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Cvaa 106

The review discusses the implications of COVID-19 on the cardiovascular system, highlighting the increased risk of severe infection and mortality associated with comorbidities such as cardiovascular disease, hypertension, and diabetes. It outlines the mechanisms of SARS-CoV-2 infection, the complications related to cardiac injury, and the importance of monitoring cardiac damage during hospitalization. The document emphasizes the need for a multidisciplinary approach to assess and treat cardiovascular conditions in COVID-19 patients to improve outcomes.

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0% found this document useful (0 votes)

11 views22 pages

Cvaa 106

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Cardiovascular Research (2020) 116, 1666–1687 REVIEW

doi:10.1093/cvr/cvaa106

COVID-19 and the cardiovascular system:

implications for risk assessment, diagnosis, and
treatment options
Tomasz J. Guzik 1,2*, Saidi A. Mohiddin 3,4, Anthony Dimarco3, Vimal Patel3,
Kostas Savvatis3, Federica M. Marelli-Berg4, Meena S. Madhur 5,
Maciej Tomaszewski 6, Pasquale Maffia 7,8, Fulvio D’Acquisto9, Stuart A. Nicklin 1,
Ali J. Marian10, Ryszard Nosalski 1,2, Eleanor C. Murray 1, Bartlomiej Guzik 11,
Colin Berry 1, Rhian M. Touyz1, Reinhold Kreutz 12, Dao Wen Wang13,
David Bhella 14, Orlando Sagliocco 15, Filippo Crea16, Emma C. Thomson7,14,17, and
Iain B. McInnes7
1
Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; 2Department of Internal Medicine, Jagiellonian
University, Collegium Medicum, Kraków, Poland; 3Barts Heart Center, St Bartholomew’s NHS Trust, London, UK; 4William Harvey Institute Queen Mary University of London, London,
UK; 5Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; 6Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester,
Manchester, UK; 7Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; 8Department of Pharmacy,
University of Naples Federico II, Naples, Italy; 9Department of Life Science, University of Roehampton, London, UK; 10Department of Medicine, Center for Cardiovascular Genetics,
Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, TX, USA; 11Jagiellonian University Medical College, Institute of Cardiology,
Department of Interventional Cardiology; John Paul II Hospital, Krakow, Poland; 12Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-
Universität zu Berlin, and Berlin Institute of Health, Institut für Klinische Pharmakologie und Toxikologie, Germany; 13Division of Cardiology and Department of Internal Medicine, Tongji
Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; 14MRC-University of Glasgow Centre for Virus Research, University of
Glasgow, UK; 15Emergency Department, Intensive Care Unit; ASST Bergamo Est Bolognini Hospital Bergamo, Italy; 16Department of Cardiovascular and Thoracic Sciences, Catholic
University of the Sacred Heart, Largo A. Gemelli, 8, 00168 Rome, Italy; and 17Department of Infectious Diseases, Queen Elizabeth University Hospital, Glasgow, UK

Received 5 April 2020; revised 11 April 2020; editorial decision 12 April 2020; accepted 14 April 2020; online publish-ahead-of-print 30 April 2020

This manuscript was independently handled by Deputy Editor Professor Charalambos Antoniades

Abstract The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical chal-
lenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and
mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial
pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the
cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is
increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer.
The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular
fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant
myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically,
SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane
angiotensin-converting enzyme 2 (ACE2) —a homologue of ACE—to enter type 2 pneumocytes, macrophages,
perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dys-
function, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for vi-
ral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis.
Hence, patients should not discontinue their use. Moreover, renin–angiotensin–aldosterone system (RAAS) inhibi-
tors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm
[interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and
continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization
may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social

* Corresponding author. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, UK. Email: Tomasz.guzik@glasgow.ac.uk
C The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
Published on behalf of the European Society of Cardiology. All rights reserved. V
COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options 1667

distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently
used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritona-
vir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.
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Keywords COVID-19 • Cardiac • Vascular • Microvascular • Endothelium • ACE2 • Myocarditis • Virus • Acute
coronary syndrome • Myocardial infarction

..
Introduction ..
..
knowledge available currently, regarding COVID-19, focusing on key
mechanistic and clinical aspects.
The novel coronavirus COVID-19 outbreak, first reported on 8
..
..
December 2019 in Hubei province in China, was designated as a pan- ..
demic by the World Health Organization (WHO) on 11 March 2020.
..
..
Properties of SARS-CoV-2
This disease, recognized as an infection with a new betacoronavirus by .. Coronaviruses are single-stranded positive-sense RNA viruses of be-
..
Dr Zhang Jixian from Hubei Provincial Hospital of Integrated Chinese .. tween 26 and 32 kb in length within the family Coronaviridae. There are
and Western Medicine, has been spreading exponentially in almost all ..
.. four genera in the subfamily Orthocoronavirinae, namely the alpha-, beta-,
countries around the world. The epicentre shifted from China to Europe .. gamma-, and deltacoronaviruses. Of these, alpha- and betacoronaviruses
in February/March 2020 and then to the USA in March/April 2020. ..
.. infect mammals while the gamma- and deltacoronaviruses infect birds.
Current data presenting information on international case numbers and .. There are seven coronaviruses that infect humans: the alphacoronavi-
case fatality are provided by the Johns Hopkins University (JHU) ..
.. ruses HCoV-NL63 and 229E, which tend to cause a mild illness in adults;
Coronavirus Resource Center (https://www.arcgis.com/apps/opsdash ... the betacoronaviruses Middle east respiratory syndrome (MERS) virus
board/index.html#/bda7594740fd40299423467b48e9ecf6).1,2 There are .. and severe acute respiratory syndrome (SARS) virus, which cause a se-
several other web-based resources that provide informative graphics on ..
.. vere respiratory illness; and OC43 and HKU1, which are associated with
the spread of the disease and the outcomes. The pandemic of COVID- .. a mild illness. An example electron microscopy image of a betacoronavi-
19 has multiple medical, psychological, and socio-economic consequen- ..
.. rus is shown in Figure 1. COVID-19 is caused by a novel betacoronavirus,
ces. COVID-19 represents probably the greatest threat that societies .. probably originating from bats following gain-of-function mutations
will face in the 21st century. Therefore, understanding its pathophysiol-
..
.. within the receptor-binding domain (RBD) and the acquisition of a furin-
ogy and clinical implications, and development of novel preventive and .. protease cleavage site. It has been named by the WHO as severe acute
therapeutic strategies are of primary importance.
..
.. respiratory syndrome coronavirus 2 (SARS-CoV-2).9
Based on reviewing the available data in the public databases, the risk .. Coronavirus receptor binding occurs via the spike protein (encoded
of infection and mortality increases with advancing age and shows sexual
..
.. by the structural S gene) which has two subunits. Subunit S1 mediates
dimorphism. Male elderly individuals are at the highest risk of infection, ..
as well as death. ..
..
Despite the tropism for the lungs where it causes interstitial pneumo- ..
nitis, in the most severe cases multiorgan failure develops. The cardiovas- ..
..
cular (CV) system appears to have complex interactions with COVID- ..
19. Published reports, medRxiv, bioRxiv, and personal communications
..
..
and experience of the co-authors detail evidence of myocardial injury in ..
20–40% of hospitalized cases manifesting as cardiac chest pain, fulminant
..
..
heart failure, cardiac arrhythmias, and cardiac death. Indeed, symptoms ..
of cardiac chest pain and palpitations are the presenting features in some
..
..
patients.3–6 ..
While COVID-19 is non-discriminatory, involving both healthy per-
..
..
sons and those with comorbid conditions, approximately half of ..
..
those admitted to hospitals in Huabei province with COVID-19 had ..
known comorbidities. The number of patients with comorbid condi- ..
..
tions increased to about two-thirds in those requiring intensive care ..
unit (ICU) admission or those that did not survive. Patients with pre- ..
..
existing CV conditions (hypertension in particular) had the highest ..
morbidity (10.5%) following infection.7,8 Non-CV comorbidities, in- ..
..
cluding diabetes, lung diseases, and obesity, the latter identified in ..
current Italian and Dutch cohorts, are also major predictors of poor ..
.. Figure 1 Characteristic structure of betacoronavirus. Negative stain
clinical outcomes. Similarly, in the recent analysis of 5700 Patients .. electron microscopy showing a betacoronavirus particles with club-
Hospitalized With COVID-19 in the New York City Area the most ..
.. shaped surface projections surrounding the periphery of the particle, a
common comorbidities were hypertension (57%), obesity (42%), and .. characteristic feature of coronaviruses. The photograph depicts a mu-
diabetes (34%).167 These aspects emphasize the importance of the .. rine coronavirus. Kindly provided by Professor David Bhella, Scottish
..
need for multidisciplinary assessment and treatment, including CV .. Centre for Macromolecular Imaging; MRC Centre for Virus Research;
evaluation and therapy, during the course of COVID-19 to reduce .. University of Glasgow.
..
mortality. In this rapid review, we summarize the state-of-the-art .
1668 T.J. Guzik et al.

..
.. severe respiratory infection in 2003 or than influenza.13 It is associated
.. with higher viral loads in infected people (up to a billion RNA copies per
..
.. milliltre of sputum) and long-term resistance on contaminated surfaces.
.. SARS-CoV-2 is more stable on plastic and stainless steel than on copper
..
.. and cardboard, and viable virus may be detected up to 72 h after applica-
.. tion to these surfaces.14 Patients with severe COVID-19 tend to have a
..
.. high viral load and a long virus-shedding period. This finding suggests that
.. the viral load of SARS-CoV-2 might be a useful marker for assessing dis-
..
.. ease severity and prognosis.15 At the same time, pronounced nucleic
.. acid shedding of SARS-CoV-2 was observed for 7 days in mild cases.15
..
.. To better appreciate the links between cardiovascular disease (CVD)
.. and COVID-19, it is important to understand the underlying pathobiol-
..
.. ogy of coronavirus infection. SARS-CoV-2 binds to the transmembrane
.. ACE2 protein (a homologue of ACE) to enter type II alveolar epithelial
..
.. cells, macrophages, and other cell types12 (Figure 2). The process
.. requires priming of viral S protein by the cellular serine protease
..
.. TMPRSS2.12 Thus, infection with SARS-CoV-2 requires co-expression of
.. ACE2 and TMPRSS2 in the same cell type, as proteolytic cleavage of viral
..
.. S protein is essential for binding of the virus to ACE2. Exploitation of
.. ACE2 by coronavirus is important in predicting potential pathology as
..
.. ACE2 is particularly highly expressed in pericytes, in addition to type II al-
.. 16
.. veolar epithelial cells, according to the single-cell human heart atlas.
.. High expression of ACE2 in pericytes could lead to development of mi-
Figure 2 Basic pathobiology of SARS-CoV-2 infection and possible ..
treatment strategies. Upon the viral spike protein priming by the trans-
.. crovascular dysfunction,17 explaining greater propensity for acute coro-
.. nary syndromes (ACS).5 Moreover, ACE2 expression is up-regulated in
membrane protease serine 2 (TMPRSS2), SARS-CoV-2 uses the host ..
angiotensin-converting enzyme 2 (ACE2) to enter and infect the cell. .. failing human hearts, suggesting a plausible explanation for a higher infec-
.. tivity of virus and a higher mortality in patients with heart failure.18
Inhibiting TMPRSS2 activity (by camostat mesylate) could be used to ..
prevent proteolytic cleavage of the SARS-CoV-2 spike protein and pro- .. Moreover, cellular entry of coronaviruses through ACE2 has implica-
tect the cell against virus–cell fusion (1). Another approach could be
.. tions for vascular instability and hypotension as well as increased mortal-
..
neutralizing the virus from entering cells and keeping it in solution by ac- .. ity of infected patients who have pre-existing hypertension, albeit the
tivation of a disintegrin and metalloprotease 17 (ADMA17) which leads .. latter association is confounded by the older age of patients with comor-
..
to shedding of the membrane-bound ACE2 and release of the soluble .. bidities. In addition to pathogenicity and transmissibility of the virus,
extracellular domain of ACE2 (2); with treatment with anti-ACE2 anti- .. these findings also have therapeutic implications, as inhibition of the cel-
bodies leading to blockage of the interaction between virus and recep- ..
.. lular serine protease TMPRSS2 and sera containing blocking antibodies
tors (3) or administration of soluble recombinant human ACE2 protein .. against ACE2 have the potential to block viral entry and hence prevent
acting as a competitive interceptor for SARS-CoV-2 (4). Alternatively, ..
purified polyclonal antibodies targeting/neutralizing the viral spike pro-
.. or attenuate COVID-19 (Figure 2). In a murine model, TMPRSS2 inhibi-
.. tion blocked viral entry and attenuated the severity of coronavirus infec-
tein may offer some protection against SARS-CoV-2 (5). Interestingly, ..
angiotensin receptor blockers (ARBs) and angiotensin-converting en- .. tion with improved survival.19,20 Two clinical trials have been started
.. to test the efficacy of inhibition of TMPRSS2 by camostat mesilate
zyme inhibitors (ACEIs), frequently used to treat hypertension, could ..
alter ACE2 expression and intensify the SARS-CoV-2 infection. .. for the treatment of patients with COVID-19 (NCT04321096 and
.. NCT04338906).
..
..
..
..
binding and a trimeric S2 stalk mediates fusion to the infected cell. The S1 .. Methodological considerations of current
.. clinical data on COVID-19
subunit is divided into two domains, the N-terminal domain (S1-NTD) ..
and the C-terminal domain (S1-CTD). These regions mediate binding to .. Our understanding of COVID-19 pathomechanisms, natural clinical his-
..
a variety of cellular receptors containing carbohydrate or protein at their .. tory, and possible therapies are evolving continuously. While in this re-
binding domains. SARS-CoV and SARS-CoV-2 (and the alphacoronavirus .. view we have collated contemporary literature regarding this pandemic
..
HCoV-NL63) all bind via the S1-CTD to the angiotensin-converting en- .. to enable a comprehensive overview, numerous methodological consid-
zyme 2 (ACE2) receptor (Figure 2).9 SARS-CoV-2 has a higher affinity for .. erations need to be taken into account regarding study design and data
..
binding to ACE2 than SARS-CoV, and binding involves a larger number .. collection. The sources used to generate this review are original articles
of interaction sites.10,11 A pre-requisite for binding of SARS-CoV-2 to .. published in PubMed, posted on medRxiv, bioRxiv, or ChinaXiv, or listed in
..
ACE2 is cleavage of the S protein of the virus by the transmembrane ser- .. clinical trial databases (ClinicalTrial.gov and EudraCT). In addition, public
ine protease TMPRSS212 (Figure 2). Replication occurs via the RNA- .. databases such as World Health Organization, Centers for Disease
..
dependent RNA polymerase and involves discontinuous transcription of .. Control (CRCs), and the JHU Coronavirus Resource Center were utilized.
subgenomic mRNAs that encode six major open reading frames com- .. The early studies in a pandemic might suffer from inclusion bias.
..
mon to all coronaviruses and multiple accessory proteins. .. Baseline demographics and pre-morbid status of study populations are
Importantly, SARS-CoV-2 transmission occurs at a higher basic repro-
.. expected to reflect the characteristics of individuals who were exposed
..
duction rate (R0 = 2–2.5) than SARS-CoV that caused an outbreak of . to the disease early in the outbreak. In addition, availability and access to
COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options 1669

..
diagnostic testing as well as a high threshold for diagnostic testing or hos- .. and bronchial epithelial cell damage.23 Lymphocyte and mononuclear
pital treatment or suitability for ICU admission, because of finite resour- .. cell infiltrates are present in alveolar septal spaces. Fibrinous exudate
..
ces, are expected to affect characteristics of the study populations and .. and high hyaline membranes fill alveolar cavities. Polynuclear giant cells
the clinical outcomes of the disease. For example, a large number of .. are prominent. There is marked proliferation of type II alveolar epithelial
..
healthcare workers and inpatients were exposed to COVID-19 in the .. cells. Such severe manifestations appear only in a fraction of patients.
hospital in the early, rather than the later phase in the pandemic in .. A recent study of COVID-19 cases in China reported up to 28 January
..
China.21 The demographics of patients in the early studies from China .. 2020 indicated that severe illness may occur in 16% of cases,22 leading to
were different from those reported later in the largest aggregate study .. an overall mortality rate estimated at 1.4% of the total reported cases22
..
of COVID-19 patients by Guan et al. in China22 (Table 1). Data on car- .. to 4.61% in the WHO reports (accessed on 28 March 2020). In some
diac involvement are unfortunately not extensively presented in the .. geographical regions, due to unexplained reasons, mortality may be
..
study of Guan et al.22 .. higher (current estimates are 11.9% in Italy, 9.0% in Spain, and 7.9% in
The National Health Commission of the People’s Republic of China .. the UK according to the JHU Coronavirus Resource Center, accessed
..
(PRC) guidance23 recommends the use of traditional Chinese medicine .. on 2 April, 20202). It is important to note, however, that great care must
alongside what is considered more conventional interventions. The pub- .. be taken when calculating fatality rates based on currently available data,
..
lished reports do not provide details of the traditional treatment regi- .. as these can be overestimated in relation to insufficient testing in the
mens in patients with COVID-19. Therefore, different choices of
.. community or underestimated, due to long lag-time between test posi-
..
therapy were made and any positive/negative impacts of such interven- .. tivity and death or the fact that there are large differences in attributing
tions, which may have influenced outcomes, might have introduced addi-
.. COVID-related mortality (‘dying with’ versus ‘dying from’ as well as dif-
..
tional bias. .. ferences in performing post-mortem testing). Limitations of healthcare
Finally, it is also difficult to assess the true prevalence, occurrence,
.. systems, abruptly overwhelmed by a surge of patients needing mechani-
..
mortality, and spectrum of the clinical course of disease since a propor- .. cal invasive ventilation, have also been considered a potential source of
..
tion of inoculated individuals might be asymptomatic and therefore were .. the differences. Finally, these differences may result from population
never tested. Some in silico modelling of the infection expansion as well .. structure, as Italian patients have been older than the average age
..
as in initial reports from Iceland and Italy suggest that an asymptomatic .. reported in the Chinese patients.
group, perhaps as high as 50% of infected individuals (DeCODE .. The typical clinical course of disease is summarized in Figure 3. The
..
Genetics, Iceland), probably exists. This finding has considerable implica- .. heterogeneity of responses between individual patients is striking.
tions in estimating the prevalence and preventing spread of the disease. .. This indicates that it is unlikely that COVID-19 can be considered
..
Likewise, some reports show that up to 80% of infected individuals have .. from the point of view of a single disease phenotype. Rather, it
mild symptoms and in theory represent a group that might not seek .. seems most likely that host characteristics, which at the moment re-
..
medical care—they might not, therefore, be tested or contribute to .. main unknown, promote progression of the disease with a range of
prevalence and case fatality rate (CFR) estimates. Secondly, practically all .. different presentarions, e.g. mild, severe multiorgan failure, and cyto-
..
countries experience shortage of the testing kits, therefore limiting the .. kine release storm.
testing only to selected groups of individuals. Moreover, some deaths .. While clinical symptoms of the disease are predominantly respiratory
..
caused by SARS-CoV-2 were not attributed to COVID-19, due to the .. and associated with severe pneumonia, both direct and indirect involve-
lag time when severe complications tend to develop even up to 2–3 .. ment of other organs is common, with the CV system being particularly
..
weeks following the initial infection.8 .. affected. Moreover, pre-existing conditions, largely linked to CVD, in-
.. crease the risk of severe outcomes of the infection.
..
Clinical course of COVID-19 ..
The incubation period between contact and the first set of symptoms is
..
..
typically 1–14 days (but up to 24 days in individual cases).23 The median .. Cardiovascular risk factors associated with
time between registered exposure and first symptoms is 5.1 days with a
.. the worse outcomes of COVID-19
..
mean of 6.1 days.24 Duration of viral nucleic acid shedding ranges be- .. A number of key comorbidities are associated with worse clinical out-
..
tween 8 and 34 days (median 20 days) after the initial symptoms .. comes in patients with COVID-19 (Table 1). Association with age seems
(Figure 3). .. to dominate this relationship22 and may affect the actual importance of
..
The main clinical symptoms develop within 11.5 days [95% confidence .. other factors reported in univariate analyses. Older patients (mean age
interval (CI) 8.2–15.6 days] and include fever, dry cough, fatigue, ageusia, .. 63 years old; range 53–71) are more likely to experience the composite
..
anosmia, and headache.24 Other non-specific symptoms have also been .. endpoint of ICU admission, mechanical ventilation, or death compared
reported, which included nasal congestion, rhinorrhea, sore throat, my- .. with younger patients (mean age 46 years old, range 35–57)22 (Table 1).
..
algia, poor appetite, and diarrhoea.21 Fever and cough typically appear .. Males seem to be more susceptible to COVID-19-related complications,
concomitantly, followed by shortness of breath and severe fatigue, which .. representing between 50% and 82% of the hospitalized patients in the
..
appear around day 6–76 and are associated with development of severe .. four publications that report these data (Table 1) and the most recent re-
bilateral (and occasional unilateral) pneumonia (Figure 4). .. port from Italy.27
..
The most common radiological findings include multiple patchy shad- .. Table 1 summarizes key comorbidities identified by the major studies
ows and interstitial changes in moderate disease, with consolidation, a .. from China showing that the presence of pre-existing morbidities
..
ground glass appearance, in 56.4% of cases,22 and very occasional pleural .. increases the severity of hospital-treated COVID-19. Notably, there is a
effusions in severe cases.23 In such severe cases, pneumomediastinum .. large heterogeneity of reporting, with some studies comparing death
..
and pneumothorax have been described.25,26 .. with survival and others comparing ICU with non-ICU cases (Table 1).
Pathological investigations of the lungs of deceased individuals indicate
.. However, regardless of the approach, pre-existing CV conditions seem
..
blockade of bronchi and bronchioles with large amounts of mucus plugs . to be particularly important predictors of COVID-19 severity.
1670 T.J. Guzik et al.

Table 1 Baseline demographic data and comorbidities in selected early studies3,6,18,21,22,32

Study Region All patients Severity qualification Lower severity High severity P-value
..............................................................................................................................................................................................................................
Gender (M = 51.3%, F = 48.7% in China); n (% men)
Huang et al. Jin Yin-Tan 41 (73%) Non-ICU/ICU 28 (68%) 13 (85%) 0.24
Wang et al. Zongnan 138 (54%) Non-ICU/ICU 102 (52%) 36 (61%) 0.34
Zhou et al. JY-T and Wuhan 191 (62%) Survive/dead 137 (59%) 54 (70%) 0.15
Ruan et al. Tongji 150 Survive/dead 82 68 0.43
Liu et al. Tongi þ three others 78 (50%) Stable/deteriorate 6 (48%) 11 (64%) 0.52
Guan et al. 31 provinces/provincial municipalities 1099 (58%) Non-severe/severe 926 (58%) 17 3 (58%) n/a
Guan et al. 31 provinces/provincial municipalities 1099 (58%) Stable/endpoint 1032 (58%) 67 (67%) n/a
Age; n, years (IQR)
Huang et al. Jin Yin-Tan 4149 (41–58) Non-ICU/ICU 2849 (41–58) 1349 (41–61) 0.6
Wang et al. Zongnan 138, 56 (42–68) Non-ICU/ICU 102, 51 (37–62) 36, 66 (57–78) <0.001
Zhou et al. JY-T and Wuhan 191, 56 (46–67) Survive/dead 137, 52 (45–58) 54 (63–67) <0.001
Ruan et al. Tongji 150 Survive/dead 82 68 <0.001
Liu et al. Tongi þ three others 78, 38 (33–57) Stable/deteriorate 66, 37 (32–41) 11, 66 (51–79) 0.001
Guan et al. 31 provinces/provincial municipalities 1099, 47 (35–58) Non-severe/severe 926, 45 (34–57) 137, 52 (40–65) <0.001
Guan et al. 31 provinces/provincial municipalities 1099, 47 (35–58) Stable/endpoint 1032, 46 (35–57) 67, 63 (53–71) <0.001
Any comorbidity; n (%)
Huang et al. Jin Yin-Tan 41 (32%) Non-ICU/ICU 28 (29%) 13 (38%) 0.53
Wang et al. Zongnan 138 (46%) Non-ICU/ICU 102 (37%) 36 (72%) <0.001
Zhou et al. JY-T and Wuhan 191 (48%) Survive/dead 137 (40%) 54 (67%) 0.001
Ruan et al. Tongji 150 (51%) Survive/dead 82 (41%) 68 (63%) 0.0069
Liu et al. Tongi þ three others 78 Stable/deteriorate 66 11 –
Guan et al. 31 provinces/provincial municipalities 1099 (24%) Non-severe/severe 926 (21%) 173 (39%) –
Guan et al. 31 provinces/provincial municipalities 1099 (24%) stable/CEP 1032 (21%) 57 (58%) –
Hypertension (prevalence 15–33% WHO data/Bundy); n (%)
Huang et al. Jin Yin-Tan 41 (15%) Non-ICU/ICU 28 (14%) 13 (15%) 0.93
Wang et al. Zongnan 138 (31%) Non-ICU/ICU 102 (22%) 36 (58%) <0.001
Zhou et al. JY-T and Wuhan 191 (30%) Survive/dead 137 (23%) 54 (48%) 0.0008
Ruan et al. Tongji 150 Survive/dead 82 68 –
Liu et al. Tongi þ three others 78 (40%) Stable/deteriorate 66 (9%) 11 (18%) 0.3
Guan et al. 31 provinces/provincial municipalities 1099 (15%) Non-severe/severe 926 (13%) 173 (24%) –
Guan et al. 31 provinces/provincial municipalities 109 (15%) Stable/endpoint 1032 (14%) 67 (36%) –
Diabetes mellitus [general rate in China is 8.4–10% (Diabetes UK, WHO)]; n (%)
Huang et al. Jin Yin-Tan 41 (20%) Non-ICU/ICU 28 (25%) 13 (8%) 0.16
Wang et al. Zongnan 138 (10%) Non-ICU/ICU 102 (6%) 36 (22%) 0.009
Zhou et al. JY-T and Wuhan 191 (19%) Survive/dead 137 (14%) 45 (31%) 0.005
Ruan et al. Tongji 150 Survive/dead 82 68 –
Liu et al. Tongi þ three others 78 (25%) Stable/deteriorate 66 (5%) 11 (18%) 0.143
Guan et al. 31 provinces/provincial municipalities 1099 (7%) Non-severe/severe 926 (5%) 173 (16%) –
Guan et al. 31 provinces/provincial municipalities 1099 (7%) Stable/endpoint 1032 (6%) 67 (27%) –
Renal disease (CKD: 10.8% in China, Wang, Jinwei et al.); n (%)
Huang et al. Jin Yin-Tan 41 Non-ICU/ICU 28 13 –
Wang et al. Zongnan 138 (3%) Non-ICU/ICU 102 (2%) 36 (6%) 0.28
Zhou et al. JY-T and Wuhan 191 (1%) Survive/dead 137 (0%) 54 (4%) 0.02
Ruan et al. Tongji 150 Survive/dead 82 68 –
Liu et al. Tongi þ three others 78 Stable/deteriorate 66 11 –
Guan et al. 31 provinces/provincial municipalities 1099 (8%) Non-severe/severe 926 (0.5%) 173 (2%) –
Guan et al. 31 provinces/provincial municipalities 1099 (8%) Stable/endpoint 1032 (0.6%) 67 (3%) –
COPD (5.7% in 2018, Zhu B); n (%)
Huang et al. Jin Yin-Tan 41 (2%) Non-ICU/ICU 28 (0%) 13 (8%) 0.14
Wang et al. Zongnan 138 (3%) Non-ICU/ICU 102 (1%) 36 (8%) 0.54
Zhou et al. JY-T and Wuhan 191 (3%) Survive/dead 137 (1%) 54 (7%) 0.047
Ruan et al. Tongji 150 Survive/dead 82 68 –
Continued
COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options 1671

Table 1 Continued

n/a, not available; ICU, intensive care unit; endpoint, composite endpoint of admission to an ICU, the use of mechanical ventilation, or death;22 CKD, chronic kidney disease.
These should be analysed in the context of recent European data which appeared after submission of this paper.27
Guan et al. present data based on disease severity at the time of assessment (using American Thoracic Society guidelines for community-acquired pneumonia) and according to
composite endpoint status (EP: ICU admission, ventilation, or death).

The Novel Coronavirus Pneumonia Emergency Response

.. accordingly, published frequencies of these comorbidities in China are
..
Epidemiology Team recently analysed all COVID-19 cases reported to .. included in Table 1. Surprisingly, a history of smoking and of chronic pul-
China’s Infectious Disease Information System up to 11 February 2020.7
.. monary disease appear to be far less powerful determinants of severity
..
The investigators found that the fatality rate for patients with no comor- .. in hospitalized patients than is the history of CVD. Curiously, the preva-
bidities was 0.9%, whereas the CFR was much higher for patients with
.. lence of smoking in hospitalized COVID-19 patients appears far lower
..
comorbidities. This included mortality of 10.5% for patients with CVD, .. than might be expected from assumed population prevalence and pri-
..
7.3% for those with diabetes, 6% for subjects with hypertension, 6.3% .. mary respiratory infection
for those with chronic respiratory disease, and 6.0% for those with can- ..
..
cer.28–30 It was as high as 14.8% for patients >_80 years of age.7,30 It is in- ..
teresting that in Italian and Dutch cohorts, there are reports of higher .. COVID-19 and hypertension
..
severity in younger obese individuals as well. Severe cases accounted for .. It is not clear if hypertension is a risk factor for susceptibility to SARS-
13.8%, and critical cases accounted for 4.7% of all cases. Of significance, .. CoV-2 infection—the available data show prevalence rates of 15–40%,
..
CVD occurrence affects the mortality rate to a larger extent than the .. largely in line with the rates of high blood pressure in the general popula-
presence of pre-existing chronic obstructive pulmonary disease .. tion (30%).22,31 At first glance, hypertension is more prevalent in sub-
..
(COPD), which had not been the case in SARS.7 .. jects with a more severe course of the disease. In a recent analysis from
These observations are confirmed by a recent meta-analysis, based .. China,22 it was present in 13.4% of subjects with non-severe disease and
..
largely on these studies and an additional 44 672 patient data set .. in 23.7% of subjects with severe disease. This study also included a com-
reported by the China CDC.28 In this large cohort, CVD was reported .. posite outcome, which was also associated with a higher prevalence of
..
in 4.2% of the total population and in 22.7% of those who died.28 By ex- .. hypertension in those with a poor composite outcome (35.8% vs.
tension, it is expected that comorbidities are associated with higher rates .. 13.7%). In the cohort of 44 672 patients reported by the China CDC,28
..
of hospitalization in patients with COVID-19, but any effects that comor- .. hypertension prevalence was reported as 12.8% in the whole group of
bidities may have on susceptibility to infection remain conjectural:
.. patients and as 39.7% in patients who eventually died.28 Hypertension
1672 T.J. Guzik et al.

Figure 3 Key symptoms, and biochemical and radiological features of the clinical course of COVID-19.

was reported to increase the odds ratio (OR) for death by 3.05 (95% CI
.. respiratory distress syndrome (ARDS), and increased mortality in unad-
..
1.57–5.92)32 in patients with COVID-19. These associations may, how- .. justed analyses, there is no strong evidence to indicate increased suscep-
..
ever, be largely confounded by the higher prevalence of hypertension in .. tibility of patients with hypertension to COVID-19, when the association
older people, as older individuals have significantly worse outcomes, .. is adjusted for other risk factors.33
..
more severe course of the disease, and a higher mortality rate than the .. The mechanisms of this possible relationship and their clinical rele-
younger patients.22 Thus, in summary, while hypertension does appear .. vance have been reviewed in a recent statement of the European
..
to be associated with more severe disease, a higher risk of acute .. Society of Hypertension.33 The putative relationship between
COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options 1673

..
.. COVID-19, that could be linked due to reduced albumin levels, which
.. are commonly seen, and/or Ca2þ consumption through excessive acti-
..
.. vation of the coagulation cascade.
.. Another mechanism linking hypertension and COVID-19 is the im-
..
.. mune system, which is dysregulated in hypertension and SARS-CoV-2 in-
.. fection.39,40 Poor control of blood pressure may contribute to further
..
.. dysregulation of the immune system. For example, it has been shown
.. that hypertension, in humans, is associated with circulating lymphocyte
..
.. counts,41 and CD8þ T cell dysfunction is observed in patients with hy-
.. pertension42. Such immunosenescent CD8þ T cells are unable to effi-
..
.. ciently combat viral infections, and contribute to pathological
.. overproduction of cytokines—a situation providing a possible link to
Figure 4 Multifocal pneumonia in a patient with COVID-19. (A) A
..
.. COVID-19. One may also postulate that ACEIs or ARBs, by providing a
cross-sectional CT image of the lungs showing two distinct pulmonary .. better control of blood pressure, may restore, at least partially, the dys-
infiltrates in the left upper lobe (arrows). (B) A large posteriorly located ..
.. regulated immune system in hypertension.
right lower lobe infiltrate on CT scan of the chest (arrows). Data were .. Overall it is essential to ensure that blood pressure control in hyper-
collected as part of a retrospective study, consent was waived, and col- ..
lection of these data was approved by local ethics committee of
.. tensive patients during viral infections is optimized, unnecessary and
.. uncontrolled changes to therapy are discouraged, and hypertensive
Wuhan, China. Kindly provided by Professor Dao Wen Wang. ..
.. patients should be carefully monitored for CV and other complications
.. during COVID-19 infection.
..
..
hypertension and COVID-19 may relate to the role of ACE2. ACE2
..
.. Cardiovascular manifestations of
is a key element in the renin–angiotensin–aldosterone system (RAAS), ..
.. COVID-19
which is critically involved in the pathophysiology of hypertension.34 .. Severe COVID-19 is associated with rapidly progressing systemic inflam-
Experimental studies demonstrated that inhibition of the RAAS with ..
.. mation, a pro-inflammatory cytokine storm, and sepsis, leading to multi-
ACE inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) .. organ failure and death (Figure 5). Selected evidence and manifestations
may result in a compensatory increase in tissue levels of ACE2,35 ..
.. of CV injury in COVID-19 patients are summarized in Table 2.
leading to suggestions that these drugs may be detrimental in patients .. Importantly, there is a delay between initiation of symptoms and myo-
exposed to SARS-CoV-2.36 It is important, however, to emphasize ..
.. cardial damage in studies reported so far (Table 3).
that there is no clear evidence that ACEIs or ARBs lead to up- ..
regulation of ACE2 in human tissues.36 Thus, currently there is no jus- ..
.. COVID-19 and cardiac arrhythmia
tification for stopping ACEIs or ARBs in patients at risk of COVID- ..
19.33 This has now been endorsed officially by many learned Societies, .. Viral infections are associated with metabolic dysfunction, myocardial in-
.. flammation, and activation of the sympathetic nervous system, all of
including the European Society of Hypertension, the International ..
Society of Hypertension, and the European Society of Cardiology.33 It .. which predispose to cardiac arrhythmia. In a recent report on 138 hospi-
.. talized COVID-19 patients,21 16.7% of patients developed arrhythmias,
also appears that in experimental models some RAAS blockers may ..
exert a potentially protective influence.37 Indeed, while angiotensin II .. which ranked only second among serious complications after ARDS.
.. Arrhythmia was observed in 7% of patients who did not require ICU
promoted the internalization and intracellular degradation of ACE2, ..
losartan reduced this effect, suggesting that ARBs may offer protection
.. treatment and in 44% of subjects who were admitted to an ICU.18
.. Further details of these manifestations remain elusive but included atrial
against viral entry into cells.36 The recent integrative antiviral drug ..
repurposing analysis implicated another ARB—irbesartan—as a poten-
.. fibrillation, conduction block, ventricular tachycardia, and ventricular fi-
.. brillation. These arrhythmias are also observed in viral myocarditis.
tial repurposable medication for COVID-19.10 In fact, the known ef- ..
fect of ARBs on potassium metabolism may be seen as clinically
.. Interestingly, the report of the National Health Commission of China
.. estimates that during the initial outbreak, some patients reported pri-
advantageous in patients infected by COVID-19 given that hypokalae- ..
mia was reported as a fairly common manifestation of COVID-19
.. marily CV symptoms, such as palpitations and chest tightness, rather
.. than respiratory symptoms.43
(possibly through increased kaliuresis rather than gastrointestinal ..
..
loss).38 Hypokalaemia in COVID-19 patients is difficult to manage, ..
correlates with the severity of the disease, and has been suggested to .. COVID-19 and myocardial injury and heart
..
be driven by activation of the RAAS.38 ACEIs or ARBs might offer .. failure
some protection in this setting. It also needs to be emphasized that .. Most reports indicate that almost all hospitalized COVID-19 patients
..
hypokalaemia has not been reported in other studies. For example, in .. show elevated serum creatine kinase (CK) and lactate dehydrogenase
a patient characterization by Guan et al.,22 the median value of the .. (LDH) levels.6,43,44 In addition, a number of studies indicate that cardiac
..
potassium level reported was 3.8 mmol/L with the lower margin of .. complications, including fulminant myocarditis, are potential outcomes
the interquartile range (IQR) at 3.5 mmol/L. Nevertheless, antihyper- .. of SARS-CoV-2 infection. Heart failure has been reported as an outcome
..
tensive medications known to increase serum levels of potassium (in- .. in 23% of COVID subjects in a recent report from in-hospital Chinese
cluding carvedilol and eplerenone) were implicated as potential drug .. subjects. Approximately 52% of non-survivors had heart failure as com-
..
repurposing opportunities for patients with COVID-19 infection.10 .. pared with 12% of survivors.32 Evidence of myocardial injury, such as an
Moreover, observations from ICUs in Italy suggest that hypocalcaemia .. increase in high-sensitivity cardiac troponin I (cTnI) levels (>28 pg/mL)
..
is a common metabolic abnormality in patients infected by . was detected in 5 of the first 41 patients diagnosed with COVID-19 in
1674 T.J. Guzik et al.

Figure 5 Cardiovascular involvement in COVID-19—key manifestations and hypothetical mechanisms. SARS-CoV-2 anchors on transmembrane ACE2
to enter the host cells including type 2 pneumocytes, macrophages, endothelial cells, pericytes, and cardiac myocytes, leading to inflammation and multiorgan
failure. In particular, the infection of endothelial cells or pericytes could lead to severe microvascular and macrovascular dysfunction. Furthermore, in con-
junction with the immune over-reactivity, it can potentially destabilize atherosclerotic plaques and explain the development of the acute coronary syn-
dromes. Infection of the respiratory tract, particularly of type 2 pneumocytes, by SARS-CoV-2 is manifested by the progression of systemic inflammation
and immune cell overactivation, leading to a ‘cytokine storm’, which results in an elevated level of cytokines such as IL-6, IL-7, IL-22, and CXCL10.
Subsequently, it is possible that activated T cells and macrophages may infiltrate infected myocardium, resulting in the development of fulminant myocarditis
and severe cardiac damage. This process could be further intensified by the cytokine storm. Similarly, the viral invasion could cause cardiac myocyte damage
directly leading to myocardial dysfunction and contribute to the development of arrhythmia.
COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options 1675

Table 2 Cardiac and associated outcomes in hospitalized COVID-19 disease in selected early studies3,6,18,21, 22,32

ICU, intensive care unit; ARDS, acute respiratory distress syndrome; AKI, acute kidney injury.
P-values are provided if they were provided in the publication.

..
.. type natriuretic peptide (NT-proBNP) in 27.5% of the cases, and cTnI in
Table 3 Delays from illness onset to complication .. 10% of deceased patients, respectively, indicating that the effects of CV
(adapted from Zhou et al.; n ¼ 191; survive ¼ 137; die ¼ 54) ..
.. injury on systemic stability may be important and should not be ignored.
All (191) Non-survivors (54)
.. In another report of 138 inpatients with COVID-19 in Wuhan, the levels
...................................................................................................... ..
.. of biomarkers of myocardial injury were significantly higher in patients
Sepsis In 59%: 9 days (7–13) In 100%: 10 days (7–14) .. treated in the ICU as compared with those not requiring ICU care (me-
..
ARDS In 31%: 12 days (8–15) In 93%: 12 days (8–15) .. dian CK-MB level 18 U/L vs. 14 U/L, P < 0.001; hs-cTnI level 11.0 pg/mL
Acute cardiac injury In 17%: 15 days (10–17) In 59%: 14.5 days (9.5–17) .. vs. 5.1 pg/mL, P = 0.004).21. In a study of 191 patients,32 cTnI levels were
..
Secondary Infection In 15%: 15 days (13–19) In 50%: 15 days (13–19) .. strongly associated with increased mortality in the univariate analysis,
Acute kidney injury In 15%: 15 days (13–19) In 50%: ? days (?) .. but the association was not tested in a multivariate model. Similar associ-
..
.. ations between cTnI elevation and disease severity are shown when ana-
.. lysing cohorts on the basis of the need for ICU care.6,21 Thus patient
..
.. monitoring should include a number of laboratory tests, summarized in
Wuhan.6,43,44 More recent reports indicate that 7.2%21 to 17%32 of hos- .. Table 4, based on current experience and studies.
..
pitalized COVID-19 patients sustain acute myocardial injury. This may .. Mechanisms underlying myocardial injury remain unknown and it is
be in the form of acute myocarditis (see below) or injury secondary to
.. unclear whether they reflect systemic/local and/or ischaemic/inflamma-
..
an oxygen supply/demand mismatch [type 2 myocardial infarction (MI)]. .. tory process. It is still not known whether acute injury is a primary infec-
In an analysis of 68 fatal cases in Wuhan, 36 patients (53%) died of re-
..
.. tive phenomenon or secondary to lung disease. Associations between
spiratory failure, 5 (7%) patients with myocardial damage died from cir- .. cTnI elevation and pre-existing CV conditions (and other pre-COVID
culatory failure, and 22 patients (33%) died from both.3 Similarly, analysis
..
.. features) have not yet been examined to detect evidence of causality,
of 120 COVID-19 patients reported elevated levels of N-terminal pro B- .. and no detailed analyses of patients with CV complications of COVID-
1676 T.J. Guzik et al.

Table 4 Diagnostic tests in patients with COVID-19 and cardiovascular involvement

Test Diagnostic considerations in COVID-19 patients

..............................................................................................................................................................................................................................
NT-pro BNP/BNP* Conflicting data on NT-proBNP. In a MERS-CoV cohort, NT-proBNP was increased but it may be normal in COVID-19-affected
patients.
Higher NT-proBNP levels in the Chinese cohort are associated with a greater need for ICU care.
Troponin* High-sensitivity troponin assay may be helpful for risk assessment in patients requiring ICU care and to identify individuals with silent
myocardial injury.
D-dimer Reports from the initial outbreak in Wuhan show a key relationship with a requirement for ICU care and mortality.
Procalcitonin A marker of bacterial infection; it is more likely to be raised in patients who will require ICU care.
Full blood count Often shows leucopenia/lymphocytopenia
Low platelets associated with adverse outcome
IL-6 Where available; high concentrations are associated with adverse outcome.
Ferritin A marker of poor outcome; very significant changes reported in COVID-19 patients.
Cardiac CT To be considered in uncertain cases of patients with elevated troponins with and without signs of obstructive coronary artery disease
(EACVI position166)
ECG In MERS-CoV, the 12-lead ECG generally shows diffuse T wave inversion where there is myocardial involvement; this can be dynamic.
Changes in COVID-19 were also described.
Echocardiography May show global or regional myocardial systolic dysfunction with or without a pericardial effusion and vice versa.

*The current ACC position advises against routine measurement of troponin or BNP (ACC 18.03).

..
19 have been published to date. As an elevated cTnI level is associated .. fulminant disease (Figure 6). Transient ECG changes are common and
with poorer outcomes in other (non-COVID) systemic illnesses,45 the .. may help detect the presence and severity of myocardial injury.
..
reported association could simply reflect the severity of systemic illness .. Myocarditis may progress to conduction block, tachyarrhythmias, and
(e.g. hypoxia or hypotension) rather than indicating a specific cardiac pa- .. impairment of left ventricular function.
..
thology. In this context, a ‘cytokine storm’ triggered by immunological .. In other clinical settings, myocarditis is often suspected when car-
dysregulation43 may be a key mediator. Plasma interleukin-6 (IL-6) con- .. diac injury is detected in the absence of an ACS. The diagnosis can of-
..
centrations are elevated in COVID-19 patients with cardiac injury,46 and .. ten be confirmed if cardiac magnetic resonance imaging (MRI) detects
abnormalities in a variety of cytokines are prominent in patients with se- .. typical acute myocardial injury signals.50 Endomyocardial biopsy
..
vere COVID-19 disease. .. (EMB), long considered the gold standard diagnostic test, can directly
Cardiac-specific mechanisms may also be important. Since ACE2 is .. demonstrate myocyte necrosis and mononuclear cell infiltrates.51 EMB
..
expressed in the CV system,47 direct cardiomyocyte infection by SARS- .. will detect evidence of a viral cause in some cases, though in others
CoV-2 may be a possibility, as discussed below. Moreover, therapies .. an immunologically autoimmune-mediated cause of the myocarditis is
..
used in treatment of severe multiorgan dysfunction in COVID-19 .. suspected.51 Biopsy studies of patients with acute myocarditis in
patients as well as antiviral drugs may result in cardiac toxicity.
.. Europe indicate that viral aetiology ranges between 37.8% and
..
Attempts to treat COVID-19 cardiac injury have included the use of .. 77.4%.52,53 In COVID-19, this evidence is at the moment sparse and
steroids, i.v. immunoglobins, hydroxychloroquine, and other antivirals,
.. based on individual case series, emphasizing the need for systematic
..
and active mechanical life support.46 While it remains uncertain if these .. assessment. While several reports emphasize that fulminant myocardi-
or other therapies successfully limit myocardial injury, the detection of
.. tis may be an important clinical presentation of the disease,46,48 the
..
cardiac damage in hospitalized COVID-19 patients may help identify a .. real prevalence of this complication remains unclear. Cardiac MRI and
subset of patients at greater risk of COVID-19 complications.
.. EMBs as diagnostic tools are likely to be inappropriate during the cur-
..
.. rent COVID-19 pandemic and associated healthcare crisis, but should
..
COVID-19 and myocarditis .. be considered in the future (Table 5).
Cardiac injury and acute myocarditis are well-recognized complications .. Animal models of viral myocarditis suggest discrete pathological
..
of acute viral infections. Myocyte necrosis and mononuclear cell infil- .. phases that begin with viral-mediated myocyte lysis.54 This cardiac injury
trates are reported in cardiac muscle autopsy specimens in a recent re- .. leads to activation of the innate immune response with release of proin-
..
port of the National Health Commission of the PRC.23 This finding, .. flammatory cytokines.54 Proteins released through cell lysis might display
along with case reports46,48 of fulminant myocarditis, suggests that myo- .. epitopes similar to the viral antigens and be presented via the major his-
..
carditis may be an important cause of the acute cardiac injury in COVID- .. tocompatibility complex (MHC). Myosin heavy chain, a cardiac sarco-
19 patients. However, the prevalence, clinical importance, and mecha- .. mere protein, appears to be a prime example of ‘molecular mimicry’.55
..
nism(s) of myocardial inflammation in COVID-19 disease remain .. At this stage, EMBs may show inflammatory changes but no detectable
unclear.6,49 .. viral particles because of clearance of the virus by the innate immune re-
..
Clinically, COVID-19 myocarditis may manifest only as mild chest dis- .. sponse. An acquired immune response is the predominant feature evi-
comfort and palpitations, which may be impossible to distinguish from
.. denced by activation of antibodies and T lymphocytes. CD4þ T helper
..
other causes in most patients. In some, however, myocarditis results in . (Th) cells and cytotoxic CD8þ T cells mediate their responses through
COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options 1677

Figure 6 Representative transthoracic echocardiography frames (selected from cine loop images) from a patient with COVID-19. (A) Apical four-cham-
ber view showing globally reduced left ventricular contraction, especially in the apical segment. The right ventricle is dilated and an echo-free space, indicat-
ing pericardial effusion, is present. (B) Parasternal short axis view showing markedly reduced left ventricular contraction, enlarged right ventricle, and a mural
thrombosis in the right ventricle outflow tract. (C) Two-dimensional speckle tracking echocardiography based on speckle tracking imaging technology (2D
STE). Left panel showing a normal 2D STE, right showing a 2D STE from a patient with COVID-19 and myocarditis, depicting reduced regional peak systolic
strain rates. Data were collected as part of a retrospective study, Wuhan, China; consent was waived and collection of these data was approved by the local
ethics committee. Kindly provided by Professor Dao Wen Wang.

..
activation of the inflammatory cascade and cytolysis [Th1–interferon .. replication (cytopathic), is immune mediated, or is due to other mecha-
(IFN)-c, Th2 – e.g. IL-4, Th17 – IL-17 and Th22 – IL-22]. Macrophages .. nisms. Given that acute myocardial injury is said to begin 2 weeks after
..
migrate to the site of injury.54 In the final stage, there is either recovery .. the onset of symptomatic COVID-19,32 adaptive T-cell-mediated immu-
or low levels of chronic inflammation with concomitant development of .. nity or dysregulated innate effector pathways are likely to play a pivotal
..
left ventricular dysfunction.54 .. in the development of myocardial inflammation. In this context, it is nota-
Interestingly, myocarditis appears in COVID-19 patients after a pro- .. ble that an increase of highly proinflammatory CCR6þ Th17 in CD4þ T
..
longed period (up to 10–15 days) after the onset of symptoms (Table 3). .. cells, prominent inflammatory mediators of myocarditis,56 has been
Moreover, investigators in China point to a lack of viral particle identifica-
.. reported in severe cases.
..
tion on EMB (personal communication). Given these observations and .. Together, the data suggest that a delay in myocardial inflammation is
the experimental context above, a question central to potential thera-
.. consistent with at least two pathogenic mechanisms: first, that the ‘cyto-
..
peutic options is the extent to which myocardial injury results from viral .. kine storm’ unleashes a subclinical autoimmune myocarditis, and
1678 T.J. Guzik et al.

..
Table 5 Proposed investigations in the case of suspicion of
.. with in-hospital mortality, and this relationship was maintained in multi-
.. variate analysis (OR 18.4, 95% CI 2.6–128.6; P = 0.003).32 Moreover,
myocarditis in COVID-19 patients ..
.. Chinese and Italian experience emphasizes that more discrete changes in
Detailed history and physical examination. .. D-dimer levels are observed earlier in the course of disease preceding
..
12-lead ECG on initial visit and periodically, as needed. .. the rapid progression stage.
Serum high-sensitivity troponin, NT-proBNP (according to index of clinical
..
..
suspicion). ..
Echocardiography to assess for global and regional wall motion abnormali-
.. COVID-19, inflammation, and the cytokine
..
ties and function. .. release storm
Cardiac rhythm monitoring.
.. After the lungs, immune organs are the second most affected system by
..
Cardiac MRI, as clinically indicated. .. COVID-19. Pathological investigations in COVID-19 victims23 have
Cardiac autoantibody titres may be helpful but not in the acute phase.
.. demonstrated splenic atrophy, with a very significant reduction in the
..
.. number of lymphocytes and neutrophils, as well as necrosis and haemor-
.. rhages. Similarly, lymphocytes are depleted in lymph nodes and the num-
..
.. bers of both CD4þ and CD8þ cells are decreased.23 This corresponds
.. to lymphopenia in peripheral blood observed in severe cases.
secondly that myocardial damage and/or molecular mimicry initiate a de ..
.. Interestingly, an increase in systemic IL-2, IL-6, IL-7, granulocyte colony-
novo autoimmune reaction. .. stimulating factor, C-X-C motif chemokine 10 (CXCL10), chemokine
Targeted therapeutic options remain elusive; as is the case for myo- ..
.. (C-C motif) ligand 2 (CCL2), and tumour necrosis factor-a (TNF-a) has
carditis in other settings, a management strategy that uses a broad range .. 6
of supportive therapies remains key. A case report recently described ef- .. been observed in subjects with COVID-19, which corresponds to the
.. characteristics of a cytokine release syndrome (CRS).16,68,69 CRS devel-
fectiveness of the early application of steroids and i.v. immunoglobins, ..
neuraminidase inhibitors, and active mechanical life support.46 .. opment in COVID-19 is associated with COVID-19 severity. CRS has
.. been characterized as a complication of immune targeted therapies in
..
.. oncology, in particular in relation to severe chimeric antigen receptor
COVID-19 and ischaemic heart disease .. (CAR) T-cell-induced CRS.70 It is also reminiscent of the cytokine profile
While little is known regarding the effects of COVID-19 on ACS, several ..
.. noted in haemophagocytic lymphohistiocytosis (HLH) syndromes.71
pathways associated with viral diseases may contribute to destabilize pla- .. Resemblance to the latter brought considerations that COVID-19 may
ques in COVID-19 patients.57 Heart failure patients are at increased risk ..
.. be a cause of secondary HLH with cytopenias, significant haemophagocy-
of acute events or exacerbation; viral illness can potentially destabilize .. tosis in bone marrow, and low fibrinogen concentration. Clinical classifi-
atherosclerotic plaques through systemic inflammatory responses,58 cy- ..
.. cations have been introduced to aid recognition of secondary HHL.71
tokine storm, as well as specific changes of immune cell polarization to- .. Fluorescence-activated cell sorting (FACS) analyses of COVID-19 active
wards more unstable phenotypes. All of these have been observed in ..
.. cases have also shown hyperactivated T lymphocytes with large fractions
COVID-19. In the case of SARS and MERS, acute MI59,60 has been .. of HLA-DRþ and CD38þ CD8þ/CD4þ T cells and CCR6þ Th17
reported in two out of the five deaths in early reports.61
..
.. CD4þ cells. High concentrations of cytotoxic granules in cytotoxic T
It is important to consider that type 2 MI is the most common subtype .. (CD8) cells have been observed. Thus, uncontrolled overactivation of T
in viral conditions, thus the usefulness of invasive management with a
..
.. cells may account for, in part, the severe immune injury,16 similarly to
view toward coronary revascularization (especially in type 2 MI) is lim- .. atherosclerosis and other CV conditions.72,73 These aspects should also
ited. The decision for invasive vs. non-invasive management of patients
..
.. be considered in the light of sexual dimorphism related to susceptibility
with an ACS and COVID-19 illness should be carefully considered. .. to CV inflammation.74–76
Moreover, a recent single-cell atlas of the human heart indicated that
..
.. High serum IL-6 levels are a common feature in CRS patients. Indeed,
pericytes express particularly high levels of ACE2 in the heart.47 One of .. in a recent retrospective multicentre analysis of 150 patients from
..
the implications of this finding is possible local microvascular inflamma- .. Wuhan, circulating IL-6 levels were a clinical predictor of mortality in
tion during SARS-CoV-2 infection of the pericytes, leading to severe mi- ..
.. COVID-19.3 IL-6 is an important biomarker and possible target for CV
crovascular dysfunction, contributing to myocardial infarction with non- .. morbidity and mortality linked to atherosclerosis.77–79 This is important
obstructive coronary arteries (MINOCA). This could explain recent ..
.. as therapeutic targeting of the IL-6 receptor (IL-6R) with tocilizumab is
reports of the clinical course of cases of MI during COVID-19. In addi- .. used in preventing and treating CRS caused by cancer therapies and
tion, the cytokine storm can contribute to development of endothelial ..
.. HLH.70 Tocilizumab is approved in >100 countries for the treatment of
dysfunction through well-characterized mechanisms.62–65 .. rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA),80
..
.. Castleman’s diseases, and giant cell or Takayasu arteritis.81 Other IL-6R-
COVID-19 and coagulation abnormalities .. targeting agents, e.g. sarilumab, are similarly potentially of use. Therefore,
..
Features of disseminated intravascular coagulation (DIC) and pulmonary .. its possible use in COVID-19 may be attractive to tackle CRS. However,
embolism, characterized by increased D-dimer levels and fibrin degrada- .. when considering immunomodulation, one has to bear in mind that the
..
tion products, are highly prevalent in COVID-19. DIC has been observed .. primary problem is an infectious disease rather than the complications of
in 71.4% of non-survivors.66 Massive pulmonary embolism has been .. cancer therapy. Therefore, its potentially utility must be carefully
..
reported.67 This might not be surprising given the critical condition of .. considered.
these subjects, although early appearance of DIC features is often evi- .. During the initial outbreak in China, the use of tocilizumab to stop se-
..
dent. Notably, experience from China indicates that a D-dimer increase .. vere CRS-associated organ failure and death in COVID-19 patients was
is highly predictive of adverse outcomes in COVID-19. In a retrospective
.. attempted.71 Twenty-one severe COVID-19 cases were treated with
..
cohort study, elevated D-dimer levels (>1 g/L) were strongly associated . tocilizumab in an initial pilot trial. Nineteen of them were discharged
COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options 1679

..
from the hospital within 2 weeks, as reported by China’s National .. formation.91 Similarly, reduced pathology has been observed in LDLr–/–
Health Commission. The drug has now been approved in China to treat .. mice treated with a fusion protein of the IL-6 trans-signalling inhibitor
..
patients developing severe complications from COVID-19 and showing .. soluble glycoprotein 130 (sgp130).92 Plasma IL-6 levels also have been
elevated plasma levels of IL-6.82 Chinese researchers have now regis- .. associated with development and progression of abdominal aortic aneu-
..
tered several clinical trials for tocilizumab, expected to enrol patients .. rysm,93 and IL-6 has been shown to influence lipid homeostasis in
with COVID-19 very soon. A partial list includes: ‘A multicenter, ran- .. mice.94 IL-6 trans-signalling contributes to experimental cardiac fibro-
..
domized controlled trial for the efficacy and safety of tocilizumab in the .. sis;87 while the up-regulation of membrane-bound IL-6R causes vascular
treatment of new coronavirus pneumonia (COVID-19)’ (ChiCTR .. remodelling in pulmonary arterial hypertension.95
..
2000029765); ‘Tocilizumab vs CRRT in Management of Cytokine .. Genetic variants leading to increased circulating levels of IL-6R and,
Release Syndrome (CRS) in COVID-19 (TACOS)’ (ClinicalTrials.gov .. therefore, reduced IL-6 cell signalling, have been shown to protect
..
Identifier: NCT04306705); and ‘Favipiravir Combined With Tocilizumab .. against coronary heart disease (CHD).96,97 Similarly, IL-6 trans-signalling
in the Treatment of Corona Virus Disease 2019’ (ClinicalTrials.gov .. is associated with increased CV risk.77,98 IL-6 is routinely used as an in-
..
Identifier: NCT04310228). .. flammatory biomarker in CV disease. The Canakinumab Anti-
Similarly, case reports originating from Italy show that in a case series .. Inflammatory Thrombosis Outcomes Study (CANTOS) trial demon-
..
of six patients treated with tocilizumab in Naples, three have shown signs .. strated a stronger effect of IL-1b inhibition in reducing secondary CV
of improvement. This has prompted several studies evaluating the role
.. events in patients with higher circulating levels of IL-6 and C-reactive
..
of IL-6 antagonism by monoclonal antibodies in COVID-19. For exam- .. protein (CRP), indicative of residual inflammatory risk.98 Whether the
ple, the Italian Medicines Agency (AIFA) approved the clinical study
.. observed cytokine storm and IL-6 increase in COVID-19 patients are
..
‘Tocilizumab in COVID-19 Pneumonia (TOCIVID-19)’ (Clinical .. transient or sustained remains unknown. Accordingly, monitoring inflam-
Trials.gov Identifier: NCT04317092). This multicentre, single-arm, open-
.. matory biomarkers in these patients in the medium to long term is of
..
label, phase II study will assess mortality at 1 month in 330 patients af- .. major importance. Similarly, CV risk should be closely evaluated during
..
fected by COVID-19 pneumonia. The inclusion criteria comprise .. the acute phase response and in the following years.
patients showing signs of respiratory distress syndrome or who had .. There are, however, likely to be a range of additional cytokine moie-
..
been subject to tracheal intubation in the preceding 24 h. The study will .. ties that will emerge to have pathway-specific contributions in the severe
be led by the Instituto Nazionale Tumori IRCCS – Fondazione Pascale in .. spectrum of COVID-19 syndrome. These include pathways driven by
..
Naples. Similarly, 30 participants will be enrolled in the Marche region, in .. granulocyte–macrophage colony-stimulating factor (GM-CSF), TNF-a,
the interventional clinical trial ‘Tocilizumab (RoActemra) as Early .. IL-17, IL-18, and IFN-c. Moreover, the imminent prospect of single-cell
..
Treatment of Patients Affected by SARS-CoV-2 Infection With Severe .. and other immunological analyses will offer a more systematic insight
Multifocal Interstitial Pneumonia’ (ClinicalTrials.gov Identifier: .. into the immune dysregulation syndrome(s) that are emerging and espe-
..
NCT04315480). In the USA, the ‘Evaluation of the Efficacy and Safety of .. cially the disease trajectory—in essence which pathways are directing
Sarilumab in Hospitalized Patients With COVID-19’ (ClinicalTrials.gov .. COVID-related CRS and which are simply adding to the inflammatory
..
Identifier: NCT04315298) has just started, aiming to recruit 400 patients, .. tissue damage burden upon which the other comorbidities are operat-
and will be shortly followed by the ‘Tocilizumab to Prevent Clinical .. ing. Thus, we propose that a useful way of thinking about this would be
..
Decompensation in Hospitalized, Non-critically Ill Patients With .. that the inflammatory burden might be considered as a direct effector
COVID-19 Pneumonitis (COVIDOSE)’ (ClinicalTrials.gov Identifier: .. (i.e. CRS-type), or a secondary amplificatory factor in terms of the con-
..
NCT04331795) trial, which is expected to start very soon. Finally, the .. tribution that pathways make to pathogenesis and clinical outcome.
most recently registered trial recruiting 330 patients: A Study to Evaluate
..
..
the Safety and Efficacy of Tocilizumab in Patients With Severe COVID- .. Lessons from SARS-CoV infection
19 Pneumonia (COVACTA) (ClinicalTrials.gov Identifier: NCT04
.. In 2002 a novel coronavirus, SARS-CoV, emerged from China, crossing
..
320615) is being initiated. Similar trials have been registered in France, .. from bats to humans, eventually leading to >8000 cases and the death of
Belgium, and Denmark. It should be noted, however, that there are cur-
.. >700 people. SARS utilized ACE2 for cell attachment and infection
..
rently no published clinical trial data on IL-6 targeting safety or efficacy .. through the viral envelope spike (S) protein99 and a subsequent interac-
against the virus. Moreover, tocilizumab has not received approval from
..
.. tion with a cellular protease, TMPRSS2, which primes S protein for cell
China’s National Medical Product Administration to be sold for COVID- .. entry.10 The closely related SARS-CoV-2, also thought to have origi-
..
19 treatment. .. nated in bats,9 encodes an S protein with 76% amino acid similarity to
The cytokine storm and increase in IL-6 signalling observed in some .. that of SARS-CoV and, importantly, SARS-CoV-2, as already discussed,
..
COVID-19 patients could have profound CV consequences causing .. has also recently been demonstrated to use the same cellular entry path-
tachycardia, hypotension, and left ventricular dysfunction. CRS-related .. way via ACE2 and TMPRSS2,12 as discussed above. Both these novel
..
cardiotoxicity has also been reported, mainly in the form of conduction .. coronaviruses are different from another recently emergent coronavi-
abnormalities, atrial fibrillation, and elevation in BNP and cTnIs.83 .. rus, MERS virus, which crossed from the dromedary camel to humans
..
In COVID-19 patients, medium- to long-term CV consequences may .. and also caused acute respiratory failure, although utilizing a different cell
be caused by increased IL-6 signalling. Experimental evidence supports .. entry mechanism via the receptor dipeptidyl peptidase 4 (DPP4).101
..
an atherogenic role for IL-6 and CRS-related cytokines,59,60,84–86 as well .. Overall, this highlights the potential divergence of respiratory coronavi-
as its effects on cardiac fibrosis and failure.87 The cytokine increases ad- .. rus infections in humans, but emphasizes the close relationship between
..
hesion molecule expression in human endothelial cells in vitro;88 at the .. SARS-CoV and SARS-CoV-2. So, what can we learn from knowledge of
same time, stimulation of human macrophages with oxidized LDLs .. SARS-CoV and associated CV risk to help in the current battle against
..
(oxLDLs) leads to increased release of IL-6.89 In experimental athero- .. COVID-19?
sclerosis, IL-6 mRNA is detectable in the aorta of hyperlipidaemic .. During human SARS-CoV infection of the murine lung, ACE2 is uti-
..
mice,90 and administration of recombinant IL-6 increased plaque . lized and subsequently almost completely lost at the protein level.102
1680 T.J. Guzik et al.

..
Importantly, delivery of the viral S protein alone also led to down- .. in parallel on development of new drugs against coronavirus as well as
regulation of ACE2 and decreased lung function in normal mice, and .. repurposing already approved drugs for the treatment of the disease.
..
worsened lung pathology in an acid challenge model of acute lung failure. .. ClinicalTrials.gov site lists >300 studies that are testing various interven-
Furthermore, disease pathology was reduced in the presence of the ARB .. tions in COVID-19 patients. This emphasis on trials as opposed to com-
..
losartan. Intriguingly, in acute lung disease triggered by acid respiration .. passionate use and case reports is a major lesson from previous
or sepsis, ACE2 has also been shown to be directly protective, acting in .. pandemics and it is good to see the community moving so robustly in
..
partnership with the angiotensin type 2 receptor (AT2R), and administra- .. this direction.
tion of recombinant ACE2 in this model is protective.103 Taking together .. Meanwhile, public health measures rely mostly on social measures
..
the evidence from multiple experimental studies, beneficial effects of .. intended to prevent viral/disease spread, in order to avoid a massive
ACEIs or ARBs and also ACE2 supplementation in various animal mod- .. surge of patients with healthcare facilities overload, and on supportive
..
els of lung injury or SARS have been shown and supported the concept .. treatment for the patients, which can be considered the mainstay of
that loss of ACE2 expression promotes the disease in lung injury models .. management. Available treatments once clinically evident can be classi-
..
(reviewed in Kreutz et al., 202025). ACE2 is also directly regulated by .. fied as supportive, immune-suppressive, antiretroviral, and potential
cytokines.104 Decreased ACE2 levels could be a direct consequence of
.. novel therapies. Supportive treatment should be the mainstay of man-
..
viral infection and/or the subsequent inflammatory and immune .. agement coordinated by the relevant specialist–multidisciplinary team.
responses that occur in the infected lung. Interestingly, ACE2 is also
.. The approaches have been provided by numerous scientific and clinical
..
reported to be detectable in macrophages,105 and its knockout in leuco- .. societies during the early stages of the European outbreak and are con-
cytes promotes adipose inflammation,106 highlighting a role for ACE2 in
.. tinuously being updated. This includes a concise but comprehensive
..
the inflammatory response. Patients suffering from SARS have over- .. guidelines of the Società Italiana di Anestesia Analgesia Rianimazione e
whelming immune and inflammatory responses and high mortality rates
.. Terapia Intensiva.114
..
from acute respiratory failure, and furthermore they are also associated .. When disease progresses to severe phenotype, supportive treatment
..
cardiac sequelae. For example, SARS patients also suffer from systolic .. includes use of oxygen therapy if SpO2 is <92% on room air,23 as well as
and diastolic dysfunction and arrythmias, leading to sudden death.107,108 .. haemodynamic support. Early intubation and invasive mechanical ventila-
..
In murine models, intranasal administration of human SARS-CoV results .. tion are essential in those with progressive symptoms and increasing ox-
in ACE2-mediated infection of the myocardium.109 These observations .. ygen requirement. High flow nasal cannulae and non-invasive positive
..
support a role for SARS-CoV in direct myocardial infection and a possi- .. pressure ventilation (NIPPV) may play a role in some patients, especially
ble causative role in cardiac disease subsequent to respiratory infection. .. where resources for mechanical ventilation are likely to be stretched.
..
In the murine heart, ACE2 was also almost completely down-regulated .. A lung-protective ventilation strategy is recommended by the WHO.
at the protein level following infection. Moreover, in autopsied cardiac .. Conservative use of i.v. fluids aiming to maintain tissue perfusion but a
..
tissue from SARS patients with SARS-CoV-positive lung infection, viral .. negative fluid balance aids lung recovery.23 Extracorporeal membrane
RNA was detected in the heart, combined with decreased cardiac ACE2 .. oxygenation (ECMO) may be required in severe cases as per standard
..
protein levels and elevated cardiac macrophage infiltration. Down- .. indications but should be considered early (veno-venous mode and
regulation of ACE2 without compensatory effects on ACE may lead to .. could be initiated prior to intubation).
..
the RAAS being tipped towards the detrimental ACE–Ang II–AT1R axis .. As cardiac damage is highly prevalent, heart failure therapies should
and away from the protective ACE2–Ang-(1-7)–Mas axis. .. be initiated where appropriate. Similarly, broad-spectrum antibiotics/an-
..
ACE2 is also up-regulated after MI in rodents and humans in macro- .. tifungal treatments and treatment of arrhythmias are needed. Finally, due
phages, endothelial cells, smooth muscle cells,110,111 and cardiomyo-
.. to the growing evidence of DIC as a cause of organ injury, anticoagula-
..
cytes,112 and may play a role in restoring RAAS homeostasis in the heart .. tion should be considered.23
post-MI. In fact, viral vector-mediated overexpression of ACE2 in
.. Approximately 75% of patients in the early Chinese cohort received
..
rodents also protects the heart from adverse cardiac remodelling and .. antiviral therapy.6,32,43,115 The Italian recommendation is to commence
dysfunction post-MI.113 Overall, these findings highlight that ACE2 has a
.. treatment with antiviral therapy when COVID-19 is confirmed in
..
key protective function in both the lung and the heart. Therefore, SARS- .. patients with mild symptoms but not in a high mortality risk category or
CoV infection-mediated down-regulation of ACE2, as a direct mechanis-
.. with moderate/severe signs of infection. Numerous antiviral therapies
..
tic consequence of viral infection and/or as a result of the subsequent in- .. have been used to try and limit viral replication. These include protease
..
flammatory responses, may lead to an imbalance in RAAS signalling and .. inhibitors such as liponovir/ritonavir (used for the treatment of HIV).
consequent CV sequelae. The knowledge that systemic spread of SARS .. However, a recent rapid randomized non-placebo-controlled trial in-
..
from primary lung infection to other CV tissues, including the heart, is .. cluding 100 patients in each arm showed no difference in the out-
also important. Given that ACE2 functions as a receptor for virus entry .. come.116 Remdesivir is a nucleotide analogue and polymerase inhibitor
..
into the cell, down-regulation of ACE2 upon infectioin with SARS-CoV .. that was previously used for the experimental treatment of Ebola in a
is expected to prevent further viral entry, serving as a negative regulatory .. large phase III study.117 While it had an acceptable safety profile, the
..
mechanism. Clearly additional investigations are needed to increase our
... remdesivir (GS-5734) arm was halted due to a higher antiviral efficacy of
understanding of the pathological mechanisms of acute disease and po- .. monoclonal antibodies in the trial. Finally chloroquine or hydroxychloro-
tential increased CV risk in COVID-19 patients. .. quine have been suggested as having antiviral activity against many RNA
..
.. viruses including SARS and SARS-CoV-2, through an increase of the
Therapeutic options for COVID-19 .. endosomal pH and interference with the glycosylation process.118
..
Managing COVID-19 is challenging as there are no specific treatments .. However, it has never been shown conclusively to have an antiviral effect
for the SARS-CoV-2 virus. Obtaining high-quality randomized clinical
.. in vivo. In alphavirus infection, while demonstrating an antiviral effect
..
trial data during an outbreak is difficult. Research and clinical efforts focus . in vitro, it was found not to be associated with clinical effects in a
COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options 1681

..
randomized clinical trial and may even be associated with prolonged vir- .. ventricular hypertrophy (22%), hypokinesia (9.4%), heart failure (26.8%),
aemia in vivo.119 While these observations cannot be directly translated .. pulmonary arterial hypertension (3.9%), and valvular dysfunction (7.1%).
..
to COVID-19, large phase III trials are underway with hydroxychloro- .. Cardiac function normalizes in a significant number of patients (44.9%)
quine, that will inform about the possible therapeutic value of this ap- .. upon withdrawal of chloroquine and hydroxychloroquine, while others
..
proach. This includes the recently initiated ‘Hydroxychloroquine Chemo .. continue to show irreversible damage (12.9%) or death (30.8%).122
prophylaxis in Healthcare Personnel in Contact With COVID-19 .. Thus, careful consideration should be given to the use of these drugs,
..
Patients (PHYDRA Trial)’ (ClinicalTrials.gov Identifier: NCT04318015). .. particularly without stronger data regarding their efficacy. Of note, tocili-
As the cytokine storm appears to be a key pathogenetic process in .. zumab treatment has been shown to influence lipid metabolism in RA
..
patients exhibiting rapid deterioration, immune suppression and immune .. patients. Following tocilizumab, total-, LDL-, and HDL-cholesterol were
modulation approaches have been tried. This includes glucocorticoids, .. increased, while CV risk biomarkers such as HDL-SAA, secretory phos-
..
which are recommended by Chinese guidelines, but not Italian guide- .. pholipase A2 IIA, and lipoprotein(a) were significantly reduced.123 Very
lines. Patients with evidence of lung fibrosis or severe cardiac involve-
.. recently, the ENTRACE clinical trial supported the CV safety of tocilizu-
..
ment in the ICU may benefit from this approach. Methylprednisolone .. mab in RA patients;124 however, to date, IL-6 targeting has not been
was used in combination with i.v. immunoglobulins in the treatment of
.. tested for secondary prevention in CVD.
..
subjects with fulminant myocarditis.118 Immunomodulatory therapies ..
..
used include monoclonal antibodies against IL-6R, discussed above. IFN- .. Follow-up of patients with cardiovascular
b, registered for treatment of multiple sclerosis, enhances suppressor T .. involvement in COVID-19
cell activity, reducing proinflammatory cytokine production. It may be
..
.. While there are currently no evidence-based recommendations, consid-
also helpful in patients with myocarditis who develop left ventricular sys- .. ering clinical presentation, it is reasonable to propose that patients who
..
tolic dysfunction; however, current experience is limited to enterovi- .. have had cardiac involvement initially should be seen every 1–3 months.
ruses.120 It is also being tried as an inhaled preparation. Finally, 27% of .. Periodic evaluation, in addition to detailed history taking and physical ex-
..
patients in the early Chinese cohort received i.v. immunoglobulins. This .. amination, should include a 12-lead ECG and 2D/Doppler echocardiog-
approach was based on the evidence of their beneficial effects in cases of ..
.. raphy125 or, preferably, cardiac MRI with late gadolinium enhancement.
myocarditis-induced dilated cardiomyopathy and is recommended in .. Appropriate heart failure therapy should be initiated and maintained
cases of viral myocarditis that are refractory to standard heart failure ..
.. when required, and plans put in place to optimize doses. Patients should
therapies.121 .. be given standard advice regarding physical activity. As regards unknown
A list of planned, ongoing, and completed clinical trials can be found ..
at: https://clinicaltrials.gov/ct2/results?cond=COVID-19&term=&cntry= ... long-term consequences of COVID-19, regular CV risk assessment
.. should be considered in all patients who survive COVID-19.
&state=&city=&dist= ..
In addition to the many ongoing clinical trials, a new trial in Europe will ..
.. Ethical dilemmas brought by COVID-19
investigate effects of APN01, the recombinant form of human ACE2 .. COVID-19 brings unprecedented ethical problems and situations facing
(rhACE2) (clinicaltrialsarena.com). HrACE2 has a dual mode of action. ..
.. the medical profession around the world. In the light of the huge imbal-
First, it has the potential to block infection of host cells by SARS-CoV-2, .. ance between therapeutic needs and resource availability of an unprece-
and secondly it may reduce lung injury through the protective actions of
..
.. dented scale in our generation, the Italian Society of Anesthesiology and
endogenous ACE2. The phase II clinical trial will be conducted in .. Intensive Care (SIAARTI),126 along with other National Societies pro-
Germany, Austria, and Denmark.
..
.. vided an ethical statement aimed to guarantee the correct psychological
.. framework to physicians massively exposed to the need to apply hard
..
Cardiovascular effects of potential .. triage rules while facing huge ethical dilemmas.126 These are derived
..
therapies for COVID-19 .. from the fact that the need for intensive care must be integrated with
The potential therapies for COVID-19 discussed above have important
.. other elements of ‘clinical suitability’, thus including: the type and severity
..
CV side effects and toxicities as well as comorbid conditions that require .. of the disease, the presence of comorbidities, the impairment of other
.. organs and systems, and their reversibility.126 Clinicians are not, either
caution or avoidance of these drugs, as listed in Table 6. It should be ..
noted that data for these side effects and toxicities come from patients .. deontologically or by training, accustomed to reasoning with criteria of
.. maxi-emergency triage, as in the current exceptional situation.126
that use these drugs chronically for the treatment of autoimmune dis- ..
eases (chloroquine/hydroxychloroquine, rocilizumab), hepatitis (riba- ..
.. Impact of COVID-19 on routine and
varin, IFN-a), or HIV infection lopinivir/ritonivir). Thus, the effect of ..
short-term use of these medications for patients without these underly- .. emergency cardiovascular care
..
ing conditions is not clear. Remdesivir is an experimental drug used in .. In preparation for the COVID-19 pandemic, many healthcare providers
the treatment of Ebola.117 Thus, its CV effects and toxicities are un- ... have had to scale down outpatient services and also defer elective car-
known. The antimalarial drugs chloroquine and hydroxychloroquine .. diac procedures and surgeries. This in some instances has led to the posi-
..
have recently received considerable attention and interest for the treat- .. tive integration of technology and development of virtual clinics.127
ment and possible prophylaxis of COVID-19. However, the data to date .. However, uptake of virtual clinics has not been universal and has also
..
in support of these drugs are weak and cardiac toxicities are consider- .. been compromised by re-deployment of the workforce to help manage
able. A systematic review of the literature performed on patients treated .. the pandemic. The long-term clinical impact of scaling down outpatient
..
with these drugs, albeit for an extended period of time (median 7 years) .. activity, reduced access to diagnostics, and deferral of routine proce-
and with a high cumulative dose, demonstrated conduction disorders as
.. dures is likely to be significant and extend beyond the pandemic.
..
the main side effect (85%).122 Other adverse cardiac events included . Similarly, the perceived risk of being exposed to COVID-19 has led to a
1682 T.J. Guzik et al.

Table 6 Potential COVID-19 therapies and their cardiovascular effects

CV side effects CV warnings/toxicities Use with caution or avoid in presence of

..............................................................................................................................................................................................................................
Antimalarials
Chloroquine/ • QT interval prolongation • Cardiomyopathy/heart failure • Cardiomyopathy
hydroxychloroquine • Thrombocytopenia • Conduction disorders (bundle • Ventricular arrhythmias
• Anaemia branch block/AV block) • Uncorrected hypokalaemia or
• Torsades de pointes hypomagnesaemia
• Ventricular arrhythmias • Bradycardia (<50 b.p.m.)
• Concomitant administration of QT-prolong-
ing agents
• Hepatic disease and co-administration with
other hepatotoxic drugs
Antivirals
Ribavarin • Thrombocytopenia • Anaemia may result in worsening • Ischaemic heart disease
• Haemolytic aanemia of CAD leading to MI
Lopinivir/ritonivir • Hyperlipidaemia • Hepatotoxicity • Conduction system disease
• Hypertriglyceridaemia • QT and PR interval prolongation • Ischaemic heart disease
• Torsades de pointes • Cardiomyopathy or structural heart disease
• Second- and third-degree AV • Uncorrected hypokalaemia or
block hypomagnesaemia
• Concomitant administration of QT- or PR-
prolonging agents
Remdesivir • Unknown • Unknown • Unknown
Biologics
Tocilizumab • Hypertension • Hepatotoxicity • Elevated liver transaminases
• Thrombocytopenia
• Elevated liver transaminases
• Hyperlipidaemia
Interferon alpha 2B • Hypertension • Hepatotoxicity • Decompensated liver disease
• Thrombocytopenia • Thyroid dysfunction • Cardiac abnormalities
• Anaemia • Pericarditis
• Elevated liver transaminases • Ischaemic and haemorrhagic cere-
• Hypertriglyceridaemia brovascular events
• Arrhythmias
• Myocardial ischaemia/infarction
• Cardiomyopathy

References: www.medscape.com; CAD, coronary artery disease; MI, myocardial infarction.

..
decline or a delay in presentation of acute cardiac emergencies which is .. socially isolated people. Similar results were reported from a UK
likely to contribute to cardiac mortality and morbidity. .. Biobank analysis.153
..
.. The mechanisms of detrimental effects of social isolation are multiple
Cardiovascular implications of social .. and are related to the activation of the hypothalamic–pituitary–adreno-
..
distancing .. cortical (HPA) axis,154–157 changes in the sympathetic vascular
.. tone,148,158,159 elevated levels of cortisol,156,160,161 and a reduced
COVID-19 implications are wider than the effects of the disease on indi- ..
vidual patients. Practically all countries affected by the disease developed .. responsivity of the glucocorticoid receptor.162–165 The social distancing
.. strategies used in COVID-19 should consider these effects and aim to
mitigation and containment strategies based on social distancing. CV ..
consequences of social distancing may be profound. Both experimental .. mitigate them using available technological advances.
..
and clinical research has shown the effects of social isolation and loneli- ..
ness on cognition and memory,128–132 metabolic disorders,133–136 can- .. Key unanswered questions
..
cer,137–139 and immune disorders.139–141 In the context of CVDs, the .. In this comprehensive review, we aimed to highlight the current state of
absence of positive relationships and the reduced chance of interaction .. the art information regarding COVID-19 and CVD (Table 7). Our under-
..
with other people (social distancing) have been identified as major risk .. standing of CV risk and consequences of COVID-19 is developing con-
factors for CV mortality.142–151 A recent meta-analysis including a total
.. tinuously. However, there are many knowledge gaps and there are many
..
of 181 006 participants152 demonstrated that the risk for ischaemic heart .. unanswered questions. Below we point out a few burning unknowns at
disease and stroke increased by 29% and 32%, respectively, in lonely and
.. the moment.
COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options 1683

Table 7 Summary of current key considerations in COVID-19 diagnosis and treatment

Key take-home messages:

• Cardiovascular patients are at increased risk of severe COVID-19 and its complications. Intensive preventive measures should be followed in this group
in accordance with WHO and CDC guidelines. This should include wider use of telemedicine tools in day to day monitoring of the patients during the out-
break to limit their exposure.
• The heterogeneity of responses between individual patients indicates that it unlikely that it can be considered as a single disease phenotype. Host charac-
teristics promotes more or less severe progression of the disease.
• The most common cardiac complications include arrhythmia (AF, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury (elevated hs-cTnI
and CK), fulminant myocarditis, and heart failure.
• Cardiac complications often appear >15 days after initiation of the fever (symptoms)
• Evaluation of cardiac damage (particularly cTnI levels) immediately after hospitalization for COVID-19, as well as monitoring during the hospital stay, may
help in identifying a subset of patients with possible cardiac injury and thereby predict the progression of COVID-19 complications.
•Some of the medications used in COVID-19 treatment may contribute to cardiac toxicity, while their effectiveness in treating COVID-19 is unconfirmed.
Cardiovascular comorbidities
• Hypertension is one of the most common risk-associated comorbidities, but this association is cofounded by age. It is not clear if hypertension is an age-
independent risk factor of COVID-19-associated outcomes. As a precaution, it is essential that hypertension remains well controlled.
• There is no evidence that ACEIs or ARBs are associated with worse prognosis, and patients should not discontinue use of these medications.
• Based on experimental evidence in other conditions, particularly ARBs and possibly also ACEIs might exert a potentially protective influence in the setting
of COVID-19.
• COVID-19 may lead to plaque instability and MI, which has a common cause of death in SARS/COVID-19 patients. However, the evidence of effective-
ness of primary PCI for type 2 MI during acute viral disease is limited.
• ACE2 can be considered as a Cinderella of cardiovascular medicine. A molecule which has been underappreciated in cardiovascular pathology is taking
centre stage in understanding and potentially combating COVID-19.

..
What are the factors, genetic or otherwise, that influence interindivid- .. Foundation (Guzik-FS/14/49/30838, RE/18/6/34217 to R.T., T.G. and
ual variability in susceptibility to COVID-19, its severity, or clinical out- .. C.B.; BHF RE/18/634217 to F.M.B. and PG/19/84/34771 to P.M and
..
comes? The mechanisms through which CVDs worsen the prognosis in .. T.J.G.), and the Medical Research Council (MC_UU_12014/1 to E.T. and
COVID-19 are unknown. It remains to be addressed to what extent indi- .. MC_UU_12014/7 to D.B.).
..
vidual CVDs are exacerbated by COVID-19. Do pre-existing hyperten- .. Conflicts of interest: none declared.
sion and CVDs increase infection risk and/or worsen the course of ..
..
disease progression? Is the severity of CVDs related to high expression ..
levels of ACE2, the SARS-CoV-2 receptor, in the heart and blood ves- .. References
.. 1. Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19
sels? What influence, if any, do inhibitors of the RAAS have on suscepti- ..
bility to COVID-19 and its clinical outcomes? What are the factors or
.. 2. inJohnrealHopkins time. Lancet Infect Dis 2020;doi: 10.1016/S1473-3099(20)30120-1.
.. University. https://www.arcgis.com/apps/opsdashboard/index.html#/
therapies for CVDs that may confer protective effects against COVID- .. bda7594740fd40299423467b48e9ecf6 (28 March 2020).
19 and its clinical outcomes? How does pre-existing CVD worsen car-
.. 3. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to
.. COVID-19 based on an analysis of data of 150 patients from Wuhan, China.
diac involvement specifically? What transferable knowledge can be ..
learned about this pathogen that would advance our understanding of
.. 4. Intensive Care Med 2020;doi: 10.1007/s00134-020-05991-x.
Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, Tai Y,
.. Bai C, Gao T, Song J, Xia P, Dong J, Zhao J, Wang FS. Pathological findings of
CV risk for SARS-CoV-2, influenza, and other virus infections in the fu- ..
ture? Finally, probably the most important question remains, what are
.. COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med
.. 2020;8:420–422.
the determinants of heterogeneous host responses to SARS-CoV-2 in- .. 5. Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, Gong W, Liu X, Liang J, Zhao Q, Huang
.. H, Yang B, Huang C. Association of cardiac injury with mortality in hospitalized
fection? The answers will be found in integrated approaches by CV im- .. patients with COVID-19 in Wuhan, China. JAMA Cardiol 2020;doi: 10.1001/
munological ID and other expertise coming together. The use of ..
.. 6. jamacardio.2020.0950.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z,
systems based on hypothesis-free in silico methodologies will be essential. ..
This pandemic is unlike any other in arriving at the same time as human- .. Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J,
.. Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected
kind being in possession of remarkable molecular data science and infor- .. with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497–506.
matic tools. This is a major test of our ability to harness such capacity for .. 7. Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. [The
.. epidemiological characteristics of an outbreak of 2019 novel coronavirus
the greater good. .. diseases (COVID-19) in China]. Zhonghua Liu Xing Bing Xue Za Zhi 2020;41:145–151.
These questions need to be answered with the highest quality science ... 8. Driggin E, Madhavan MV, Bikdeli B, Chuich T, Laracy J, Bondi-Zoccai G, Brown TS,
and clinical research since the current pandemic of coronavirus might .. Nigoghossian C, Zidar DA, Haythe J, Brodie D, Beckman JA, Kirtane AJ, Stone GW,
.. Krumholz HM, Parikh SA. Cardiovascular considerations for patients, health care
not be the last. .. workers, and health systems during the coronavirus disease 2019 (COVID-19) pan-
..
.. 9. demic. J Am Coll Cardiol 2020;doi: 10.1016/j.jacc.2020.03.031.
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang
..
Acknowledgments .. CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang
.. X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao
This work was supported by the European Research Council (TJG- .. GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable
InflammaTENSION: ERC-CoG-726318) and the British Heart
.. bat origin. Nature 2020;579:270–273.
1684 T.J. Guzik et al.

10. Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F. Network-based drug repur-
.. factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retro-
..
posing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov 2020;6:14. .. spective cohort study. Lancet 2020;395:1054–1062.
11. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, Graham BS, .. 33. Kreutz R, Algharably E, Azizi M, Dobrowolski P, Guzik T, Januszewicz A, Persu A,
McLellan JS. Cryo-EM structure of the 2019-nCoV spike in the prefusion conforma- .. Prejbisz A, Riemer T, Wang J, Burnier M. Hypertension, the renin–angiotensin sys-
tion. Science 2020;367:1260–1263. .. tem, and the risk of lower respiratory tract infections and lung injury: implications
12. Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, .. for COVID-19. European Society of Hypertension COVID-19 Task Force Review
Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. .. of Evidence. Cardiovasc Res 2020;116:1688–1699.
SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clini-
.. 34. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD.
..
cally proven protease inhibitor. Cell 2020;doi: 10.1016/j.cell.2020.02.052. .. Renin–angiotensin–aldosterone system inhibitors in patients with Covid-19. N Engl J
13. Zhao S, Lin Q, Ran J, Musa SS, Yang G, Wang W, Lou Y, Gao D, Yang L, He D, .. Med 2020; doi: 10.1056/NEJMsr2005760.
Wang MH. Preliminary estimation of the basic reproduction number of novel coro- .. 35. Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, Diz DI,
navirus (2019-nCoV) in China, from 2019 to 2020: a data-driven analysis in the early .. Gallagher PE. Effect of angiotensin-converting enzyme inhibition and angiotensin II
phase of the outbreak. Int J Infect Dis 2020;92:214–217. .. receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005;
14. van Doremalen N, Bushmaker T, Morris DH, Holbrook MG, Gamble A, Williamson .. 111:2605–2610.
BN, Tamin A, Harcourt JL, Thornburg NJ, Gerber SI, Lloyd-Smith JO, de Wit E,
.. 36. Danser AHJ, Epstein M, Batlle D. Renin–angiotensin system blockers and the
..
Munster VJ. Aerosol and surface stability of SARS-CoV-2 as compared with SARS- .. COVID-19 oandemic: at present there is no evidence to abandon renin–angiotensin
CoV-1. N Engl J Med 2020;382:1564–1567. .. system blockers. Hypertension 2020:HYPERTENSIONAHA12015082.
15. Liu Y, Yan LM, Wan L, Xiang TX, Le A, Liu JM, Peiris M, Poon LLM, Zhang W. Viral .. 37. Sun ML, Yang JM, Sun YP, Su GH. [Inhibitors of RAS might be a good choice for the
dynamics in mild and severe cases of COVID-19. Lancet Infect Dis 2020;doi: .. therapy of COVID-19 pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi 2020;43:
10.1016/S1473-3099(20)30232-2. .. 219–222.
16. Shi Y, Wang Y, Shao C, Huang J, Gan J, Huang X, Bucci E, Piacentini M, Ippolito G, .. 38. Chen DJ, Li X, Song PS, Hu CJ, Su F, Dai J. Hypokalemia and clinical implications in
Melino G. COVID-19 infection: the perspectives on immune responses. Cell Death .. patients with coronavirus disease 2019 (COVID-19). medRxiv 2020;doi: https:
Differ 2020;doi: 10.1038/s41418-020-0530-3.
.. //doi.org/10.1101/2020.02.27.20028530.
..
17. Bairey Merz CN, Pepine CJ, Shimokawa H, Berry C. Treatment of coronary micro- .. 39. Drummond G, Vinh A, Guzik T, Sobey CG. Immune mechanisms of hypertension.
vascular dysfunction. Cardiovasc Res 2020;116:856–870. .. Nat Rev Immunol 2019;19:517–532.
18. Liu K, Fang YY, Deng Y, Liu W, Wang MF, Ma JP, Xiao W, Wang YN, Zhong MH, Li .. 40. Loperena R, Van Beusecum JP, Itani HA, Engel N, Laroumanie F, Xiao L, Elijovich F,
CH, Li GC, Liu HG. Clinical characteristics of novel coronavirus cases in tertiary .. Laffer CL, Gnecco JS, Noonan J, Maffia P, Jasiewicz-Honkisz B, Czesnikiewicz-Guzik
hospitals in Hubei Province. Chin Med J (Engl) 2020; doi: .. M, Mikolajczyk T, Sliwa T, Dikalov S, Weyand CM, Guzik TJ, Harrison DG.
0.1097/CM9.0000000000000744. .. Hypertension and increased endothelial mechanical stretch promote monocyte dif-
19. Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M, Nagata N.
.. ferentiation and activation: roles of STAT3, interleukin 6 and hydrogen peroxide.
..
TMPRSS2 contributes to virus spread and immunopathology in the airways of mu- .. Cardiovasc Res 2018;114:1547–1563.
rine models after coronavirus infection. J Virol 2019;93:e01815–18. .. 41. Siedlinski M, Jozefczuk E, Xu X, Teumer A, Evangelou E, Schnabel RB, Welsh P,
20. Zhou Y, Vedantham P, Lu K, Agudelo J, Carrion R Jr, Nunneley JW, Barnard D, .. Maffia P, Erdmann J, Tomaszewski M, Caulfield MJ, Sattar N, Holmes MV, Guzik TJ.
Pohlmann S, McKerrow JH, Renslo AR, Simmons G. Protease inhibitors targeting .. White blood cells and blood pressure: a Mendelian randomization study. Circulation
coronavirus and filovirus entry. Antiviral Res 2015;116:76–84. .. 2020;doi: 10.1161/CIRCULATIONAHA.119.045102.
21. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, .. 42. Youn JC, Yu HT, Lim BJ, Koh MJ, Lee J, Chang DY, Choi YS, Lee SH, Kang SM, Jang
Zhao Y, Li Y, Wang X, Peng Z. Clinical characteristics of 138 hospitalized patients .. Y, Yoo OJ, Shin EC, Park S. Immunosenescent CD8þ T cells and C-X-C chemokine
with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;doi:
.. receptor type 3 chemokines are increased in human hypertension. Hypertension
..
10.1001/jama.2020.1585. .. 2013;62:126–133.
22. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, .. 43. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat
Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, .. Rev Cardiol 2020;doi: 10.1038/s41569-020-0360-5.
Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, .. 44. Lippi G, Lavie CJ, Sanchis-Gomar F. Cardiac troponin I in patients with coronavirus
Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS, China Medical Treatment .. disease 2019 (COVID-19): evidence from a meta-analysis. Prog Cardiovasc Dis 2020;
Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in .. doi: 10.1016/j.pcad.2020.03.001.
China. N Engl J Med 2020;doi: 10.1056/NEJMoa2002032.
.. 45. Gualandro DM, Puelacher C, LuratiBuse G, Lampart A, Strunz C, Cardozo FA, Yu
..
23. National Health Commission of the People’s Republic of China. Chinese Clinical .. PC, Jaffe AS, Barac S, Bock L, Badertscher P, du Fay de Lavallaz J, Marbot S, Sazgary
Guidance for COVID-19 Pneumonia Diagnosis and Treatment (7th edition). http:// .. L, Bolliger D, Rentsch K, Twerenbold R, Hammerer-Lercher A, Melo ES, Calderaro
kjfy.meetingchina.org/msite/news/show/cn/3337.html 2020. .. D, Duarte AJ, de Luccia N, Caramelli B, Mueller C, TropoVasc and BASEL-PMI
24. Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, Azman AS, Reich .. Investigators. Comparison of high-sensitivity cardiac troponin I and T for the predic-
NG, Lessler J. The incubation period of coronavirus disease 2019 (COVID-19) .. tion of cardiac complications after non-cardiac surgery. Am Heart J 2018;203:67–73.
from publicly reported confirmed cases: estimation and application. Ann Intern Med .. 46. Chen C, Zhou Y, Wang DW. SARS-CoV-2: a potential novel etiology of fulminant
2020; doi: 10.7326/M20-0504.
.. myocarditis. Herz 2020;doi: 10.1007/s00059-020-04909-z.
25. Zhou C, Gao C, Xie Y, Xu M. COVID-19 with spontaneous pneumomediastinum.
.. 47. Chen L, Li X, Chen M, Feng Y, Xiong C. The ACE2 expression in human heart indi-
..
Lancet Infect Dis 2020;20:510. .. cates new potential mechanism of heart injury among patients infected with SARS-
26. Sun R, Liu H, Wang X. Mediastinal emphysema, giant bulla, and pneumothorax de- .. CoV-2. Cardiovasc Res 2020;116:1097–1100.
veloped during the course of COVID-19 pneumonia. Korean J Radiol 2020;doi: .. 48. Inciardi RM, Lupi L, Zaccone G, Italia L, Raffo M, Tomasoni D, Cani DS, Cerini M,
10.3348/kjr.2020.018. .. Farina D, Gavazzi E, Maroldi R, Adamo M, Ammirati E, Sinagra G, Lombardi CM,
27. Grasselli G, Zangrillo A, Zanella A, Antonelli M, Cabrini L, Castelli A, Cereda D, .. Metra M. Cardiac involvement in a patient with coronavirus disease 2019 (COVID-
Coluccello A, Foti G, Fumagalli R, Iotti G, Latronico N, Lorini L, Merler S, Natalini .. 19). JAMA Cardiol 2020;doi: 10.1001/jamacardio.2020.1096.
G, Piatti A, Ranieri MV, Scandroglio AM, Storti E, Cecconi M, Pesenti A, COVID-19
.. 49. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia
..
Lombardy ICU Network. Baseline characteristics and outcomes of 1591 patients .. J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of
infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy. JAMA .. 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet
2020;doi: 10.1001/jama.2020.5394. .. 2020;395:507–513.
28. Epidemiology Working Group for NCIP Epidemic Response. The epidemiological .. 50. Gallagher S, Jones DA, Anand V, Mohiddin S. Diagnosis and management of patients
characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in .. with acute cardiac symptoms, troponin elevation and culprit-free angiograms. Heart
China. Chin J Epidemiol 2020;41:145–151. .. 2012;98:974–981.
29. The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The
.. 51. Kindermann I, Barth C, Mahfoud F, Ukena C, Lenski M, Yilmaz A, Klingel K, Kandolf
epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases
..
.. R, Sechtem U, Cooper LT, Bohm M. Update on myocarditis. J Am Coll Cardiol 2012;
(COVID-19)—China, 2020. China CDC Weekly 2020;2:x. .. 59:779–792.
30. Ruan S. Likelihood of survival of coronavirus disease 2019. Lancet Infect Dis 2020; .. 52. Pankuweit S, Moll R, Baandrup U, Portig I, Hufnagel G, Maisch B. Prevalence of the
doi: 10.1016/S1473-3099(20)30257-7. .. parvovirus B19 genome in endomyocardial biopsy specimens. Hum Pathol 2003;34:
31. Beaney T, Burrell LM, Castillo RR, Charchar FJ, Cro S, Damasceno A, Kruger R, .. 497–503.
Nilsson PM, Prabhakaran D, Ramirez AJ, Schlaich MP, Schutte AE, Tomaszewski M, .. 53. Kuhl U, Pauschinger M, Seeberg B, Lassner D, Noutsias M, Poller W, Schultheiss
Touyz R, Wang JG, Weber MA, Poulter NR, May Measurement Month .. HP. Viral persistence in the myocardium is associated with progressive cardiac dys-
Investigators. May Measurement Month 2018: a pragmatic global screening cam-
.. function. Circulation 2005;112:1965–1970.
..
paign to raise awareness of blood pressure by the International Society of .. 54. Blyszczuk P. Myocarditis in humans and in experimental animal models. Front
Hypertension. Eur Heart J 2019;40:2006–2017. .. Cardiovasc Med 2019;6:64.
32. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, .. 55. Gangaplara A, Massilamany C, Brown DM, Delhon G, Pattnaik AK, Chapman N,
Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk . Rose N, Steffen D, Reddy J. Coxsackievirus B3 infection leads to the generation of
COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options 1685

cardiac myosin heavy chain-alpha-reactive CD4 T cells in A/J mice. Clin Immunol .. 77. Ziegler L, Gajulapuri A, Frumento P, Bonomi A, Wallen H, de Faire U, Rose-John S,
2012;144:237–249.
.. Gigante B. Interleukin 6 trans-signalling and risk of future cardiovascular events.
..
56. Myers JM, Cooper LT, Kem DC, Stavrakis S, Kosanke SD, Shevach EM, Fairweather .. Cardiovasc Res 2019;115:213–221.
D, Stoner JA, Cox CJ, Cunningham MW. Cardiac myosin–Th17 responses promote .. 78. Hofmann P, Sommer J, Theodorou K, Kirchhof L, Fischer A, Li Y, Perisic L, Hedin U,
heart failure in human myocarditis. JCI Insight 2016;1:doi: 10.1172/jci.insight.85851. .. Maegdefessel L, Dimmeler S, Boon RA. Long non-coding RNA H19 regulates endo-
57. Musher DM, Abers MS, Corrales-Medina VF. Acute infection and myocardial infarc- .. thelial cell aging via inhibition of STAT3 signalling. Cardiovasc Res 2019;115:230–242.
tion. N Engl J Med 2019;380:171–176. .. 79. Ferrante G, Condorelli G. Interleukin-6 trans-signalling and risk of future cardiovas-
58. Cole JE, Park I, Ahern DJ, Kassiteridi C, Danso Abeam D, Goddard ME, Green P, .. cular events: a new avenue for atheroprotection? Cardiovasc Res 2019;115:8–9.
Maffia P, Monaco C. Immune cell census in murine atherosclerosis: cytometry by
.. 80. Smolen JS, Landewe R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M,
..
time of flight illuminates vascular myeloid cell diversity. Cardiovasc Res 2018;114: .. Nam J, Ramiro S, Voshaar M, van Vollenhoven R, Aletaha D, Aringer M, Boers M,
1360–1371. .. Buckley CD, Buttgereit F, Bykerk V, Cardiel M, Combe B, Cutolo M, van Eijk-
59. Steven S, Dib M, Hausding M, Kashani F, Oelze M, Kroller-Schon S, Hanf A, Daub S, .. Hustings Y, Emery P, Finckh A, Gabay C, Gomez-Reino J, Gossec L, Gottenberg JE,
Roohani S, Gramlich Y, Lutgens E, Schulz E, Becker C, Lackner KJ, Kleinert H, .. Hazes JMW, Huizinga T, Jani M, Karateev D, Kouloumas M, Kvien T, Li Z, Mariette
Knosalla C, Niesler B, Wild PS, Munzel T, Daiber A. CD40L controls obesity- .. X, McInnes I, Mysler E, Nash P, Pavelka K, Poor G, Richez C, van Riel P, Rubbert-
associated vascular inflammation, oxidative stress, and endothelial dysfunction in .. Roth A, Saag K, da Silva J, Stamm T, Takeuchi T, Westhovens R, de Wit M, van der
high fat diet-treated and db/db mice. Cardiovasc Res 2018;114:312–323.
.. Heijde D. EULAR recommendations for the management of rheumatoid arthritis
60. Kusters PJH, Lutgens E, Seijkens TTP. Exploring immune checkpoints as potential
.. with synthetic and biological disease-modifying antirheumatic drugs: 2016 update.
..
therapeutic targets in atherosclerosis. Cardiovasc Res 2018;114:368–377. .. Ann Rheum Dis 2017;76:960–977.
61. Peiris JS, Chu CM, Cheng VC, Chan KS, Hung IF, Poon LL, Law KI, Tang BS, Hon .. 81. Kishimoto T. Discovery of IL-6 and development of anti-IL-6R antibody. Keio J Med
TY, Chan CS, Chan KH, Ng JS, Zheng BJ, Ng WL, Lai RW, Guan Y, Yuen KY, HKU/ .. 2019;68:96.
UCH SARS Study Group. Clinical progression and viral load in a community out- .. 82. The Chinese National Health Commission. Chinese Clinical Guidance for COVID-
break of coronavirus-associated SARS pneumonia: a prospective study. Lancet 2003; .. 19 Pneumonia Diagnosis and Treatment–American College of Cardiology. 2020.
361:1767–1772. .. https://www.acc.org/latest-in-cardiology/articles/2020/03/17/11/22/chinese-clinical-
62. Levy BI, Heusch G, Camici PG. The many faces of myocardial ischaemia and angina.
.. guidance-for-covid-19-pneumonia-diagnosis-and-treatment
..
Cardiovasc Res 2019;115:1460–1470. .. 83. Jamal FA, Khaled SK. The cardiovascular complications of chimeric antigen receptor
63. Carnevale D, Wenzel P. Mechanical stretch on endothelial cells interconnects in- .. T cell therapy. Curr Hematol Malig Rep 2020;doi: 10.1007/s11899-020-00567-4.
nate and adaptive immune response in hypertension. Cardiovasc Res 2018;114: .. 84. Wang HX, Li WJ, Hou CL, Lai S, Zhang YL, Tian C, Yang H, Du J, Li HH. CD1d-de-
1432–1434. .. pendent natural killer T cells attenuate angiotensin II-induced cardiac remodeling via
64. Petrie JR, Guzik TJ, Touyz RM. Diabetes, hypertension, and cardiovascular disease: .. IL-10 signaling in mice. Cardiovasc Res 2018;115:83–93.
clinical insights and vascular mechanisms. Can J Cardiol 2018;34:575–584. .. 85. van der Heijden C, Deinum J, Joosten LAB, Netea MG, Riksen NP. The mineralo-
65. Wilk G, Osmenda G, Matusik P, Nowakowski D, Jasiewicz-Honkisz B, Ignacak A,
.. corticoid receptor as a modulator of innate immunity and atherosclerosis.
Czesnikiewicz-Guzik M, Guzik TJ. Endothelial function assessment in atherosclero-
.. Cardiovasc Res 2018;114:944–953.
..
sis: comparison of brachial artery flowmediated vasodilation and peripheral arterial .. 86. Brauner S, Jiang X, Thorlacius GE, Lundberg AM, Ostberg T, Yan ZQ, Kuchroo VK,
tonometry. Pol Arch Med Wewn 2013;123:443–452. .. Hansson GK, Wahren-Herlenius M. Augmented Th17 differentiation in Trim21 defi-
66. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated .. ciency promotes a stable phenotype of atherosclerotic plaques with high collagen
with poor prognosis in patients with novel coronavirus pneumonia. J Thromb .. content. Cardiovasc Res 2018;114:158–167.
Haemost 2020;18:844–847. .. 87. Chou CH, Hung CS, Liao CW, Wei LH, Chen CW, Shun CT, Wen WF, Wan CH,
67. Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and .. Wu XM, Chang YY, Wu VC, Wu KD, Lin YH, TAIPAI Study Group. IL-6 trans-
COVID-19 pneumonia: a random association? Eur Heart J 2020;doi:
.. signalling contributes to aldosterone-induced cardiac fibrosis. Cardiovasc Res 2018;
..
10.1093/eurheartj/ehaa254. .. 114:690–702.
68. Ketelhuth DFJ, Lutgens E, Back M, Binder CJ, Van den Bossche J, Daniel C, Dumitriu .. 88. Watson C, Whittaker S, Smith N, Vora AJ, Dumonde DC, Brown KA. IL-6 acts on
IE, Hoefer I, Libby P, O’Neill L, Weber C, Evans PC. Immunometabolism and ath- .. endothelial cells to preferentially increase their adherence for lymphocytes. Clin Exp
erosclerosis: perspectives and clinical significance: a position paper from the .. Immunol 1996;105:112–119.
Working Group on Atherosclerosis and Vascular Biology of the European Society .. 89. van Tits LJ, Stienstra R, van Lent PL, Netea MG, Joosten LA, Stalenhoef AF.
of Cardiology. Cardiovasc Res 2019;115:1385–1392. .. Oxidized LDL enhances pro-inflammatory responses of alternatively activated M2
69. Ketelhuth DFJ. The immunometabolic role of indoleamine 2,3-dioxygenase in ath-
.. macrophages: a crucial role for Kruppel-like factor 2. Atherosclerosis 2011;214:
..
erosclerotic cardiovascular disease: immune homeostatic mechanisms in the artery .. 345–349.
wall. Cardiovasc Res 2019;115:1408–1415. .. 90. Sukovich DA, Kauser K, Shirley FD, DelVecchio V, Halks-Miller M, Rubanyi GM.
70. Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, Przepiorka D, Farrell AT, .. Expression of interleukin-6 in atherosclerotic lesions of male ApoE-knockout mice:
Pazdur R. FDA approval summary: tocilizumab for treatment of chimeric antigen re- .. inhibition by 17beta-estradiol. Arterioscler Thromb Vasc Biol 1998;18:1498–1505.
ceptor T cell-induced severe or life-threatening cytokine release syndrome. .. 91. Huber SA, Sakkinen P, Conze D, Hardin N, Tracy R. Interleukin-6 exacerbates early
Oncologist 2018;23:943–947. .. atherosclerosis in mice. Arterioscler Thromb Vasc Biol 1999;19:2364–2367.
71. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, HLH Across .. 92. Schuett H, Oestreich R, Waetzig GH, Annema W, Luchtefeld M, Hillmer A,
Speciality Collaboration UK. COVID-19: consider cytokine storm syndromes and
.. Bavendiek U, von Felden J, Divchev D, Kempf T, Wollert KC, Seegert D, Rose-John
..
immunosuppression. Lancet 2020;395:1033–1034. .. S, Tietge UJ, Schieffer B, Grote K. Transsignaling of interleukin-6 crucially contrib-
72. Gast M, Rauch BH, Nakagawa S, Haghikia A, Jasina A, Haas J, Nath N, Jensen L, .. utes to atherosclerosis in mice. Arterioscler Thromb Vasc Biol 2012;32:281–290.
Stroux A, Bohm A, Friebel J, Rauch U, Skurk C, Blankenberg S, Zeller T, Prasanth .. 93. Nishihara M, Aoki H, Ohno S, Furusho A, Hirakata S, Nishida N, Ito S, Hayashi M,
KV, Meder B, Kuss A, Landmesser U, Poller W. Immune system-mediated athero- .. Imaizumi T, Fukumoto Y. The role of IL-6 in pathogenesis of abdominal aortic aneu-
sclerosis caused by deficiency of long non-coding RNA MALAT1 in ApoE–/– mice. .. rysm in mice. PLoS One 2017;12:e0185923.
Cardiovasc Res 2019;115:302–314. .. 94. Schieffer B, Selle T, Hilfiker A, Hilfiker-Kleiner D, Grote K, Tietge UJ, Trautwein C,
73. Gast M, Rauch BH, Haghikia A, Nakagawa S, Haas J, Stroux A, Schmidt D,
.. Luchtefeld M, Schmittkamp C, Heeneman S, Daemen MJ, Drexler H. Impact of
..
Schumann P, Weiss S, Jensen L, Kratzer A, Kraenkel N, Muller C, Bornigen D, .. interleukin-6 on plaque development and morphology in experimental atheroscle-
Hirose T, Blankenberg S, Escher F, Kuhl AA, Kuss AW, Meder B, Landmesser U, .. rosis. Circulation 2004;110:3493–3500.
Zeller T, Poller W. Long noncoding RNA NEAT1 modulates immune cell functions .. 95. Tamura Y, Phan C, Tu L, Le Hiress M, Thuillet R, Jutant EM, Fadel E, Savale L,
and is suppressed in early onset myocardial infarction patients. Cardiovasc Res 2019; .. Huertas A, Humbert M, Guignabert C. Ectopic upregulation of membrane-bound
115:1886–1906. .. IL6R drives vascular remodeling in pulmonary arterial hypertension. J Clin Invest
74. van Koeverden ID, de Bakker M, Haitjema S, van der Laan SW, de Vries JPM, .. 2018;128:1956–1970.
Hoefer IE, de Borst GJ, Pasterkamp G, den Ruijter HM. Testosterone to oestradiol .. 96. Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium,
ratio reflects systemic and plaque inflammation and predicts future cardiovascular
.. Swerdlow DI, Holmes MV, Kuchenbaecker KB, Engmann JE, Shah T, Sofat R, Guo Y,
..
events in men with severe atherosclerosis. Cardiovasc Res 2019;115:453–462. .. Chung C, Peasey A, Pfister R, Mooijaart SP, Ireland HA, Leusink M, Langenberg C,
75. Penson P, Long DL, Howard G, Howard VJ, Jones SR, Martin SS, Mikhailidis DP, .. Li KW, Palmen J, Howard P, Cooper JA, Drenos F, Hardy J, Nalls MA, Li YR, Lowe
Muntner P, Rizzo M, Rader DJ, Safford MM, Sahebkar A, Toth PP, Banach M. .. G, Stewart M, Bielinski SJ, Peto J, Timpson NJ, Gallacher J, Dunlop M, Houlston R,
Associations between cardiovascular disease, cancer, and very low high-density lipo- .. Tomlinson I, Tzoulaki I, Luan J, Boer JM, Forouhi NG, Onland-Moret NC, van der
protein cholesterol in the REasons for Geographical and Racial Differences in .. Schouw YT, Schnabel RB, Hubacek JA, Kubinova R, Baceviciene M, Tamosiunas A,
Stroke (REGARDS) study. Cardiovasc Res 2019;115:204–212. .. Pajak A, Topor-Madry R, Malyutina S, Baldassarre D, Sennblad B, Tremoli E, de
76. Crnko S, Ernens I, Van Laake LW. New dimensions in circadian clock function: the
.. Faire U, Ferrucci L, Bandenelli S, Tanaka T, Meschia JF, Singleton A, Navis G, Mateo
..
role of biological sex. Cardiovasc Res 2018;114:203–204. . Leach I, Bakker SJ, Gansevoort RT, Ford I, Epstein SE, Burnett MS, Devaney JM,
1686 T.J. Guzik et al.

Jukema JW, Westendorp RG, Jan de Borst G, van der Graaf Y, de Jong PA, Mailand-
.. and dysfunction in a rat model of myocardial infarction. Hum Gene Ther 2010;21:
..
van der Zee AH, Klungel OH, de Boer A, Doevendans PA, Stephens JW, Eaton CB, .. 1545–1554.
Robinson JG, Manson JE, Fowkes FG, Frayling TM, Price JF, Whincup PH, Morris .. 114. SIAARTI, Società Italiana di Anestesia Analgesia Rianimazione e Terapia Intensiva.
RW, Lawlor DA, Smith GD, Ben-Shlomo Y, Redline S, Lange LA, Kumari M, .. Percorso assistenziale per il paziente affetto da COVID-19. http://www.siaarti.it/
Wareham NJ, Verschuren WM, Benjamin EJ, Whittaker JC, Hamsten A, Dudbridge .. SiteAssets/News/COVID19%20-%20documenti%20SIAARTI/Percorso%20COVID-
F, Delaney JA, Wong A, Kuh D, Hardy R, Castillo BA, Connolly JJ, van der Harst P, .. 19%20-%20Sezione%201%20-%20Procedura%20Area%20Critica%20-%20Rev%202.
Brunner EJ, Marmot MG, Wassel CL, Humphries SE, Talmud PJ, Kivimaki M, .. 0.pdf 2020 (4 April 2020).
Asselbergs FW, Voevoda M, Bobak M, Pikhart H, Wilson JG, Hakonarson H, Reiner
.. 115. Yang W, Cao Q, Qin L, Wang X, Cheng Z, Pan A, Dai J, Sun Q, Zhao F, Qu J, Yan
..
AP, Keating BJ, Sattar N, Hingorani AD, Casas JP. The interleukin-6 receptor as a .. F. Clinical characteristics and imaging manifestations of the 2019 novel coronavirus
target for prevention of coronary heart disease: a Mendelian randomisation analysis. .. disease (COVID-19): a multi-center study in Wenzhou city, Zhejiang, China. J Infect
Lancet 2012;379:1214–1224. .. 2020;80:388–393.
97. Sarwar N, Butterworth AS, Freitag DF, Gregson J, Willeit P, Gorman DN, Gao P, .. 116. Geng L, Wang W, Chen Y, Cao J, Lu L, Chen Q, He R, Shen W. Elevation of
Saleheen D, Rendon A, Nelson CP, Braund PS, Hall AS, Chasman DI, Tybjaerg- .. ADAM10, ADAM17, MMP-2 and MMP-9 expression with media degeneration fea-
Hansen A, Chambers JC, Benjamin EJ, Franks PW, Clarke R, Wilde AA, Trip MD, .. tures CaCl2-induced thoracic aortic aneurysm in a rat model. Exp Mol Pathol 2010;
Steri M, Witteman JC, Qi L, van der Schoot CE, de Faire U, Erdmann J, Stringham
.. 89:72–81.
..
HM, Koenig W, Rader DJ, Melzer D, Reich D, Psaty BM, Kleber ME, Panagiotakos .. 117. Nakkazi E. Randomised controlled trial begins for Ebola therapeutics. Lancet 2018;
DB, Willeit J, Wennberg P, Woodward M, Adamovic S, Rimm EB, Meade TW, .. 392:2338.
Gillum RF, Shaffer JA, Hofman A, Onat A, Sundstrom J, Wassertheil-Smoller S, .. 118. Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, Li Y, Hu Z, Zhong W, Wang M.
Mellstrom D, Gallacher J, Cushman M, Tracy RP, Kauhanen J, Karlsson M, Salonen .. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting
JT, Wilhelmsen L, Amouyel P, Cantin B, Best LG, Ben-Shlomo Y, Manson JE, Davey- .. SARS-CoV-2 infection in vitro. Cell Discov 2020;6:16.
Smith G, de Bakker PI, O’Donnell CJ, Wilson JF, Wilson AG, Assimes TL, Jansson .. 119. Bettadapura J, Herrero LJ, Taylor A, Mahalingam S. Approaches to the treatment of
JO, Ohlsson C, Tivesten A, Ljunggren O, Reilly MP, Hamsten A, Ingelsson E, .. disease induced by chikungunya virus. Indian J Med Res 2013;138:762–765.
Cambien F, Hung J, Thomas GN, Boehnke M, Schunkert H, Asselbergs FW,
.. 120. Kuhl U, Lassner D, von Schlippenbach J, Poller W, Schultheiss HP. Interferon-Beta
..
Kastelein JJ, Gudnason V, Salomaa V, Harris TB, Kooner JS, Allin KH, Nordestgaard .. improves survival in enterovirus-associated cardiomyopathy. J Am Coll Cardiol 2012;
BG, Hopewell JC, Goodall AH, Ridker PM, Holm H, Watkins H, Ouwehand WH, .. 60:1295–1296.
Samani NJ, Kaptoge S, Di Angelantonio E, Harari O, Danesh J. Interleukin-6 recep- .. 121. Maisch B, Alter P. Treatment options in myocarditis and inflammatory cardiomyopa-
tor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. .. thy: focus on i.v. immunoglobulins. Herz 2018;43:423–430.
Lancet 2012;379:1205–1213. .. 122. Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers YM. Cardiac complications at-
98. Maffia P, Guzik TJ. When, where, and how to target vascular inflammation in the .. tributed to chloroquine and hydroxychloroquine: a systematic review of the litera-
post-CANTOS era? Eur Heart J 2019;40:2492–2494.
.. ture. Drug Saf 2018;41:919–931.
..
99. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan .. 123. Gabay C, Riek M, Hetland ML, Hauge EM, Pavelka K, Tomsic M, Canhao H,
JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. Angiotensin-converting enzyme .. Chatzidionysiou K, Lukina G, Nordstrom DC, Lie E, Ancuta I, Hernandez MV, van
2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450–454. .. Riel PL, van Vollenhoven R, Kvien TK. Effectiveness of tocilizumab with and without
100. Matsuyama S, Nagata N, Shirato K, Kawase M, Takeda M, Taguchi F. Efficient activa- .. synthetic disease-modifying antirheumatic drugs in rheumatoid arthritis: results from
tion of the severe acute respiratory syndrome coronavirus spike protein by the .. a European collaborative study. Ann Rheum Dis 2016;75:1336–1342.
transmembrane protease TMPRSS2. J Virol 2010;84:12658–12664. .. 124. Giles JT, Sattar N, Gabriel S, Ridker PM, Gay S, Warne C, Musselman D, Brockwell
101. Raj VS, Mou H, Smits SL, Dekkers DHW, Müller MA, Dijkman R, Muth D, .. L, Shittu E, Klearman M, Fleming TR. Cardiovascular safety of tocilizumab versus
Demmers JAA, Zaki A, Fouchier RAM, Thiel V, Drosten C, Rottier PJM, Osterhaus
.. etanercept in rheumatoid arthritis: a randomized controlled trial. Arthritis Rheumatol
..
ADME, Bosch BJ, Haagmans BL. Dipeptidyl peptidase 4 is a functional receptor for .. 2020;72:31–40.
the emerging human coronavirus-EMC. Nature 2013;495:251–254. .. 125. Zuo H, Li R, Ma F, Jiang J, Miao K, Li H, Nagel E, Tadic M, Wang H, Wang DW.
102. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, .. Temporal echocardiography findings in patients with fulminant myocarditis: beyond
Bao L, Zhang B, Liu G, Wang Z, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada .. ejection fraction decline. Front Med 2019;doi: 10.1007/s11684-019-0713-9.
T, Slutsky AS, Liu D, Qin C, Jiang C, Penninger JM. A crucial role of angiotensin con- .. 126. Vergano M, Bertolini G, Giannini A, Gristina G, Livigni S, Mistraletti G, Petrini F.
verting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nature Med .. Clinical Ethics Recommendations for the Allocation of Intensive Care Treatments, in
2005;11:875–879.
.. Exceptional, Resource-Limited Circumstances. Società Italiana di Anestesia Analgesia
..
103. Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi .. Rianimazione e Terapia Intensiva.
H, Crackower MA, Fukamizu A, Hui CC, Hein L, Uhlig S, Slutsky AS, Jiang C, .. 127. Frederix I, Caiani EG, Dendale P, Anker S, Bax J, Bohm A, Cowie M, Crawford J, de
Penninger JM. Angiotensin-converting enzyme 2 protects from severe acute lung .. Groot N, Dilaveris P, Hansen T, Koehler F, Krstacic G, Lambrinou E, Lancellotti P,
failure. Nature 2005;436:112–116. .. Meier P, Neubeck L, Parati G, Piotrowicz E, Tubaro M, van der Velde E. ESC e-
104. de Lang A, Osterhaus AD, Haagmans BL. Interferon-gamma and interleukin-4 .. Cardiology Working Group Position Paper: overcoming challenges in digital health
downregulate expression of the SARS coronavirus receptor ACE2 in Vero E6 cells. .. implementation in cardiovascular medicine. Eur J Prev Cardiol 2019;26:1166–1177.
Virology 2006;353:474–481.
.. 128. Cacioppo JT, Hawkley LC. Perceived social isolation and cognition. Trends Cogn Sci
105. Zulli A, Burrell LM, Widdop RE, Black MJ, Buxton BF, Hare DL. Immunolocalization
.. 2009;13:447–454.
..
of ACE2 and AT2 receptors in rabbit atherosclerotic plaques. J Histochem Cytochem .. 129. Liu Y, Lv L, Wang L, Zhong Y. Social isolation induces Rac1-dependent forgetting of
2006;54:147–150. .. social memory. Cell Rep 2018;25:288–295.
106. Thatcher SE, Gupte M, Hatch N, Cassis LA. Deficiency of ACE2 in bone-marrow- .. 130. Matthews GA, Nieh EH, Vander Weele CM, Halbert SA, Pradhan RV, Yosafat AS,
derived cells increases expression of TNF-alpha in adipose stromal cells and aug- .. Glober GF, Izadmehr EM, Thomas RE, Lacy GD, Wildes CP, Ungless MA, Tye KM.
ments glucose intolerance in obese C57BL/6 mice. Int J Hypertens 2012;2012: .. Dorsal Raphe dopamine neurons represent the experience of social isolation. Cell
762094. .. 2016;164:617–631.
107. Li SS, Cheng CW, Fu CL, Chan YH, Lee MP, Chan JW, Yiu SF. Left ventricular per-
.. 131. Jaremka LM, Peng J, Bornstein R, Alfano CM, Andridge RR, Povoski SP, Lipari AM,
..
formance in patients with severe acute respiratory syndrome: a 30-day echocardio- .. Agnese DM, Farrar WB, Yee LD, Carson WE 3rd, Kiecolt-Glaser JK. Cognitive
graphic follow-up study. Circulation 2003;108:1798–1803. .. problems among breast cancer survivors: loneliness enhances risk. Psychooncology
108. Yu CM, Wong RS, Wu EB, Kong SL, Wong J, Yip GW, Soo YO, Chiu ML, Chan YS, .. 2014;23:1356–1364.
Hui D, Lee N, Wu A, Leung CB, Sung JJ. Cardiovascular complications of severe .. 132. Ellwardt L, Aartsen M, Deeg D, Steverink N. Does loneliness mediate the relation
acute respiratory syndrome. Postgrad Med J 2006;82:140–144. .. between social support and cognitive functioning in later life? Soc Sci Med 2013;98:
109. Oudit GY, Kassiri Z, Jiang C, Liu PP, Poutanen SM, Penninger JM, Butany J. SARS-co- .. 116–124.
ronavirus modulation of myocardial ACE2 expression and inflammation in patients
.. 133. Nonogaki K, Nozue K, Oka Y. Social isolation affects the development of obesity
with SARS. Eur J Clin Invest 2009;39:618–625.
.. and type 2 diabetes in mice. Endocrinology 2007;148:4658–166.
..
110. Touyz RM, Alves-Lopes R, Rios FJ, Camargo LL, Anagnostopoulou A, Arner A, .. 134. Volden PA, Wonder EL, Skor MN, Carmean CM, Patel FN, Ye H, Kocherginsky M,
Montezano AC. Vascular smooth muscle contraction in hypertension. Cardiovasc .. McClintock MK, Brady MJ, Conzen SD. Chronic social isolation is associated with
Res 2018;114:529–539. .. metabolic gene expression changes specific to mammary adipose tissue. Cancer Prev
111. Lacolley P, Regnault V, Avolio AP. Smooth muscle cell and arterial aging: basic and .. Res (Phila) 2013;6:634–645.
clinical aspects. Cardiovasc Res 2018;114:513–528. .. 135. Whisman MA. Loneliness and the metabolic syndrome in a population-based sam-
112. Burrell LM, Risvanis J, Kubota E, Dean RG, MacDonald PS, Lu S, Tikellis C, Grant .. ple of middle-aged and older adults. Health Psychol 2010;29:550–554.
SL, Lew RA, Smith AI, Cooper ME, Johnston CI. Myocardial infarction increases
.. 136. Jaremka LM, Fagundes CP, Peng J, Belury MA, Andridge RR, Malarkey WB, Kiecolt-
..
ACE2 expression in rat and humans. Eur Heart J 2005;26:369–375. .. Glaser JK. Loneliness predicts postprandial ghrelin and hunger in women. Horm
113. Zhao YX, Yin HQ, Yu QT, Qiao Y, Dai HY, Zhang MX, Zhang L, Liu YF, Wang LC, .. Behav 2015;70:57–63.
Liu DS, Deng BP, Zhang YH, Pan CM, Song HD, Qu X, Jiang H, Liu CX, Lu XT, Liu .. 137. Budiu RA, Vlad AM, Nazario L, Bathula C, Cooper KL, Edmed J, Thaker PH, Urban
B, Gao F, Dong B. ACE2 overexpression ameliorates left ventricular remodeling . J, Kalinski P, Lee AV, Elishaev EL, Conrads TP, Flint MS. Restraint and social isolation
COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options 1687

..
stressors differentially regulate adaptive immunity and tumor angiogenesis in a .. 153. Hakulinen C, Pulkki-Raback L, Virtanen M, Jokela M, Kivimaki M, Elovainio M. Social
breast cancer mouse model. Cancer Clin Oncol 2017;6:12–24. .. isolation and loneliness as risk factors for myocardial infarction, stroke and mortal-
138. Lutgendorf SK, DeGeest K, Dahmoush L, Farley D, Penedo F, Bender D, .. ity: UK Biobank cohort study of 479 054 men and women. Heart 2018;104:
Goodheart M, Buekers TE, Mendez L, Krueger G, Clevenger L, Lubaroff DM, Sood .. 1536–1542.
AK, Cole SW. Social isolation is associated with elevated tumor norepinephrine in .. 154. Koss KJ, Hostinar CE, Donzella B, Gunnar MR. Social deprivation and the HPA axis
ovarian carcinoma patients. Brain Behav Immun 2011;25:250–255. .. in early development. Psychoneuroendocrinology 2014;50:1–13.
139. Hawkley LC, Cacioppo JT. Loneliness and pathways to disease. Brain Behav Immun .. 155. Cacioppo JT, Cacioppo S, Capitanio JP, Cole SW. The neuroendocrinology of social
2003;17 Suppl 1:S98–105.
.. isolation. Annu Rev Psychol 2015;66:733–767.
..
140. Pyter LM, Yang L, McKenzie C, da Rocha JM, Carter CS, Cheng B, Engeland CG. .. 156. Stafford M, Gardner M, Kumari M, Kuh D, Ben-Shlomo Y. Social isolation and diur-
Contrasting mechanisms by which social isolation and restraint impair healing in .. nal cortisol patterns in an ageing cohort. Psychoneuroendocrinology 2013;38:
male mice. Stress 2014;17:256–265. .. 2737–2745.
141. Jaremka LM, Fagundes CP, Glaser R, Bennett JM, Malarkey WB, Kiecolt-Glaser JK. .. 157. Hawkley LC, Cole SW, Capitanio JP, Norman GJ, Cacioppo JT. Effects of social iso-
Loneliness predicts pain, depression, and fatigue: understanding the role of immune .. lation on glucocorticoid regulation in social mammals. Horm Behav 2012;62:
dysregulation. Psychoneuroendocrinology 2013;38:1310–1317. .. 314–323.
142. Steptoe A, Kivimaki M. Stress and cardiovascular disease: an update on current
.. 158. Lewis R, Wilkins B, Benjamin B, Curtis JT. Cardiovascular control is associated with
..
knowledge. Annu Rev Public Health 2013;34:337–54. .. pair-bond success in male prairie voles. 2017;208:93–102.
143. Leigh-Hunt N, Bagguley D, Bash K, Turner V, Turnbull S, Valtorta N, Caan W. An .. 159. Custaud MA, Belin de Chantemele E, Larina IM, Nichiporuk IA, Grigoriev A,
overview of systematic reviews on the public health consequences of social isola- .. Duvareille M, Gharib C, Gauquelin-Koch G. Hormonal changes during long-term
tion and loneliness. Public Health 2017;152:157–171. .. isolation. Eur J Appl Physiol 2004;91:508–515.
144. Heidari Gorji MA, Fatahian A, Farsavian A. The impact of perceived and objective .. 160. Lyons DM, Ha CM, Levine S. Social effects and circadian rhythms in squirrel monkey
social isolation on hospital readmission in patients with heart failure: a systematic .. pituitary–adrenal activity. Horm Behav 1995;29:177–190.
review and meta-analysis of observational studies. Gen Hosp Psychiatry 2019;60: .. 161. Vaernes RJ, Bergan T, Warncke M, Ursin H, Aakvaag A, Hockey R. European isola-
27–36.
.. tion and confinement study. Workload and stress: effects on psychosomatic and
..
145. Pantell M, Rehkopf D, Jutte D, Syme SL, Balmes J, Adler N. Social isolation: a predic- .. psychobiological reaction patterns. Adv Space Biol Med 1993;3:95–120.
tor of mortality comparable to traditional clinical risk factors. Am J Public Health .. 162. Murray DR, Haselton MG, Fales M, Cole SW. Subjective social status and inflamma-
2013;103:2056–2062. .. tory gene expression. Health Psychol 2019;38:182–186.
146. Thurston RC, Kubzansky LD. Women, loneliness, and incident coronary heart dis- .. 163. Mumtaz F, Khan MI, Zubair M, Dehpour AR. Neurobiology and consequences of
ease. Psychosom Med 2009;71:836–842. .. social isolation stress in animal model—a comprehensive review. Biomed
147. Dennis J, Sealock J, Levinson RT, Farber-Eger E, Franco J, Fong S, Straub P, Hucks D, .. Pharmacother 2018;105:1205–1222.
Song WL, Linton MF, Fontanillas P, Elson SL, Ruderfer D, Abdellaoui A, Sanchez-
.. 164. Kamal A, Ramakers GM, Altinbilek B, Kas MJ. Social isolation stress reduces hippo-
..
Roige S, Palmer AA, Boomsma DI, Cox NJ, Chen G, Mosley JD, Wells QS, Davis .. campal long-term potentiation: effect of animal strain and involvement of glucocor-
LK. Genetic risk for major depressive disorder and loneliness in sex-specific associa- .. ticoid receptors. Neuroscience 2014;256:262–270.
tions with coronary artery disease. Mol Psychiatry 2019;doi: 10.1038/s41380- .. 165. Barik J, Marti F, Morel C, Fernandez SP, Lanteri C, Godeheu G, Tassin JP,
019-0614-y. .. Mombereau C, Faure P, Tronche F. Chronic stress triggers social aversion via gluco-
148. Xia N, Li H. Loneliness, social isolation, and cardiovascular health. Antioxid Redox .. corticoid receptor in dopaminoceptive neurons. Science 2013;339:332–335.
Signal 2018;28:837–851. .. 166. Skulstad H, Cosyns B, Popescu BA, Galderisi M, Salvo GD, Donal E, Petersen S,
149. Vigorito C, Giallauria F. Loneliness, social isolation and risk of cardiovascular .. Gimelli A, Haugaa KH, Muraru D, Almeida AG, Schulz-Menger J, Dweck MR,
disease in the English Longitudinal Study of Ageing. Eur J Prev Cardiol 2018;25:
.. Pontone G, Sade LE, Gerber B, Maurovich-Horvat P, Bharucha T, Cameli M, Magne
..
1384–1386. .. J, Westwood M, Maurer G, Edvardsen T. COVID-19 pandemic and cardiac imaging:
150. Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the patho- .. EACVI recommendations on precautions, indications, prioritization, and protection
genesis of cardiovascular disease and implications for therapy. Circulation 1999;99: .. for patients and healthcare personnel. Eur Heart J Cardiovasc Imaging 2020;doi:
2192–217. .. 10.1093/ehjci/jeaa072.
151. Knox SS, Uvnas-Moberg K. Social isolation and cardiovascular disease: an athero- .. 167. Richardson S, Hirsch JS, Narasimhan M, Crawford DM, McGinn T, Davidson KW,
sclerotic pathway? Psychoneuroendocrinology 1998;23:877–890. .. and the Northwell COVID-19 Research Consortium. Presenting characteristics,
152. Valtorta NK, Kanaan M, Gilbody S, Ronzi S, Hanratty B. Loneliness and social
.. Comorbidities, and outcomes among 5700 patients hospitalized With COVID-19 in
..
isolation as risk factors for coronary heart disease and stroke: systematic review and .. the New York City area. JAMA 2020;doi:10.1001/jama.2020.6775.
meta-analysis of longitudinal observational studies. Heart 2016;102:1009–1016. ..
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Cardiovascular Research (2020) 116, 1666–1687 REVIEW

COVID-19 and the cardiovascular system:

Table 1 Baseline demographic data and comorbidities in selected early studies3,6,18,21,22,32

The Novel Coronavirus Pneumonia Emergency Response

Table 4 Diagnostic tests in patients with COVID-19 and cardiovascular involvement

Test Diagnostic considerations in COVID-19 patients

Table 6 Potential COVID-19 therapies and their cardiovascular effects

CV side effects CV warnings/toxicities Use with caution or avoid in presence of

References: www.medscape.com; CAD, coronary artery disease; MI, myocardial infarction.

Table 7 Summary of current key considerations in COVID-19 diagnosis and treatment

Key take-home messages:

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