key: cord-0828646-rkhuekpb
authors: Martínez-Rubio, Antoni; Ascoeta, Soledad; Taibi, Fadwa; Soldevila, Josep Guindo
title: Coronavirus Disease 2019 and Cardiac Arrhythmias
date: 2020-11-09
journal: Eur Cardiol
DOI: 10.15420/ecr.2020.23
sha: 350d4f508435912ea993382c043677a0bc8caee3
doc_id: 828646
cord_uid: rkhuekpb

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.

The most common symptoms are fever in up to 90%, followed by cough, fatigue, sputum production and shortness of breath. 8 Less common symptoms include headache, myalgia, sore throat, nausea, vomiting, and diarrhoea, but anosmia and dysgeusia have also been described. Blood abnormalities include lymphopenia, elevations in D-dimer, lactate dehydrogenase, transaminases and C-reactive protein (CRP), and interleukin (IL)-6, ferritin and others. [8] [9] [10] [11] [12] Development of acute respiratory disease syndrome (ARDS), along with acute cardiac injury, have been described as independent predictors of death. 13 Importantly, hypoxaemic respiratory failure is the leading cause of death in COVID-19, contributing to 60% of deaths. 14 

The reported rate of cardiac injury varies between studies, from 7% to 28% of hospitalised patients, and is related to worse outcomes, including intensive care unit (ICU) admission and death. 9, 10, [12] [13] [14] [15] Importantly, early cardiac injury has been reported, even in the absence of respiratory symptoms and signs of interstitial pneumonia. 16 The mortality rate for those hospitalised with subsequent evidence of cardiac injury was significantly higher than for those without cardiac injury (51.2% versus 4.5%, respectively, p<0.001) and hence, along with ARDS, it is an independent predictor of death. 13 The presence of previous cardiovascular risk factors (such as diabetes or arterial hypertension) or cardiac disease (previous MI or heart 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 prognosis of infected people. [10] [11] [12] 15 Furthermore, the infection is also associated with de novo cardiac complications (approximately 8-12% of myocardial lesions and 7-16% of myocarditis and arrhythmias). 17 SARS-CoV-2 infection can affect the cardiac structures via various mechanisms of injury (Figure 1) , such as by direct damage to the myocytes and the vascular cells, and also indirectly by cytokine expression after systemic inflammation. The infection provokes a disarray of the coagulation and fibrinolytic system, with a clinical picture consistent with disseminated intravascular thrombosis. Therefore, empiric anticoagulation is being used in some centres. In addition, an oxygen supply/demand mismatch or severe hypoxia caused by respiratory failure may modulate the cardiac affects, which may include myocarditis, acute coronary syndrome (ACS; type 2 MI) and arrhythmia, which might lead to acute or chronic heart failure. [12] [13] [14] [15] [16] [17] [18] [19] Furthermore, the arrhythmia occurrence (e.g. AF with fast ventricular response) may facilitate ischaemia, which can also cause arrhythmias (e.g. VF). In addition, some cardiotoxic drugs or drugs affecting the electrical properties of the heart may facilitate proarrhythmia (e.g. reporting sustained ventricular tachycardia (VT) or VF in 5.9% (n=11) of the patients. 9 Interestingly, the incidence of these arrhythmias was 1.5% and 17.3% in those patients without and with troponin elevation (p<0.001), 9 suggesting that new-onset malignant ventricular arrhythmias could be a marker of acute myocardial injury, and therefore a more aggressive immunosuppressive and antiviral treatment is needed. Figure 2 shows recommendations for acute therapy for patients with VT/VF. 18 

moderate to severe mitral stenosis or antiphospholipid syndrome) in order to avoid the need for regular determination of international normalised ratio but, considering possible drug-drug interactions, appropriate doses should be ensured. 25, 26 There is no specific information regarding the use of DOACs in COVID-19 patients. If necessary, apixaban, edoxaban and rivaroxaban (but not dabigatran) can be given in a crushed form. This is because dabigatran should always be given in capsule form in clinical use to avoid unintentionally increased bioavailability of dabigatran etexilate. However, if antiretroviral drugs are used, apixaban and rivaroxaban should be avoided because of potential interactions. 18 Severely ill patients may be switched to parenteral anticoagulation, given that heparin does not present significant drug-drug interactions with COVID-19 treatment (except azithromycin, which should not be coadministered with unfractionated heparin). After recovery from COVID-19, the therapeutic choices of rate or rhythm control of AF/flutter should be re-evaluated, but long-term anticoagulation should be continued based on CHA 2 DS 2 -VASC score. 18, 22, 25, 26 Transient atrioventricular block has been rarely reported in COVID- 19. 27 A lower heart rate than expected in patients with fever has been observed in COVID-19 patients. In addition, some drugs used for 

Presently, there are no coronavirus-specific drugs available, and different approaches based on previous antiviral experience are used. 29 The most widely applied inhibitor of viral genome replication agent against SARS-CoV-2 is remdesivir, which has in vitro activity against the virus. 18, 29, 30 In addition, remdesivir has been reported to reduce the time to clinical improvement, but without statistically significant clinical benefits. 31 Thus, the precise role of this drug (and several others) deserves further investigation. 15 The antiviral properties (inhibition of membrane fusion) of chloroquine were previously observed in HIV and other viruses. 32, 33 Similarly, hydroxychloroquine is being widely used with an emergency authorisation. 18, 19, [34] [35] [36] However, data are needed to prove efficacy against SARS-CoV-2 in humans. In an observational study, among patients hospitalised in metropolitan New York with COVID-19, treatment with hydroxychloroquine, azithromycin or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. 35 However, in a US multi-centre retrospective observational study analysing data from 2,541 patients, treatment with hydroxychloroquine alone and in combination with azithromycin was associated with reduction in COVID-19-associated mortality when controlling for COVID-19 risk factors. 36 It should be noted that chloroquine and hydroxychloroquine prolong the QT interval and may induce life-threatening arrhythmias. 37, 38 Thus, caution should be used in starting these agents in patients with QTc >450 ms. Concomitant use of other QT-prolonging agents is not recommended, and abnormal electrolyte levels must be avoided. 37, 38 Importantly, kalaemia must be maintained in a high to normal range. Other antiviral strategies (e.g. specific neutralising antibodies) are under investigation. Detailed lists of interactions of antiviral and commonly used drugs are available at https://www.covid19-druginteractions.org from the University of Liverpool; at https://www.crediblemeds.org; and also in Driggin et al. 16 Importantly, single-lead ECG with handheld devices will underestimate the QTc interval. Thus, for QT measurement, it is recommended to 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 (incremental QTc) is required to establish the baseline risk and proarrhythmia. 39 It is important to balance the risk of QTc measurement inaccuracy versus the risk of 12-lead ECG measurements in the pandemic situation. Maybe only high-risk patients should undergo systematic 12-lead ECG. Previous authors have been developing scores to predict the risk of QT prolongation with drugs. Although they are not validated for COVID-19, they are a clinical option. 40 Advanced stages of COVID-19 are related to cytokine storm syndromes with elevated levels of inflammatory biomarkers (e.g. IL-6 and highsensitivity CRP), identifying patients at high risk of progressing to severe disease and even death. 12, 41 Therefore, corticosteroids and IL-6 inhibitors have been used for patients with refractory shock or advanced ARDS in small cohorts. 42 Very limited data suggesting that adjunctive azithromycin to hydroxychloroquine might be useful has been published. 18 However, this drug might prolong the QT interval and special caution should be paid if combined with hydroxychloroquine.

Several other anti-inflammatory therapies are being investigated and might change the scenario in the future. Vaccines against SARS-CoV-2 are obviously meaningful but unavailable yet, although promising results begin to be published. 43,44

Because of limited testing and a large asymptomatic population, the true burden of SARS-CoV-2-infected people is still unknown and underestimated. Differing prevalences and clinical results might be (at least partially) explained by major differences in testing capacities between countries and regions, and by differences in test quality (sensitivity and specificity) but also by differences between populations.

Diverse (direct and indirect) mechanisms may facilitate cardiac involvement resulting in myocarditis, ACS and diverse cardiac arrhythmias. Several antiviral strategies are under investigation. It can be hypothesised that (as for HIV treatment) a combination of drugs will probably achieve the best clinical results. Vaccines against SARS-CoV-2 are urgently needed. Anti-arrhythmic treatments for COVID-19 are similar or identical to that for non-infected individuals. However, the avoidance of QT prolongation is essential, and possible drug-drug interactions must be considered. Elective procedures should be delayed, whereas urgent situations might require immediate treatment by trained and sufficiently equipped teams to ensure that healthcare workers do not become hosts or vectors of virus transmission.

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