. The role of stress (takotsubo) cardiac injury was significantly higher than for those without cardiac cardiomyopathy in COVID-19 patients is not known. However, several of injury (51.2% versus 4.5%, respectively, p<0.001) and hence, along with the proposed mechanisms of COVID-19-related cardiac injury are also ARDS, it is an independent predictor of death.13 thought to be implicated in the pathophysiology of stress cardiomyopathy (particularly microvascular dysfunction, cytokine The presence of previous cardiovascular risk factors (such as diabetes storm and sympathetic surge), and one typical takotsubo syndrome or arterial hypertension) or cardiac disease (previous MI or heart triggered by SARS-CoV-2 infection has already been reported.20 failure), as well as the presence of other clinically relevant comorbidities (e.g. older age, renal failure or prior lung disease), seems to worsen the Arrhythmia prognosis of infected people.10–12,15 Furthermore, the infection is also The clinical manifestations (i.e. palpitations, syncope etc.) of associated with de novo cardiac complications (approximately 8–12% bradyarrhythmias or tachyarrhythmias in COVID-19 do not differ from of myocardial lesions and 7–16% of myocarditis and arrhythmias).17 the usual presentation. No specific ECG patterns have been described EUROPEAN CARDIOLOGY REVIEW COVID-19 and Cardiac Arrhythmias Figure 2: Acute Treatment Recommendations for Patients with Ventricular Tachycardia and VF New episode of VT/VF in COVID-19 NO Urgent Haemodynamic stability cardioversion/ defibrillation YES Monomorphic VT Polymorphic VT/VF QTc-prolonging antiviral therapy QTc prolonged or TdP VT NO Yes NO Yes IV Cardioversion if IV lidocaine IV magnesium amiodarone ventilated IV beta-blocker Isoprenaline (esmolol) Stop QT-prolonging Recurrence or Recurrence or Recurrent antiviral drugs continuing VT continuing VT VT or VF Recurrent TdP IV beta-blocker (esmolol) IV lidocaine or or bradycardia procaininamide IV Temporary Recurrence or Recurrence or amiodarone pacing continuing VT continuing VT Cardioversion IV amiodarone COVID-19 = coronavirus disease 2019; IV = intravenous; QTc = corrected QT interval; TdP = torsades de pointes; VT = ventricular tachycardia. Sources: European Society of Cardiology 202018 and Giudicessi et al. 2020.21 in SARS-CoV-2-infected people. Thus, ECG diagnostic criteria are the if it increases >60 ms from baseline.21 Electrolyte disturbances must be same for infected and for the general population. avoided and kalaemia should be kept at >4.5 mEq/l. To avoid fever- triggered ventricular tachyarrhythmias in patients with Brugada Surprisingly, there is limited literature regarding arrhythmias in syndrome, fever must be intensively treated (mainly with paracetamol) COVID-19. The true incidence and type of arrhythmia is unknown. A and continuous ECG monitoring is recommended. Drug interactions large observational multicentre study from China of data on 1,099 with antivirals should also be strictly monitored in patients with patients did not report any arrhythmia.8 In a case series of 138 catecholaminergic polymorphic VT taking beta-blockers and flecainide. hospitalised patients with COVID-19, 16.7% (n=23) developed non- Catecholamines should be avoided if possible in these patients.18,22 Also, specified arrhythmias during their hospitalisation; higher rates were as part of the anti-arrhythmia treatment, all possible underlying noted in patients admitted to the ICU (44.4%, n=16).10 A case series of reversible triggers (e.g. hypoxia, acidosis, electrolyte abnormalities and 187 hospitalised patients provided insight into specific arrhythmias, ischaemia) for arrhythmias should be eliminated. reporting sustained ventricular tachycardia (VT) or VF in 5.9% (n=11) of the patients.9 Interestingly, the incidence of these arrhythmias was The true incidence of new-onset AF in SARS-CoV-2 infection is unknown. 1.5% and 17.3% in those patients without and with troponin elevation Half of severely ill patients with cardiac involvement present with AF, (p<0.001),9 suggesting that new-onset malignant ventricular given that it may be triggered by the infection alterations (e.g. fever, arrhythmias could be a marker of acute myocardial injury, and therefore hypoxia and adrenergic tone).23 In a report from Italy, a retrospective a more aggressive immunosuppressive and antiviral treatment is chart review identified a history of AF in 24.5% of 355 COVID-19 patients needed. Figure 2 shows recommendations for acute therapy for who died (mean age 79.5 years).24 patients with VT/VF.18,21 After recovery from COVID-19, the need for secondary prophylactic ICD, catheter ablation, or wearable defibrillator If inpatients present with AF or flutter with haemodynamic stability, (in the case of suspected transient cardiomyopathy due to myocarditis) a rate control strategy is reasonable, whereas cardioversion should be needs to be evaluated. There is currently no specific recommendation considered if haemodynamic instability occurs. Discontinuation of anti- for acute myocarditis treatment. arrhythmic drugs should be considered in patients with new-onset AF/ flutter with haemodynamic stability under antiviral treatment, using Furthermore, there are no specific reports on COVID-19 in patients with rate control therapy with beta-blockers with/without digoxin. channelopathies. There are, however, some special considerations. In patients with congenital long QT syndrome with SARS-CoV-2 infection, Anticoagulation should be guided by CHA2DS2-VASC score. Direct oral QT-prolonging antiviral drugs must be closely monitored and anticoagulants (DOACs) are preferred over vitamin K antagonists in reconsidered if the corrected QT interval (QTc) is prolonged >500 ms or eligible patients (i.e. those without mechanical prosthetic heart valves, EUROPEAN CARDIOLOGY REVIEW COVID-19 moderate to severe mitral stenosis or antiphospholipid syndrome) in benefits.31 Thus, the precise role of this drug (and several others) order to avoid the need for regular determination of international deserves further investigation.15 normalised ratio but, considering possible drug–drug interactions, appropriate doses should be ensured.25,26 There is no specific information The antiviral properties (inhibition of membrane fusion) of chloroquine regarding the use of DOACs in COVID-19 patients. If necessary, apixaban, were previously observed in HIV and other viruses.32,33 Similarly, edoxaban and rivaroxaban (but not dabigatran) can be given in a crushed hydroxychloroquine is being widely used with an emergency form. This is because dabigatran should always be given in capsule form authorisation.18,19,34–36 However, data are needed to prove efficacy in clinical use to avoid unintentionally increased bioavailability of against SARS-CoV-2 in humans. In an observational study, among dabigatran etexilate. However, if antiretroviral drugs are used, apixaban patients hospitalised in metropolitan New York with COVID-19, and rivaroxaban should be avoided because of potential interactions.18 treatment with hydroxychloroquine, azithromycin or both, compared Severely ill patients may be switched to parenteral anticoagulation, given with neither treatment, was not significantly associated with differences that heparin does not present significant drug–drug interactions with in in-hospital mortality.35 However, in a US multi-centre retrospective COVID-19 treatment (except azithromycin, which should not be observational study analysing data from 2,541 patients, treatment with coadministered with unfractionated heparin). After recovery from hydroxychloroquine alone and in combination with azithromycin was COVID-19, the therapeutic choices of rate or rhythm control of AF/flutter associated with reduction in COVID-19-associated mortality when should be re-evaluated, but long-term anticoagulation should be controlling for COVID-19 risk factors.36 It should be noted that continued based on CHA2DS2-VASC score.18,22,25,26 chloroquine and hydroxychloroquine prolong the QT interval and may induce life-threatening arrhythmias.37,38 Thus, caution should be used in Transient atrioventricular block has been rarely reported in COVID-19.27 starting these agents in patients with QTc >450 ms. Concomitant use of A lower heart rate than expected in patients with fever has been other QT-prolonging agents is not recommended, and abnormal observed in COVID-19 patients. In addition, some drugs used for electrolyte levels must be avoided.37,38 Importantly, kalaemia must be COVID-19. (e.g. chloroquine and, less frequently, hydroxychloroquine) maintained in a high to normal range. Other antiviral strategies (e.g. might increase the likelihood for AV block (sometimes after many specific neutralising antibodies) are under investigation. Detailed lists weeks of treatment). Thus, patients must be informed about possible of interactions of antiviral and commonly used drugs are available at corresponding symptoms (i.e. dizziness or syncope). If persistent https://www.covid19-druginteractions.org from the University of bradycardia occurs, all drugs that might aggravate this clinical problem Liverpool; at https://www.crediblemeds.org; and also in Driggin et al.16 should be stopped and heart rate-increasing drugs (e.g. isoprenaline or atropine), or temporary pacing must be considered. Implantation in Importantly, single-lead ECG with handheld devices will underestimate patients with an indication for a permanent device should be delayed if the QTc interval. Thus, for QT measurement, it is recommended to possible to diminish the risk of nosocomial infection. record 12-lead ECG, multi-lead handheld ECG, or single-lead handheld ECG in at least three lead positions.39 Both the absolute and delta QTc Although amiodarone has experimental antiviral properties that should (incremental QTc) is required to establish the baseline risk and be further analysed, anti-arrhythmic drugs should be used with caution proarrhythmia.39 It is important to balance the risk of QTc measurement to avoid proarrhythmia.28 However, in critically ill patients with inaccuracy versus the risk of 12-lead ECG measurements in the haemodynamic instability caused by recurrent VT/VF, IV amiodarone is pandemic situation. Maybe only high-risk patients should undergo the anti-arrhythmic drug of choice, but its combination with other QT- systematic 12-lead ECG. Previous authors have been developing scores prolonging drugs (e.g. hydroxychloroquine and/or azithromycin) should to predict the risk of QT prolongation with drugs. Although they are not be avoided.18,22 validated for COVID-19, they are a clinical option.40 Ventricular function and myocardial involvement should be assessed Advanced stages of COVID-19 are related to cytokine storm syndromes on echocardiography in patients with new severe ventricular with elevated levels of inflammatory biomarkers (e.g. IL-6 and high- arrhythmias. However, all diagnostic and therapeutic procedures sensitivity CRP), identifying patients at high risk of progressing to severe should be restricted to those mandatory for immediate therapeutic disease and even death.12,41 Therefore, corticosteroids and IL-6 management of critically ill patients, in order to preserve healthcare inhibitors have been used for patients with refractory shock or resources and minimise the risk of nosocomial infection. advanced ARDS in small cohorts.42 Very limited data suggesting that adjunctive azithromycin to hydroxychloroquine might be useful has Monitoring and follow-up of patients with implanted devices (e.g. been published.18 However, this drug might prolong the QT interval and pacemakers and ICDs) should be done remotely as much as possible. In special caution should be paid if combined with hydroxychloroquine. this context, elective procedures should be postponed and urgent ones Several other anti-inflammatory therapies are being investigated and undertaken only after consideration of pharmacological alternatives might change the scenario in the future. Vaccines against SARS-CoV-2 and in designated catheterisation laboratory areas with appropriate are obviously meaningful but unavailable yet, although promising personal protection equipment. results begin to be published.43,44 Other Treatments Conclusion Presently, there are no coronavirus-specific drugs available, and Because of limited testing and a large asymptomatic population, the different approaches based on previous antiviral experience are used.29 true burden of SARS-CoV-2-infected people is still unknown and The most widely applied inhibitor of viral genome replication agent underestimated. Differing prevalences and clinical results might be (at against SARS-CoV-2 is remdesivir, which has in vitro activity against the least partially) explained by major differences in testing capacities virus.18,29,30 In addition, remdesivir has been reported to reduce the time between countries and regions, and by differences in test quality to clinical improvement, but without statistically significant clinical (sensitivity and specificity) but also by differences between populations. EUROPEAN CARDIOLOGY REVIEW COVID-19 and Cardiac Arrhythmias Diverse (direct and indirect) mechanisms may facilitate cardiac similar or identical to that for non-infected individuals. However, the involvement resulting in myocarditis, ACS and diverse cardiac avoidance of QT prolongation is essential, and possible drug–drug arrhythmias. Several antiviral strategies are under investigation. It can interactions must be considered. Elective procedures should be be hypothesised that (as for HIV treatment) a combination of drugs will delayed, whereas urgent situations might require immediate treatment probably achieve the best clinical results. Vaccines against SARS-CoV-2 by trained and sufficiently equipped teams to ensure that healthcare are urgently needed. Anti-arrhythmic treatments for COVID-19 are workers do not become hosts or vectors of virus transmission. 1. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak 16. Inciardi RM, Lupi L, Zaccone G, et al. Cardiac involvement in a novel coronavirus in the United States. N Engl J Med associated with a new coronavirus of probable bat origin. patient with coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020;382:929–36. https://doi.org/10.1056/NEJMoa2001191; Nature 2020;579:270–3. https://doi.org/10.1038/s41586-020- 2020; 5:819–24. https://doi.org/10.1001/jamacardio.2020.1096; PMID: 32004427. 2012-7; PMID: 32015507. PMID: 32219357. 31. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with 2. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in 17. Siripanthong B, Nazarian S, Muser D, et al. Recognizing COVID- severe COVID-19: a randomized, double-blind, placebo- different types of clinical specimens. JAMA 2020;323:1843–4. 19-related myocarditis: the possible pathophysiology and controlled, multicenter trial. Lancet 2020;395:1569–78. https://doi.org/10.1001/jama.2020.3786; PMID: 32159775. proposed guideline for diagnosis and management. Heart https://doi.org/10.1016/S0140-6736(20)31022-9; 3. van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and Rhythm 2020;17:1463–71. https://doi.org/10.1016/j. PMID: 32423584. surface stability of SARS-CoV-2 as compared with SARS-CoV-1. hrthm.2020.05.001; PMID: 32387246. 32. Savarino A, Gennero L, Chen HC, et al. Anti-HIV effects of N Engl J Med 2020;382:1564–7. https://doi.org/10.1056/ 18. European Society of Cardiology. ESC guidance for diagnosis chloroquine: mechanisms of inhibition and spectrum of NEJMc2004973; PMID: 32182409. and management of CVD during the COVID-19 pandemic. activity. AIDS 2001;15:2221–9. https://doi.org/10.1097/ 4. De Abajo F, Rodriguez Martín S, Lerma V, et al. Use of renin– https://www.escardio.org/Education/COVID-19-and-Cardiology 00002030-200111230-00002; PMID: 11698694. angiotensin–aldosterone system inhibitors and risk of COVID- (accessed 10 May 2020). 33. Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a 19 requiring admission to hospital: a case-population study. 19. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting potent inhibitor of SARS coronavirus infection and spread. Lancet 2020; 395:1705-1714. https://doi.org/10.1016/S0140- characteristics, comorbidities, and outcomes among 5700 Virol J 2005;2:69. https://doi.org/10.1186/1743-422X-2-69; 6736(20)31030-8; PMID: 32416785. patients hospitalized with COVID-19 in the New York City Area. PMID: 16115318. 5. American College of Cardiology. HFSA/ACC/AHA statement JAMA 2020;323:2052–9. https://doi.org/10.1001/jama. 34. Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic addresses concerns re: using RAAS antagonists in COVID-19. 2020.6775; PMID: 32320003. derivative of chloroquine, is effective in inhibiting SARS-CoV-2 17 March 2020. https://www.acc.org/latest-in-cardiology/ 20. Meyer P, Degrauwe S, Van Delden C, et al. Typical takotsubo infection in vitro. Cell Discov 2020;6:16. https://doi.org/10.1038/ articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses- syndrome triggered by SARS-CoV-2 infection. Eur Heart J s41421-020-0156-0; PMID: 32194981. concerns-re-using-raas-antagonists-in-covid-19 (accessed 3 2020;41:1860. https://doi.org/10.1093/eurheartj/ehaa306; Rosenberg ES, Dufort EM, Udo T, et al. Association of September 2020). PMID: 32285915. treatment with hydroxychloroquine or azithromycin with 6. European Society of Cardiology. Position statement of the ESC 21. Giudicessi JR, Noseworthy PA, Friedman PA, et al. Urgent in-hospital mortality in patients with COVID-19 in New York Council on Hypertension on ACE-inhibitors and angiotensin guidance for navigating and circumventing the QTc-prolonging State. JAMA 2020;323:2493–502. https://doi.org/10.1001/ receptor blockers. 13 March 2020. https://www.escardio.org/ and torsadogenic potential of possible pharmacotherapies for jama.2020.8630; PMID: 32392282. Councils/Council-on-Hypertension-(CHT)/News/position- coronavirus disease 29 (COVID-19). Mayo Clin Proc Arshad S, Kilgore P, Chaudhry Z, et al. Treatment with statement-of-the-esc-council-on-hypertension-on-ace- 2020;95:1213–21. https://doi.org/10.1016/j.mayocp.2020. hydroxychloroquine, azithromycin, and combination in inhibitors-and-ang (accessed 3 September 2020).). 03.024; PMID: 32359771. patients hospitalized with COVID-19. Int J Infect Dis 2020;97:396- 7. Wu Z, McGoogan JM. Characteristics of and important lessons 22. Dan GA, Martinez-Rubio A, Agewall S, et al. Antiarrhythmic 403. https://doi.org/10.1016/j.ijid.2020.06.099; PMID: 32623082. from the coronavirus disease 2019 (COVID-19) outbreak in drugs – clinical use and clinical decision making: a consensus 35. Bessière F, Roccia H, Delinière A, et al. Assessment of QT China: summary of a report of 72 314 cases from the Chinese document from the European Heart Rhythm Association intervals in a case series of patients with coronavirus Center for Disease Control and Prevention. JAMA (EHRA) and European Society of Cardiology (ESC) Working disease 2019 (COVID-19) infection treated with 2020;323:1239–42. https://doi.org/10.1001/jama.2020.2648; Group on Cardiovascular Pharmacology, endorsed by the hydroxychloroquine alone or in combination with azithromycin PMID: 32091533. Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society in an intensive care unit. JAMA Cardiol 2020;5:1067–9. https:// 8. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of (APHRS) and International Society of Cardiovascular doi.org/10.1001/jamacardio.2020.1787; PMID: 32936266. coronavirus disease 2019 in China. N Engl J Med Pharmacotherapy (ISCP). Europace 2018;20:731–2. https://doi. 36. Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT interval 2020;382:1708–20. https://doi.org/10.1056/NEJMoa2002032; org/10.1093/europace/eux373; PMID: 29438514. prolongation associated with use of hydroxychloroquine PMID: 32109013. 23. Liu PP, Blet A, Smyth D, Li H. The science underlying COVID-19: with or without concomitant azithromycin among 9. Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal implications for the cardiovascular system. Circulation hospitalized patients testing positive for coronavirus outcomes of patients with coronavirus disease 2019 (COVID- 2020;142:68–78. https://doi.org/10.1161/CIRCULATIONAHA. disease 2019 (COVID-19). JAMA Cardiol 2020;5:1036–41. https:// 19). JAMA Cardiol 2020;5:811–8. https://doi.org/10.1001/ 120.047549; PMID: 32293910. doi.org/10.1001/jamacardio.2020.1834; PMID: 32936252. jamacardio.2020.1017; PMID: 32219356. 24. Onder G, Rezza G, Brusaferro S. Case-fatality rate and 37. Cheung CC, Davies B, Gibbs K, et al. Multi-lead QT screening is 10. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 characteristics of patients dying in relation to COVID-19 in necessary for QT measurement: implications for management hospitalized patients with 2019 novel coronavirus-infected Italy. JAMA 2020;323:1775–6. https://doi.org/10.1001/ of patients in the COVID-19 era. JACC Clin Electrophysiol pneumonia in Wuhan, China. JAMA 2020;323:1061–9. https:// jama.2020.4683; PMID: 32203977. 2020;6:878–80. https://doi.org/10.1016/j.jacep.2020.04.001; doi.org/10.1001/jama.2020.1585; PMID: 32031570. 25. Martínez-Rubio A, Dan GA. Cardiovascular pharmacotherapies PMID: 32703574. 11. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute focus: are low doses of direct-acting oral anticoagulants 38. Tisdale JE, Jaynes HA, Kingery JR, et al. Development and respiratory distress syndrome and death in patients with justified and appropriate in patients with nonvalvular atrial validation of a risk score to predict QT interval prolongation in coronavirus disease 2019 pneumonia in Wuhan, China. JAMA fibrillation? Eur Cardiol 2016;11:115–7. https://doi.org/10.15420/ hospitalized patients. Circ Cardiovasc Qual Outcomes Intern Med 2020;180:934–43. https://doi.org/10.1001/ ecr.2016.11.2.ED2; PMID: 30310458. 2013;6:479–87. https://doi.org/10.1161/CIRCOUTCOMES. jamainternmed.2020.0994; PMID: 32167524. 26. Martínez-Rubio A, DiazNuila Alcazar M, Soria Cadena A, 113.000152; PMID: 23716032. 12. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for Martinez-Torrecilla R. Using direct oral anticoagulants in 39. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider mortality of adult inpatients with COVID-19 in Wuhan, China: a patients with atrial fibrillation: assessment, monitoring and cytokine storm syndromes and immunosuppression. Lancet retrospective cohort study. Lancet 2020;395:1054–62. https:// treatment reversal. Eur Cardiol 2016;11:118–22. https://doi. 2020;395:1033–4. https://doi.org/10.1016/S0140- doi.org/10.1016/S0140-6736(20)30566-3; PMID: 32171076. org/10.15420/ecr.2016:30:1; PMID: 30310459. 6736(20)30628-0; PMID: 32192578. 13. Shi S, Qin M, Shen B, et al. Association of cardiac injury with 27. Azarkish M, Laleh Far V, Eslami M, Mollazadeh R. Transient 40. Alhazzani W, Moller MH, Arabi YM, et al. Surviving Sepsis mortality in hospitalized patients with COVID-19 in Wuhan, complete heart block in a patient with critical COVID-19. Eur Campaign: guidelines on the management of critically ill China. JAMA Cardiol 2020;5:802–10. https://doi.org/10.1001/ Heart J 2020;41:2131. https://doi.org/10.1093/eurheartj/ adults with coronavirus disease 2019 (COVID-19). jamacardio.2020.0950; PMID: 32211816. ehaa307; PMID: 32285920. Crit Care Med 2020;48:e440–69. https://doi.org/10.1097/ 14. Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality 28. Aimo A, Baritussio A, Emdin M, Tascini C. Amiodarone as a CCM.0000000000004363; PMID: 32224769. due to COVID-19 based on an analysis of data of 150 patients possible therapy for coronavirus infection. Eur J Prev Cardiol 41. Yu J, Tostanoski LH, Peter L, et al. DNA vaccine protection from Wuhan, China. Intensive Care Med 2020;46:846–8. https:// 2020. https://doi.org/10.1177/2047487320919233; against SARS-CoV-2 in rhesus macaques. Science doi.org/10.1007/s00134-020-05991-x; PMID: 32125452. PMID: 32295404; epub ahead of press. 2020;369:806–11. https://doi.org/10.1126/science.abc6284; 15. Driggin E, Madhavan MV, Bikdeli B, et al. Cardiovascular 29. Kalil AC. Treating COVID-19: off-label drug use, compassionate PMID: 32434945. considerations for patients, health care workers, and health use, and randomized clinical trials during pandemics. JAMA 42. Chandrashekar A, Liu J, Martinot AJ, et al. SARS-CoV-2 infection systems during the COVID-19 pandemic. J Am Coll Cardiol 2020;323:1897–8. https://doi.org/10.1001/jama.2020.4742; protects against rechallenge in rhesus macaques. Science 2020;75:2352–71. https://doi.org/10.1016/j.jacc.2020.03.031; PMID: 32208486. 2020;369:812–7. https://doi.org/10.1126/science.abc4776; PMID: 32201335. 30. Holshue ML, DeBolt C, Lindquist S, et al. First case of 2019 PMID: 32434946. EUROPEAN CARDIOLOGY REVIEW