key: cord-302821-b9ikg0xy
authors: Gawałko, Monika; Kapłon-Cieślicka, Agnieszka; Hohl, Mathias; Dobrev, Dobromir; Linz, Dominik
title: COVID-19 associated atrial fibrillation: Incidence, putative mechanisms and potential clinical implications
date: 2020-09-01
journal: Int J Cardiol Heart Vasc
DOI: 10.1016/j.ijcha.2020.100631
sha: 
doc_id: 302821
cord_uid: b9ikg0xy

Coronavirus disease 2019 (COVID-19) is a novel, highly transmittable and severe strain disease, which has rapidly spread worldwide. Despite epidemiological evidence linking COVID-19 withcardiovascular diseases, little is knownabout whether and how COVID-19 influences atrial fibrillation(AF), the most prevalent arrhythmia in clinical practice. Here, we review the available evidence for prevalence and incidence of AF in patients infected with the severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) and discuss disease management approaches and potential treatment options for COVID-19 infected AF patients.

Coronavirus disease 2019 (COVID-19) is a novel, highly transmittable and severe strain disease, which has rapidly spread worldwide. Currently, almost 11 million cases have been diagnosed and more than 500,000 infected people have died.(1) However, the true prevalence is likely much higher, as many individuals are asymptomatic and therefore never tested. Some reports show that up to 80% of infected individuals have mild to moderate symptoms and, in theory, represent a group that might not seek medical care and thus do not contribute to the estimated prevalence biasing the calculation of real infection rate. (2) (3) (4) Despite the fact that the pandemic is decelerating in most countries, the question remains whether an asymptomatic infection can affect and facilitate, like a "Trojan horse", the development of other diseases in the near future.

Although COVID-19 is mostly characterized by symptoms in the respiratory tract, cardiovascular diseases and complications frequently accompany COVID-19 infections increasing morbidity and mortality of COVID-19 patients. (5) Arrhythmias are frequently reported in COVID-19 patients, with atrial fibrillation (AF) being the most common form. Although electrical, calcium handling, and structural remodeling plays a key role in AF pathophysiology (6) (7) (8) (9) , the clinical presentation of AF is diverse and the precise mechanisms of AF remain unclear in a large proportion of patients. (10) The underlying causes of AF in COVID-19 patients are largely unknown. Here, we review the available evidence for prevalence and incidence of AF in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and discuss disease management approaches and potential treatment options for COVID-19 infected AF patients.

There are no specific reports on the occurrence of AF during COVID-19 infection. Based on available literature, among COVID-19 patients, AF was detected in 19% to 21% of all cases. (11, 12) One study reported a prevalence of 36% in patients with cardiovascular diseases, with AF being observed in 42% of patients who did not survive. (11) In a small report, up to 75% of hospitalized COVID-19 geriatric patients had a past history of AF. (13) The most recent statistics by the COVID-19 Task Force of Italian National Institute of Health showed that 24.5% of 355 non-surviving COVID-19 patients (mean age 79.5 years, 70% men) presented with AF before the SARS-CoV-2 infection. (14) In patients with severe pneumonia, acute respiratory distress syndrome (ARDS) and sepsis, the incidence of AF during hospitalization is usually high. (15- The adjusted odds ratio of a related event (ischemic stroke or all-cause death) during lockdown compared with the corresponding weeks was 1.41 (95% confidence interval 0.93-2.12).(25) These results likely reflect the fact that the majority of patients with first symptoms of AF were delaying or refusing care. Perhaps they were afraid of contact with medical services due to the pandemic, thereby postponing the initiation of anticoagulation and increasing their risk of thromboembolic complications.

It is very likely that only those who consequently did suffer from those complications were eventually hospitalized.

The COVID-19 infection is an acute disease with incubation period on average of five to six days, in some cases up to 14 days.(26) This relatively short time period is not sufficient to increase the risk of AF by for instance causing fibrosis, which usually requires weeks to months to develop. While atrial structural remodeling is important in providing the AF-maintaining substrate, AF onset and its paroxysms are often temporally related to acute COVID-19 infections. Of note, COVID-19 patients developing AF were older and most of them had at least one preexisting risk factor, including hypertension (19, 23) , while some did not report any illness. (19, 20, 27) Older age and occurrence of heart failure were also associated with greater likelihood of incident AF during the COVID-19

infection.(21) Therefore, COVID-19 patients with newly diagnosed AF may have a preexisting substrate for AF and the acute COVID-19 infection may provide the trigger for AF initiation, which is consistent with the temporal relationship between new-onset AF and the COVID-19 infection.

The pathophysiology of COVID-19 related AF is not well understood and proposed putative mechanisms include a reduction in angiotensin-converting enzyme 2 (ACE2) receptor availability, CD147-and sialic acid-spike protein interaction, enhanced inflammatory signalling eventually culmination in inflammatory cytokine storm, direct viral endothelial damage, electrolytes and acid-base balance abnormalities in the acute phase of severe illness and increased adrenergic drive.(28) (Fig. 1) .

ACE2, a membrane-bound protease, has been identified as a functional receptor for coronaviruses. (29) Although other receptors/facilitators on the surface of human cells such as sialic acid (30) and extracellular matrix metalloproteinase inducer (CD147) (31) have been also shown to mediate the entry of SARS-CoV-2, ACE2 appears to be the major and most studied entry pathway. Upon cleavage (priming) of the viral spike protein of SARS-CoV-2 by the transmembrane protease serine 2 (TMPRSS2), SARS-CoV-2 uses ACE2 to enter and infect multiple types of host cells such as pneumocytes, macrophages, endothelial cells, pericytes, and cardiomyocytes, among others.

ACE2 internalization after binding with SARS-CoV-2 results in a reduction of ACE2 at the cell surface suppressing a key pathway for angiotensin II (AngII) degradation to cardioprotective Ang1-7. The subsequent increase in AngII:Ang1-7 ratio following ACE2 internalization shifts the balance to AngII thereby promoting cardiac hypertrophy, vasoconstriction, tissue fibrosis and oxidative stress (32), potentially increasing the susceptibility to AF. AngII increases the activity of a disintegrin and metalloproteinase 17 (ADAM17) that cleaves its primary substrate to release soluble tumor necrosis factor-α (TNF-α) into the extracellular space where it exerts auto-and paracrine functions, along with ACE2 shedding from the cell membrane. Loss of ACE2 in the brain may also increase the sympathetic drive and impair the baroreflex, potentially promoting AF. (32) (33) (34) In addition, reduced expression of ACE2 in the vasculature may cause an activation of the kallikrein-bradykinin system, thereby increasing vascular permeability, promoting endothelial dysfunction and inflammation and exacerbating existing atherosclerosis and diabetes (35) , two common risk factors of AF. Decreases in cell surface ACE2 in the tubular epithelium of the kidney may also alter sodium transport causing kidney injury and hypertension (36) , also potentially promoting AF. Finally, loss of ACE2 promotes epicardial adipose tissue inflammation (37) , pericarditis and the development of pericardial effusion (22) , all of which may predispose to the development of AF, as epicardial fat has been linked to atrial electrical remodeling, progression and outcome of ablation AF. (38, 39) The spike proteins of a number of coronaviruses are able to bind to sialic acids present on the cell surface. N-acetylneuraminic acid is the predominant sialic acid found in human glycoproteins and gangliosides. (47) As N-acetylneuraminic acid plays a key role in severe coronary artery diseases, involving RhoA signaling pathway activation, which is critically involved in cardiac fibrosis, Nacetylneuraminic acid may contribute AF pathophysiology. (48) Future work should test this hypothesis.

Infection by SARS-CoV-2 is manifested by the evolution of systemic inflammation and immune cell overactivation, leading to a 'cytokine storm' triggered by an imbalance between T-helper-1 (Th1) and 

Hypokalemia is prevailing in patients with COVID-19 (61) and occurs in up to 61% of hospitalized patients. (61) This is assumed to be due to increased urinary and/or gastrointestinal loss of potassium. 

Severe infections activate the sympathetic nervous system (SNS), and there is also a relationship between SNS activity and AF. (69, 70) The putative underlying mechanisms likely involves a SNSmediated increase in calcium influx into the cardiomyocytes (71), with subsequent calcium overload of the sarcoplasmic reticulum, thereby increasing the frequency of spontaneous diastolic calcium releases via ryanodine receptor channels with subsequent generation of delayed afterdepolarizations and triggered action potentials, increasing the likelihood of AF induction. (72) It has been also demonstrated that inflammatory cytokines, particularly IL-6, can cause SNS hyperactivation, via both central hypothalamus-mediated (inflammatory reflex) and a peripheral (left stellate ganglia activation) pathways. (73) In some COVID-19 patients, anxiety may also cause a SNS hyperactivation with subsequent promotion of arrhythmias. (28) 

Contemporary therapy of AF with antiarrhythmic drugs and anticoagulants is complex and suboptimal and is associated with substantial side effects. (74, 75) Little data are available on the value of rhythm and rate control strategies in AF patients with COVID-19 patients. Intensified treatment of the underlying hypoxemia, inflammation and other reversible triggers (i.e. hypokalemia, hypomagnesaemia, acidosis) appears the empiric basis for treatment.

Urgent cardioversion (performed within days) should be considered in hemodynamically instable patients (also in case of acute myocardial infarction or acute heart failure) due to new-onset AF or in whom AF may be a participating factor". In the rest of patients, not in need of urgent cardioversion, the need for cardioversion should be balanced against the need for more equipment and personnel at the side of the patients, and the possible need for intubation (with the risk of increased viral aerosol creation). In critically ill patients with hemodynamic instability due to new-onset AF intravenous amiodarone is the antiarrhythmic drug of choice for rhythm control. (76) Notably, intravenous amiodarone can cause acute pulmonary toxicity and severe hypotension (76, 77) , therefore used with caution by clinicians. Sufficient rate control may be also achieved in critically ill patients using (Table S1 ; supplementary material) and several web pages (e.g. https://www.crediblemeds.org; www.covid19-druginteractions.org) provide a clinically useful, up-to-date, drug-drug interaction resource, freely available to healthcare workers, patients and researchers. Possible workflow of acute AF management is shown in Fig. 2 .

All AF ablation procedures should be postponed at least for three months, expect cases of AF causing severe symptoms such as in heart failure related AF. Medically refractory AF with repeated emergency room visits should be performed within less than three months.(18)

The first experiences in the Wuhan province in China and then in other parts of the world allowed to estimate the putative incidence of thromboembolic complications ranging from around 15% to 85% in hospitalized COVID-19 patients. (80) Of note, thromboembolic risk is influenced by race and ethnicity, and is significantly lower in Chinese compared to Caucasian individuals.(81) It is also genderdependent: men have a worse outcome compared to women, perhaps because the activation of endothelial estrogen receptors increases nitrogen oxide and decreases reactive oxygen species, protecting the vascular system from AngII-mediated vasoconstriction, inflammation, endothelial dysfunction and associated coagulation response. Impairment of the coagulation system, caused by SARS-CoV-2 infection, seems to increase the risk of thromboembolism in patients with AF, although this requires further investigation and validation. Given that during treatment with VKAs regular international normalized ratio monitoring is necessary, which may contribute to spreading of the infection, VKAs should be considered in specific patient populations such as those with mechanical prosthetic valves or antiphospholipid syndrome. Although data about the effects of VKAs in patients with COVID-19 are lacking, deficiency of vitamin K might be suspected to be associated with worse COVID-19 outcome. Based on pleiotropic effects of various vitamin K-dependent anticoagulant factors (proteins C and S) as well as a protein outside the coagulation cascade (matrix Gla protein, MGP), it is likely that vitamin K might play a key role in the pathogenesis of COVID-19. Recently, a Dutch study discovered that low vitamin K levels, assessed by measuring desphospho-uncarboxylated MGP (dp-ucMGP; inversely related to vitamin K status), are more often observed in patients with COVID-19 infection (vs healthy controls), and higher dp-ucMGP levels are found in COVID-19 patients who needed mechanical ventilation or died (vs patients without need of invasive ventilation).(88) Idiopathic pulmonary fibrosis (IPF) shows similarities with pulmonary COVID-19 infection, therefore the effects of VKA therapy in IPF patients that have been studied in two prospective clinical trials (89, 90) could be similar in COVID-19 patients. In contrast to the first study which showed a favorable effect of anticoagulants (LMWH followed by VKA therapy) on mortality related to IPF (89) , the second study demonstrated an increased mortality in patients treated with VKA alone. (90) It is important to bear in mind that vitamin K deficiency induced by administration of VKAs causes both elastic fiber degradation and calcification in an animal model (91) , which could contribute to the worse prognosis in IPF patients.

As heparins are not expected to interact with drugs used for COVID-19 treatment, they may be considered a safe and appealing alternative to oral anticoagulants for stroke prevention in AF patients hospitalized for COVID-19. Interestingly, in addition to the antithrombotic effect, the antiinflammatory actions of heparin might be also relevant in this setting. Heparan sulfate proteoglycans bind to SARS-CoV2 spike proteins and may decrease binding ability to host protein, and reduce the proinflammatory activities of damage associated molecular patterns, chemokines, neutrophil chemotaxis and leukocyte migration.(18) Consistent with this notion, LMWH therapy was associated with lower 28-day mortality in SARS-CoV-2-infected patients with signs of coagulopathy.(92) After recovery from the COVID-19 infection, the long-term anticoagulation should be continued based on the CHA2DS2-VASc score.

To protect vulnerable patients with AF from being infected by COVID-19, social distancing was implemented in vast majority of healthcare centers to prevent extensive spread of the virus between healthcare staff and patients, and face-to-face outpatient appointments were transferred into teleconsultations. Some of the centers moved forward and combined teleconsultations with remote rhythm and rate monitoring, enabling comprehensive AF management. An example of such approach is TeleCheck-AF project, integrated, so far, in 37 European centers. (93, 94) Further, this approach will change the current standard of care by reducing the number of hospital visits (planned and unplanned) and thereby reduce healthcare costs while maintaining appropriate AF treatment. Additionally, it may represent a good strategy to prepare for future crisis, when attendance of outpatient clinics or travelling to the hospital is not possible or undesirable.

Acute SARS-CoV-2 infection may increase the susceptibility to AF and promote the evolution of a prothrombotic state. The potential development of long-term complications including development of cardiac arrhythmias in COVID-19 survivors remains to be established, especially as COVID-19

survivors are unlikely to produce long-lasting protective antibodies against this virus (95, 96) , hence may be susceptible to reinfection within weeks or months. As in the acute phase of COVID-19 infection, the susceptibility to AF is increased and a worsening of existing AF likely, utilization of personal electrocardiogram devices as well as remote monitoring (teleconsultations) could optimize care of patients with AF and those with a high risk for developing AF. Infection by SARS-CoV-2, facilitated by TMPRSS2, is manifested by the progression of immune cell over-activation leading to "cytokine storm", ACE2 internalization and loss of both ACE2-mediated cardiovascular protection and fluid-electrolyte homeostasis, atrial structural changes via CD147-and sialic acid-spike protein, and hypoxemia. Subsequently, all abovementioned mechanisms result in myocardial injury and remodelling, sympathetic nervous system activation that coupled with electrolytes and fluids disturbances lead to conduction system disorder, hence atrial fibrillation susceptibility. 

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