REVIEwS

COVID-19 and cardiovascular disease:

from basic mechanisms to clinical
perspectives
Masataka Nishiga   1,2 ✉, Dao Wen Wang3, Yaling Han4, David B. Lewis5
and Joseph C. Wu   1,2,6 ✉
Abstract | Coronavirus disease 2019 (COVID-19), caused by a strain of coronavirus known as
severe acute respiratory syndrome coronavirus 2 (SARS-​CoV-2), has become a global pandemic
that has affected the lives of billions of individuals. Extensive studies have revealed that
SARS-CoV-2 shares many biological features with SARS-​CoV, the zoonotic virus that caused the
2002 outbreak of severe acute respiratory syndrome, including the system of cell entry, which is
triggered by binding of the viral spike protein to angiotensin-​converting enzyme 2. Clinical
studies have also reported an association between COVID-19 and cardiovascular disease.
Pre-​existing cardiovascular disease seems to be linked with worse outcomes and increased risk
of death in patients with COVID-19, whereas COVID-19 itself can also induce myocardial injury,
arrhythmia, acute coronary syndrome and venous thromboembolism. Potential drug–disease
interactions affecting patients with COVID-19 and comorbid cardiovascular diseases are also
becoming a serious concern. In this Review, we summarize the current understanding of COVID-19
from basic mechanisms to clinical perspectives, focusing on the interaction between COVID-19
and the cardiovascular system. By combining our knowledge of the biological features of the virus
with clinical findings, we can improve our understanding of the potential mechanisms underlying
COVID-19, paving the way towards the development of preventative and therapeutic solutions.

Acute respiratory distress Coronavirus disease 2019 (COVID-19) was first reported can trigger a cytokine storm, whereby pro-​inflammatory
syndrome in Wuhan, China, in late December 2019 (refs1–3). Since cytokines and chemokines such as tumour necrosis
(ARDS). A type of severe, then, COVID-19 has spread rapidly worldwide and has factor-​α, IL-1β and IL-6 are overproduced by the immune
acute respiratory failure become a global pandemic affecting >200 countries system, resulting in multiorgan damage5. Furthermore,
characterized by bilateral
pulmonary infiltrates and
and territories, with an unprecedented effect not only COVID-19 causes coagulation abnormalities in a sub-
severe hypoxaemia that occurs on public health, but also social and economic activi- stantial proportion of patients, which can lead to throm-
as a result of illness or injury. ties. The exponential increase in the number of patients boembolic events6,7. The genomic sequence1–3,8 and viral
with COVID-19 in the past 6 months has overwhelmed protein structure9–11 of SARS-​CoV-2 have been studied
Cytokine storm
health-​care systems in numerous countries across the intensively since its emergence. To date, research shows
A form of severe immune
reaction characterized by
world. At present, preventive vaccines and prophylactic that SARS-​CoV-2 shares many biological features with
overproduction of cytokines therapies for COVID-19 are not available. SARS-​CoV owing to 79.6% genomic sequence identity1,2.
and chemokines that can be COVID-19 is caused by severe acute respiratory syn- In particular, both SARS-​CoV and SARS-​CoV-2 use the
triggered by a variety of factors drome coronavirus 2 (SARS-​CoV-2), which is a member same system of cell entry, which is triggered by binding
such as infection and drugs.
of the genus Betacoronavirus like the two other coro- of the viral spike (S) protein to angiotensin-​converting
naviruses that have caused pandemic diseases (severe enzyme 2 (ACE2) on the surface of the host cell4.
acute respiratory syndrome coronavirus (SARS-​CoV) Understanding the biological features of the virus
and Middle East respiratory syndrome coronavirus will contribute to the development of diagnostic tests,
(MERS-​CoV))1–4. As with SARS-​CoV and MERS-​CoV, vaccines and pharmacological therapies and can further
✉e-​mail: mnishiga@
SARS-​CoV-2 causes a respiratory infection, which leads our knowledge of tissue tropism. Early clinical data indi-
stanford.edu; joewu@
stanford.edu to viral pneumonia and acute respiratory distress syndrome cate that both the susceptibility to and the outcomes of
https://doi.org/10.1038/ (ARDS) in some patients1. However, in addition to res- COVID-19 are strongly associated with cardiovascular
s41569-020-0413-9 piratory symptoms, uncontrolled SARS-​CoV-2 infection disease (CVD)12–16. A high prevalence of pre-​existing

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Key points and susceptibility to COVID-19 and the potential

cardiovascular effects of drugs used to treat COVID-19.
• Severe acute respiratory syndrome coronavirus 2 (SARS-​CoV-2), the virus that Of note, several limitations of this Review need to
causes coronavirus disease 2019 (COVID-19), shares many biological features with be acknowledged. First, given the fast-​moving nature
SARS-​CoV, the virus that causes severe acute respiratory syndrome, owing to 80%
of this research field, we will discuss and cite data from
genomic sequence identity.
preprint reports on bioRxiv or medRxiv in addition to
• The interaction between the viral spike (S) protein and angiotensin-​converting
peer-​reviewed articles that have cited preprint reports.
enzyme 2, which triggers entry of the virus into host cells, is likely to be involved
These findings need to be interpreted with care and
in the cardiovascular manifestations of COVID-19.
require validation in larger studies. Second, the major-
• The presence of underlying cardiovascular comorbidities in patients with COVID-19
ity of clinical COVID-19 data mentioned in this Review
is associated with high mortality.
are from China, given their early experience with the
• COVID-19 can cause cardiovascular disorders, including myocardial injury,
disease. Finally, the clinical data on COVID-19 are
arrhythmias, acute coronary syndrome and venous thromboembolism.
predominantly derived from non-​randomized studies.
• Several medications used for the treatment of COVID-19 have uncertain safety and
Therefore, potential biases and confounding factors
efficacy profiles.
associated with observational data, such as differences in
patient background, diagnostic methods and health-​care
Tissue tropism CVD has been observed among patients with COVID-19, systems, should be taken into account.
The ability of a given pathogen and these comorbidities are associated with increased
to infect specific cell or tissue mortality17–22. Furthermore, COVID-19 seems to pro- Biology of SARS-​CoV-2
types of a host. mote the development of cardiovascular disorders, Genome, genes and proteins
Kawasaki disease
such as myocardial injury, arrhythmias, acute coronary Since the emergence of SARS-​CoV-2, extensive efforts
An acute febrile illness of syndrome (ACS) and venous thromboembolism23–25. have been made to characterize the features of this
unknown cause that primarily Children with COVID-19 have also been reported to novel coronavirus through genomic sequence studies1–3
affects children aged <5 years develop hyperinflammatory shock with features akin and the evaluation of viral protein structure9–11,27,28.
and can cause coronary artery
to Kawasaki disease, including cardiac dysfunction and Coronaviruses, which are a large family of single-​stranded
aneurysms.
coronary vessel abnormalities26. Together, these data enveloped RNA viruses, were not recognized as being
Positive-​sense, indicate the presence of a bidirectional interaction highly pathogenic in humans until the outbreak of SARS
single-​stranded RNA between COVID-19 and the cardiovascular system, caused by SARS-​CoV in 2002–2003 (refs29,30). A decade
A sequence of RNA, also but the mechanisms underlying this interaction remain after the SARS pandemic, an outbreak of MERS was
known as plus-​strand RNA,
that can be directly translated
elusive. The high burden of systemic inflammation detected in Saudi Arabia, caused by MERS-​CoV, another
to a sequence of amino acids to associated with COVID-19 has been proposed to accel- highly pathogenic coronavirus29. In the ensuing years,
synthesize proteins without a erate the development of subclinical disorders or cause extensive studies of SARS and MERS have contributed to
complementary RNA de novo cardiovascular damage5,12–14. ACE2, which is a our understanding of coronavirus biology. On the basis
intermediate.
key surface protein for virus entry and part of the renin– of phylogenic analyses, both SARS-​CoV and MERS-​CoV
angiotensin–aldosterone system (RAAS), is also thought are thought to have originated in bats, which are likely to
to be involved in this interaction on the basis of findings be a major natural reservoir of coronaviruses29. A num-
from animal models12–15. ber of genetically diverse coronaviruses that are related
The fast-​moving nature of this research field neces- to SARS-​CoV or MERS-​CoV have been discovered in
sitates the integration of available biological data with bats worldwide1,29,31. SARS-​CoV-2 has been shown to
clinical findings of COVID-19 to improve our under- have 79.6% genomic sequence identity with SARS-​CoV
standing of the pathophysiology of the disease and to and 96.0% with the bat coronavirus RaTG13 (refs1–3,8).
contribute to the development of potential therapies. Given this genomic sequence homology, SARS-​CoV-2
In this Review, we summarize our current knowledge is thought to share many biological features with
of SARS-​CoV-2 from a biological viewpoint, with an SARS-​C oV, suggesting that we can apply, at least in
emphasis on the interaction between the viral S protein part, our rich knowledge of SARS-​C oV biology and
and human ACE2. Furthermore, we provide an overview pathogenesis to understanding SARS-​CoV-2 (refs4,29,30).
of the clinical findings related to the effects of COVID-19 For example, both SARS-​CoV and SARS-​CoV-2 use
on the cardiovascular system. Finally, we discuss the ACE2 as an attachment receptor to enter host cells,
possible link between common cardiovascular drugs whereas MERS-​CoV uses dipeptidyl peptidase 4 as the
attachment receptor1,2,29,30.
Coronaviruses have a crown-​like morphology, con-
author addresses sisting of four structural proteins known as spike (S),
envelope (E), membrane (M) and nucleocapsid (N)
1
Stanford Cardiovascular Institute, Stanford, CA, USA. proteins29,30,32 (Fig. 1a). The viral genome surrounded
2
Department of Medicine, Division of Cardiovascular Medicine, Stanford University by the N protein is a positive-​sense, single-​stranded RNA
School of Medicine, Stanford, CA, USA. that functions as both a genome and an mRNA29,30,32.
3
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical
Coronaviruses can be divided into four genera: α, β, γ
College, Huazhong University of Science & Technology, Wuhan, China.
4
Cardiovascular Research Institute, Department of Cardiology, General Hospital of and δ, of which only α and β-​coronaviruses are known to
Northern Theater Command, Shenyang, China. infect humans. Phylogenetic studies have revealed that
5
Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Stanford all three highly pathogenic coronaviruses (SARS-​CoV,
University School of Medicine, Stanford, CA, USA. MERS-​C oV and SARS-​C oV-2) belong to the genus
6
Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA. Betacoronavirus1–3,29. Like other coronaviruses, the

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a Structure of SARS-CoV-2 b Genome of SARS-CoV-2

S protein Non-structural proteins Structural proteins

M protein ORF1a S M N
5′ 3′
ORF1b E
Primary
translation
11
pp1a nsp1 nsp2 PLpro nsp4 3CL 6 7 8 910 S protein

pp1ab nsp1 nsp2 PLpro nsp4 3CL 6 7 8 9 10 RdRp Hel 14 15 16

E protein S1: attachment S2: fusion

ssRNA genome RBD S1/S2

N protein 1 1,273

Compared with Mutations Insertion (four amino acids)

c Life cycle of SARS-CoV-2 SARS-CoV: Furin cleavage site

Activation TMPRSS2 Attachment Release

ACE2 ACE2 Plasma
S protein priming membrane
by TMPRSS2 and
membrane fusion Endocytosis and
membrane fusion

Assembly Budding

Viral RNA release Viral RNA release

RNA genome Golgi
5′ 3′
RNA replication
Translation and packaging
pp1a and
pp1ab
RdRP M E
Replicase S
Proteolysis ER
– + Transcription
and translation

Nucleus

Fig. 1 | Structure, genome and life cycle of SarS-CoV-2. a | Corona­ in SARS-​CoV-2 but not in SARS-​CoV, which introduces a novel furin
viruses form an enveloped spherical particle that consists of four struc- cleavage site. c | SARS-​CoV-2 infection is triggered by the binding of the
tural proteins (spike (S), envelope (E), membrane (M) and nucleocapsid S protein to ACE2 on the surface of host cells, and the viral complex is
(N)) and a positive-​sense, single-​stranded RNA (ssRNA) genome that is incorporated into the cytoplasm either by direct fusion with the cell
30 kb in length. b | The 5′-​terminal two-​thirds of the severe acute respira- membrane or via endocytosis with later release into the cytoplasm from
tory syndrome coronavirus 2 (SARS-​CoV-2) genome encodes poly­ the endocytic vesicle. The S protein is cleaved at the S1/S2 boundary
proteins pp1a and pp1ab, which are cleaved into 16 different non-​ and the S2 subunit facilitates membrane fusion. The viral genome
structural proteins. Structural proteins are encoded in the 3′-​terminal RNA is released into the cytoplasm, and the first open reading frame
one-​third of the genome. The S protein consists of two subunits; the (ORF) is translated into polyproteins pp1a and pp1ab, which are then
S1 subunit contains a receptor-​binding domain (RBD) that binds to cleaved by viral proteases into small, non-​structural proteins such as RNA-​
angiotensin-​converting enzyme 2 (ACE2) on the surface of host cells, dependent RNA polymerase (RdRP). The viral genomic RNA is replicated
whereas the S2 subunit mediates fusion between the membranes by RdRP. Viral nucleocapsids are assembled from genomic RNA and
of the virus and the host cell. Compared with the S protein of SARS-​CoV, N proteins in the cytoplasm, whereas budding of new particles occurs
the S protein of SARS-​CoV-2 has two notable features. First, within the at the membrane of the endoplasmic reticulum (ER)–Golgi intermedi­
RBD of the S1 subunit, five of the six residues that are crucial for binding ate compartment. Finally, the genomic RNA and structural proteins are
to human ACE2 are mutated. Second, an insertion of four amino acid assembled into new viral particles, leading to their release via exocytosis.
residues at the boundary between the S1 and S2 subunits is present 3CL, 3-​chymotrypsin-​like protease.

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Open reading frames

genome of SARS-​CoV-2 is approximately 30 kb in length into the cytoplasm4,29,30,40 (Fig.  1c). Respiratory tract
ORFs. Continuous stretches and contains ten open reading frames (ORFs) that encode epithelial cells express both ACE2 and TMPRSS2 on
of nucleotide sequences in 24–27 genes1,2. The 5′-​terminal two-​thirds of the genome their surface, and this direct or ‘early’ entry pathway
genomic DNA or mRNA encodes polyproteins pp1a and pp1ab, which are cleaved seems to be the predominant mode of in vivo entry by
between a start codon (usually
into 16 non-​structural proteins, such as RNA-​dependent SARS-​CoV and, probably, SARS-​CoV-2 into the respira-
ATG in DNA) and a stop codon
(usually TAA, TAG or TGA in RNA polymerase (RdRP). The S, E, M and N structural tory tissue40. Alternatively, SARS-​CoV-2 can also use an
DNA) that are potentially proteins are encoded in the 3′-​terminal one-​third of the endosomal entry pathway, whereby the ACE2–virus
translated into proteins. genome29,30,33 (Fig. 1b). complex is translocated to endosomes and S protein
Among the structural proteins, the S protein has priming is performed by the endosomal cysteine pro-
Furin cleavage site
A specific peptide sequence in
pivotal roles in virus attachment and entry and disease teases cathepsin B and cathepsin L, after which the
precursor proteins that can be pathogenesis9–11,29,30. In SARS-​CoV and SARS-​CoV-2, virus is released from the endosome into the cytoplasm.
cleaved by an enzyme furin to the binding of the viral S protein to ACE2 triggers This endosomal entry pathway, which can be blocked
facilitate conversion to a virus entry into the host cell. Therefore, the interaction by either lysosomotropic agents (such as hydroxychlo-
biologically active state.
between the S protein and ACE2 has been considered to roquine) or cathepsin inhibitors, might be the pre-
Lysosomotropic agents be a promising therapeutic target for the development dominant entry pathway used by coronaviruses in the
Drugs that are taken up of vaccines34,35, neutralizing antibodies36,37 and antiviral infection of cells cultured in vitro40, but the importance
selectively into lysosomes. compounds38,39 for SARS-​CoV and SARS-​CoV-2. The of this pathway for infection in vivo remains unclear.
sequence similarity between the S protein of SARS-​CoV After the release of the viral genomic RNA into the
and that of SARS-​CoV-2 is approximately 76% for the cytoplasm, the first ORF is translated into polyproteins
whole protein, 73% for the receptor-​binding domain and pp1a and pp1ab, which are then cleaved by viral pro-
50% for the receptor-​binding motif11. teases into small non-​structural proteins such as RdRP.
The S protein of SARS-​C oV-2 contains two dis- The viral genomic RNA is then replicated using viral
tinctive features that are not present in the S protein of RdRP, and the four structural proteins (S, E, M and N)
SARS-​CoV4,8. First, the S protein of SARS-​CoV-2 main- are translated through the endoplasmic reticulum and
tains a high binding affinity to human ACE2 even though Golgi complex of the host cell. Finally, the genomic RNA
five of the six residues present in the SARS-​CoV recep- and structural proteins are assembled into new viral
tor binding motif that are critical for binding to human particles, leading to their release through exocytosis29,30
ACE2 are mutated in the S protein of SARS-​C oV-2 (Fig. 1c). Each step of the viral life cycle described here is a
(L455, F486, Q493, S494 and N501)4,8. Cryogenic elec- potential therapeutic target, including S protein priming
tron microscopy studies have demonstrated that the by TMPRSS2 (a target of the serine protease inhibitor
S protein of SARS-​CoV-2 can bind directly to human camostat mesylate), membrane fusion and endocyto-
ACE2 with a similar or even higher affinity than that sis (a target of the antimalarial drug chloroquine and
of SARS-​CoV9–11. This high binding affinity is likely to anti-​influenza drug umifenovir) and RNA replication
be related to the high transmissibility of SARS-​CoV-2 by RdRP (a target of the antiviral agents favipiravir,
and the severity of COVID-19. Second, the S protein remdesivir and ribavirin)41,42.
of SARS-​C oV-2 has an insertion of four amino acid
residues (12 nucleotides) at the boundary between The cardiovascular system and COVID-19
the S1 and S2 subunits, which introduces a novel Underlying cardiovascular comorbidities
furin cleavage site4,8. This novel cleavage site has not been CVD is a common comorbidity observed in patients
observed in SARS-​CoV or other SARS-​related corona- infected with SARS or MERS (with a prevalence of 10%
viruses originating from bats and seems to facilitate the and 30%, respectively)12–14,43,44. A series of reports on
processing of S protein at the S1 and S2 subunit bound- the clinical characteristics of patients with COVID-19
ary by ubiquitously expressed furin-​like proteases for have also described similar findings12–15. Early reports
preliminary activation4. Although the function of this from China found that CVD and its risk factors, such
novel cleavage site is unknown, similar cleavage sites as hypertension and diabetes mellitus, were common
have been described in highly pathogenic avian influenza pre-​existing conditions in patients with COVID-19,
viruses and the Newcastle disease virus4,8. This notable but the definition of CVD used in each study was
feature has been proposed to have a role in expanding vague17,18,21,22,45 (Table 1). In an early report from Wuhan
cell or tissue tropism of SARS-​CoV-2 (ref.4), contributing involving 41  patients who were hospitalized with
to the multiorgan effects of COVID-19 (Fig. 1b). COVID-19 by 2 January 2020, the prevalence of any
comorbidity was 32% and the most common under-
Life cycle of the virus lying diseases were diabetes (20%), hypertension
Infection with either SARS-​C oV or SARS-​C oV-2 (15%) and other CVDs (15%)17. The high prevalence
involves binding of the viral S protein to ACE2 on the of these comorbidities was confirmed in subsequent
surface of the host cell. The receptor-​binding domain studies18–22,45–47. Importantly, the prevalence of these
on the surface subunit S1 of the S protein is responsi- pre-​existing conditions was higher in critically ill patients
ble for attachment of the virus to ACE2. After binding, (such as those admitted to the intensive care unit (ICU))
the S protein is cleaved at the S1/2 and S2′ regions (in and in those who died. In a single-​centre cohort study
a process known as S protein priming) by the trans- of 138 patients hospitalized with COVID-19 in Wuhan,
membrane serine protease TMPRSS2, which in turn 46% of patients had any comorbidity (72% of patients
facilitates the fusion of the viral membrane with the in the ICU), 31% of patients had hypertension (58% of
membrane of the host cell and direct entry of the virus patients in the ICU), 15% of patients had other CVDs

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Table 1 | Prevalence of cardiovascular comorbidities in patients with CoVid-19 of comorbid obesity among patients with COVID-19,
which had not been reported in the studies on patients in
Country Number of Prevalence of comorbidity among all patients ref. China probably owing to differences in the background
patients (among patients who were ventilated or in iCU)
prevalence of obesity between the USA and China.
Cardiovascular Hypertension diabetes obesity Investigators in this study suggest that obesity might
disease (%) (%) (%) (%)
also be a risk factor for respiratory failure and the need
China 41 15 (23) 15 (15) 20 (8) NR 17
for invasive mechanical ventilation47.
China 138 14.5 (25.0) 31.2 (58.3) 10.1 (22.2) NR 18

China 191 8 (24)

a a,b
30 (48)b
19 (31) b
NR 19 Diverse cardiovascular manifestations
Although the predominant clinical manifestation of
China 150 8.7 (19.1)b 34.7 (42.6)b 16.7 (17.6)b NR 22
COVID-19 is viral pneumonia1,2,48,49, COVID-19 can
China 1,099 2.5 (5.8)
a a
15.0 (23.7) 7.4 (16.2) NR 20
also cause cardiovascular disorders such as myocardial
China 44,672 4.2 (22.7) 12.8 (39.7) 5.3 (19.7) NR 21 injury, arrhythmias, ACS and thromboembolism12–15
(Fig. 2). Some patients who present without the typical
Italy 1,591 NR (21) NR (49) NR (17) NR 46
symptoms of fever or cough have cardiac symptoms as
USA 393 13.7a (19.2)a 50.1 (53.8) 25.2 (27.7) 35.8 47
the first clinical manifestation of COVID-19 (refs52,53).
(43.4)
Myocardial injury during the course of COVID-19
USA 5,700 11.1a (NR) 56.6 (NR) 33.8 (NR) 41.7 (NR) 51
is independently associated with high mortality23.
Prevalence of comorbidity among critically ill patients is shown in parentheses. Prevalence
a
Furthermore, a possible link between COVID-19 and
of coronary artery disease specifically. bPrevalence of comorbidity among patients who died.
COVID-19, coronavirus disease 2019; ICU, intensive care unit; NR, not reported.
a Kawasaki disease-​like syndrome has been described
in children26.

(25% of patients in the ICU) and 10% of patients had Myocardial injury and myocarditis. Acute myocar-
diabetes (22% of patients in the ICU)18. Similarly, in a dial injury, as evidenced by elevated levels of cardiac
multicentre cohort study involving 191 patients hos- biomarkers or electrocardiogram abnormalities, was
pitalized with COVID-19 in Wuhan, 48% of patients observed in 7–20% of patients with COVID-19 in early
had any comorbidity (67% of those who died), 30% of studies in China17–21. The presence of myocardial injury
patients had hypertension (48% of those who died), was associated with a significantly worse prognosis23.
19% of patients had diabetes (31% of those who died) In the initial report of 41 patients with COVID-19 in
and 8% of patients had coronary heart disease (24% of Wuhan, 5 patients had myocardial injury with elevated
those who died)19. Furthermore, in a report involving levels of high-​sensitivity cardiac troponin I (>28 pg/ml),
1,099 patients with COVID-19 from mainland China, and 4 of these 5 patients were admitted to an ICU17. In a
24% of patients had any comorbidity (39% of critically multicentre cohort study of 191 patients with COVID-19,
ill patients), 15% of patients had hypertension (24% 33 patients (17%) had acute cardiac injury, of whom
of critically ill patients), 7% of patients had diabetes 32 died19. In a subsequent study of 416 patients hospi-
(16% of critically ill patients) and 3% of patients had talized with COVID-19, 82 patients (20%) had evidence
coronary heart disease (6% of critically ill patients)20. of cardiac injury, which was associated with a 5-​fold
The overall case fatality rate of COVID-19 reported by the increase in the need for invasive mechanical ventilation
Chinese Center for Disease Control and Prevention as of and an 11-​fold increase in mortality23. Of note, cardiac
11 February 2020 was 2.3% (1,023 deaths among 44,672 injury was found to be an independent risk factor for in-​
confirmed cases)21,45. The individual case fatality rate of hospital mortality23. Another study confirmed this find-
patients with CVD was 10.5% (highest among those with ing and reported that the rate of death in patients with
any comorbidities, including chronic respiratory disease elevated levels of cardiac troponin T was 37.5%, whereas,
(6.3%) or cancer (5.6%)), the case fatality rate of patients in patients with underlying cardiovascular comorbidi-
with diabetes was 7.3% and that of patients with hyper- ties plus elevated levels of cardiac troponin T, it was
tension was 6.0%45. Of note, these early approximations almost double (69.4%)24. Furthermore, a subsequent
of case fatality rate are likely to be overestimated given study demonstrated that markers of myocardial injury
that the estimates did not account for the many people were predictive of the risk of in-​hospital mortality in
who had the virus but were not tested. patients with severe COVID-19 (ref.25). The area under
A similar trend in the prevalence of comorbidities has the receiver operating characteristic curve of the initial
been reported by researchers in other countries46–51. In cardiac troponin I level for predicting in-​hospital mor-
a report involving 1,591 patients with COVID-19 who tality was as high as 0.92. Other predictors of myocardial
were admitted to the ICU in Italy, 49% of patients had injury include advanced age, presence of comorbidities
pre-​existing hypertension, 21% had CVD and 17% and high levels of C-​reactive protein.
had diabetes46. Furthermore, in a report of 393 con- Whether typical clinical features of myocarditis were
secutive patients hospitalized with COVID-19 in New present in patients who had elevated levels of cardiac
York, USA, up to 50% of patients had hypertension troponins during the course of COVID-19 is unclear
Case fatality rate (54% of ventilated patients), 36% had obesity (43% of because most of the early studies did not include echo-
The proportion of people who ventilated patients), 25% of patients had diabetes (28% cardiography or MRI data12–14,54. In a cohort study involv-
die from a certain disease
among all individuals
of ventilated patients) and 14% of patients had coronary ing 112 patients with COVID-19, the 14 patients with
diagnosed with the disease artery disease (19% of ventilated patients)47. Of note, this myocardial injury who had elevated high-​sensitivity lev-
over a certain period of time. study from New York highlighted the high prevalence els of cardiac troponin I (>0.12 ng/ml) plus abnormalities

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Cardiovascular diseases COVID-19

Underlying comorbidities
• Hypertension Susceptibility
• Coronary heart disease
• Diabetes mellitus Viral
infection
Severity
Cardiovascular complications

Acute cardiac injury No

↑ Troponin level association?

Myocarditis Direct infection?

Acute Heart failure

coronary
syndrome

Pneumonia

Arrhythmia
• QT prolongation Acute respiratory
• VF or VT distress syndrome
• AF
Thromboembolism
Systemic inflammation
Long-term effect

Common cardiovascular drugs Potential COVID-19 drugs with

• ACE inhibitors possible cardiovascular side effects
• ARBs • Hydroxychloroquine
• Thiazolidinediones • Azithromycin
• Lopinavir–ritonavir
• Remdesivir?

Fig. 2 | Bidirectional interaction between cardiovascular diseases and CoVid-19. Cardiovascular comorbidities such
as hypertension and coronary artery disease are associated with high mortality in patients with coronavirus disease 2019
(COVID-19). Drugs used to reduce cardiovascular risk such as angiotensin-​converting enzyme (ACE) inhibitors and
angiotensin II receptor blockers (ARBs) have numerous effects that might influence susceptibility to or the severity of
COVID-19. Furthermore, although the main presentation of COVID-19 is viral pneumonia, COVID-19 can also induce
cardiovascular manifestations including myocardial injury, myocarditis, arrhythmias, acute coronary syndrome and
thromboembolism. Among these cardiovascular manifestations, myocardial injury has been independently associated
with high mortality among patients with COVID-19 (ref.23). Finally, medications that have been proposed as treatments for
COVID-19 such as hydroxychloroquine and azithromycin have pro-​arrhythmic effects. AF, atrial fibrillation; VF, ventricular
fibrillation; VT, ventricular tachycardia.

on echocardiography and/or electrocardiogram did not and ST segment elevation, echocardiography revealed
have typical signs of myocarditis such as segmental wall an enlarged heart (LV diastolic dimension = 58 mm) and
motion abnormality or reduced left ventricular (LV) LV dysfunction (LVEF = 27%)56. This patient was diag-
ejection fraction (LVEF), suggesting that myocardial nosed with COVID-19-​induced fulminant myocarditis
injury was secondary to systemic causes rather than and treated with methylprednisolone. Cardiac size and
a result of direct viral infection of the heart53. By con- function recovered to normal after 1 week (LV diastolic
trast, several case reports have described typical signs dimension = 42 mm, LVEF = 66%).
of myocarditis in patients with COVID-19. A woman Histological evidence of myocardial injury or myo-
aged 53 years with myocardial injury, as evidenced by carditis in COVID-19 is also limited. An autopsy of a
elevated levels of cardiac biomarkers and diffuse ST seg- patient with COVID-19 and ARDS who died of a sud-
ment elevation on the electrocardiogram, had diffuse den cardiac arrest showed no evidence of myocardial
biventricular hypokinesis on cardiac MRI, especially in structural involvement, suggesting that COVID-19 did
the apical segments, in addition to severe LV dysfunc- not directly impair the heart57. By contrast, another case
tion (LVEF = 35%)55. MRI data also revealed marked report described a patient with low-​grade myocardial
biventricular interstitial oedema, diffuse late gadolin- inflammation and myocardial localization of coronavi-
ium enhancement and circumferential pericardial effu- rus particles (outside of cardiomyocytes), as measured
sion, features that are consistent with acute myocarditis. by endomyocardial biopsy, suggesting that SARS-​CoV-2
Furthermore, in a man aged 37 years with chest pain might infect the myocardium directly58. Autopsy reports

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have also revealed the presence of mild inflammation known to secrete tissue factor, a potent procoagulant that
and viral RNA in the hearts of patients with COVID-19 triggers thrombus formation when the plaque ruptures67.
(refs59,60). However, whether these patients had myo- Direct endothelial or vascular injury caused by SARS-​
carditis or whether the findings were a consequence of CoV-2 infection might also increase the risk of thrombus
systemic inflammation remains unclear. formation and ACS69.
Our understanding of the pathophysiology underly- Despite the potential for COVID-19 to induce ACS,
ing SARS might help to determine whether SARS-​CoV-2 the number of reported cases of ACS during the COVID-19
can infect cardiac cells directly, given that SARS-​CoV and outbreak in Italy, Spain and the USA was actually sig-
SARS-​CoV-2 share the same mechanisms of entry into nificantly lower than during pre-​COVID-19 periods,
the host cell4,12,43 and that the heart expresses high levels of with a reported 42–48% reduction in hospitalizations
ACE2 (refs15,61). In a report that described autopsy samples for ACS and a 38–40% reduction in percutaneous cor-
from ten Canadian patients with SARS, the viral RNA of onary interventions for ST segment elevation myo-
SARS-​CoV was detected in 35% of the heart samples, but cardial infarction70–73. By contrast, the incidence of
the infected cell types were unknown62. A marked increase out-​of-​hospital cardiac arrest increased during the
in macrophage infiltration with evidence of myocardial COVID-19 outbreak in Italy, which was strongly associ-
damage was also detected, suggesting that SARS-​CoV ated with the cumulative incidence of COVID-19 (ref.74).
can infect the heart directly62. This observation is in accordance with the finding that
Taken together, these findings suggest that myo- the number of patients with myocardial infarction
cardial injury is not only a common manifestation of seeking urgent hospital care declined by >50% during
COVID-19, but also a risk factor for poor prognosis. the peak of the COVID-19 outbreak, as reported in an
At present, we do not understand the mechanisms under- extensive global survey by the ESC75.
lying COVID-19-related myocardial injury. However, on
the basis of the available clinical evidence, myocardial Heart failure. In an early study from Wuhan involving
injury seems to be largely attributable to advanced sys- 799 patients, heart failure was one of the most commonly
temic inflammation. SARS-​CoV-2 might also infect the observed complications of COVID-19, with a reported
myocardium directly, resulting in viral myocarditis in a incidence of 24% in all patients and 49% in patients who
small proportion of patients with COVID-19. died76. Elevated levels of amino-​terminal pro-​B-​type
natriuretic peptide were identified in 49% of all patients
Acute coronary syndrome. As with other infectious dis- (85% of those who died)76. Similarly, in another study
eases, including SARS and influenza, COVID-19 can of 191 patients in Wuhan, heart failure was identified
trigger ACS44,63–66. In early studies from China, a small in 23% of all patients and in 52% of patients who died19.
proportion of patients with COVID-19 presented with The aetiology of acute or decompensated heart fail-
chest pain on admission to hospital, but the charac- ure in COVID-19 has not been studied77. Given that
teristics of the chest pain were not described17,18. In a patients with COVID-19 are likely to be older and to
case series from New York involving 18 patients with have pre-​existing comorbidities such as coronary artery
COVID-19 and ST segment elevation, which is indica- disease, hypertension and diabetes, heart failure might
tive of potential acute myocardial infarction, five of the be the result of an exacerbation of these pre-​existing
six patients with myocardial infarction required percuta- conditions, whether already diagnosed or unknown,
neous coronary intervention66. In a case series from Italy or the uncovering of subclinical cardiac dysfunction.
involving 28 patients with COVID-19 and ST segment In particular, elderly patients with reduced diastolic func-
elevation myocardial infarction, assessment by coro- tion might develop heart failure with preserved EF dur-
nary angiography showed that 17 patients had evidence ing the course of COVID-19, which can be triggered by
of a culprit lesion that required revascularization52. Of high fever, tachycardia, excessive hydration and impaired
note, ST segment elevation myocardial infarction was renal function77. In patients with heart failure with pre-
the first clinical manifestation of COVID-19 in 24 of served ejection fraction, cardiac MRI might help to detect
these 28 patients who had not yet received a positive changes induced by COVID-19 (refs78,79). Acute myo-
test result for COVID-19 at the time of coronary angi- cardial injury and ACS triggered by COVID-19 can also
ography. These observations suggest that COVID-19 aggravate pre-​existing heart disease or provoke contrac-
can cause ACS even in the absence of substantial sys- tile dysfunction. In the advanced stages of COVID-19, the
temic inflammation. However, the incidence of ACS in response of the immune system to infection might trig-
patients with COVID-19 is still unknown. Considering ger the development of stress-​induced cardiomyopathy
the overwhelmed health-​care facilities of many cities or cytokine-​related myocardial dysfunction, as with
during the COVID-19 outbreak, the number of cases sepsis-​associated cardiac dysfunction80,81.
of acute myocardial infarction among patients with Given that COVID-19 primarily causes respira-
COVID-19 might be underestimated in early studies. tory symptoms and viral pneumonia with bilateral,
The mechanisms underlying COVID-19-​induced ACS peripheral and lower lung distribution, the pulmonary
might involve plaque rupture, coronary spasm or micro- oedema that is observed in these patients, which is
thrombi owing to systemic inflammation or cytokine usually accompanied by ARDS, is mainly regarded as
storm67,68. For example, activated macrophages secrete non-​cardiogenic. However, given that approximately
collagenases that degrade collagen, a major constituent 25% of patients hospitalized with COVID-19 develop
of the fibrous cap on atherosclerotic plaques, which can heart failure, the potential contribution of pulmo-
lead to plaque rupture67. Activated macrophages are also nary congestion by heart failure should be taken into

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consideration77. Additional haemodynamic data from embolism, is a common complication in critically ill
patients with COVID-19-​related respiratory failure are patients with COVID-19. An autopsy study revealed that
needed to validate this involvement. deep vein thrombosis was present in 7 of 12 patients who
died with COVID-19 in whom venous thromboembo-
Arrhythmias and sudden cardiac arrest. Arrhythmias lism was not suspected before death, whereas pulmo-
and sudden cardiac arrest are common manifestations of nary embolism was identified in 4 of the 12 patients59.
COVID-19. Heart palpitations have been reported to be Arterial thrombotic events have also been reported.
the main presenting symptom of COVID-19 in patients A case series from New York described five patients
without a fever or cough82. In a cohort of 138 patients with aged ≤50 years who presented to the same hospital
COVID-19 in Wuhan, China, the presence of cardiac with large-​vessel ischaemic stroke and who all tested
arrhythmia was reported in 17% of all patients (44% of positive for SARS-​C oV-2 infection87. Furthermore,
patients in the ICU), but the specific types of arrhythmia acute limb ischaemia was also reported in 20 patients
were not recorded18. In another study in Wuhan involv- with COVID-19 (90% men, mean age 75 ± 9 years) in a
ing 187 patients hospitalized with COVID-19, those with case series from Italy88. All 20 patients were diagnosed
elevated levels of troponin T were more likely to develop with COVID-19-​related pneumonia before acute limb
malignant arrhythmias, such as ventricular tachycardia ischaemia was detected.
and fibrillation, than those with normal levels of troponin The mechanisms underlying these coagulation
T (12% versus 5%)24. In-​hospital and out-​of-​hospital sud- abnormalities, particularly hypercoagulation, in the
den cardiac arrests have also been reported in patients setting of COVID-19 are unclear. One hypothesis is
with COVID-19 (refs57,66,74). However, the exact contribu- that the severe inflammatory response and endothelial
tion of COVID-19 to cardiac arrhythmias remains uncer- damage induced by COVID-19 in combination with
tain given that arrhythmias, such as atrial and ventricular underlying comorbidities might predispose patients
tachycardia and fibrillation, can be triggered by myocar- to a hypercoagulable state6. Of note, certain antiviral
dial injury or other systemic causes such as fever, sepsis, medications and investigational therapies given to these
hypoxia and electrolyte abnormalities24,83. Furthermore, patients might promote thrombosis or bleeding events
patients with advanced COVID-19 are often treated with through drug–drug interactions with antiplatelet agents
antiviral medications and antibiotics that are known and anticoagulants41.
to induce arrhythmias in some patients (described in A retrospective study in New York showed that sys-
detail below)13,41. temic anticoagulation was associated with prolonged
survival in patients hospitalized with COVID-19 (ref.89).
Coagulation abnormalities and thrombosis. COVID-19 Among 2,773 patients, 786 (28%) received systemic
is associated with coagulation abnormalities, which anticoagulation. The median survival time of patients
can result in thromboembolic events73. Patients with who were treated with anticoagulation was longer than
COVID-19 often have elevated levels of d-​ d imer, in those who were not treated (21 days versus 14 days),
modestly reduced platelet counts and slightly prolonged although overall mortality between the two groups
prothrombin time. In an early study of 1,099 patients remained similar (22.5% versus 22.8%)89. The differ-
with COVID-19 from China, elevated levels of d-​dimer ences in median survival time and mortality were more
(>0.5 mg/l) were observed in 46% of all patients (60% of pronounced among patients who required mechanical
those with severe illness)20. Similarly, another study in ventilation (21 days versus 9 days and 29.1% versus
patients with COVID-19 in Wuhan showed that d-​dimer 62.7%, respectively)89. Another retrospective study in
levels were elevated (>1 mg/l) in 42% of all patients (81% China also showed reduced mortality in patients with
of those who died), which, if detected at admission to COVID-19-​associated coagulopathy who were treated
hospital, was associated with an 18-​fold increased risk of with prophylactic heparin90. Importantly, findings from
death19. By contrast, the changes in platelet counts and these retrospective studies are limited by potential selec-
prothrombin time were modest. Among 41 patients with tion bias, the presence of confounding factors and the
COVID-19 in Wuhan, only 5% had a low platelet count undefined indication of anticoagulation treatment. In
(<100 × 109 cells per litre) and the prolongation of pro- addition, the optimal anticoagulation agent to prevent
thrombin time was mild even in patients admitted to the thromboembolic events in these patients is not known
ICU (11.1 s versus 12.2 s)17. Moreover, levels of fibrinogen (for example, low-​molecular-​weight heparin, unfrac-
and factor VIII were elevated in these patients, indicating tionated heparin, direct oral anticoagulants or others).
a hypercoagulable state84,85. These findings show that a Prospective, randomized trials are needed to validate the
substantial proportion of patients with COVID-19 have protective effect of anticoagulation therapy in patients
coagulation abnormalities that typically do not meet the with COVID-19.
criteria of disseminated intravascular coagulation estab-
lished by the International Society on Thrombosis and Kawasaki disease. Children are thought to be less sus-
Haemostasis86, but nevertheless might contribute to the ceptible than adults to COVID-19, and the majority of
development of the diverse cardiovascular manifestations children with COVID-19 are asymptomatic or present
of COVID-19. with only mild symptoms91. However, COVID-19 has
Clinical observations of increased thromboembolic been reported to cause severe inflammatory symptoms
events in patients with COVID-19 suggest the presence in a small proportion of paediatric patients26,92. A case
of a hypercoagulable state. Venous thromboembolism, series from the UK reported an unprecedented cluster
which includes deep vein thrombosis and pulmonary of eight children (aged 4–14 years) presenting with a

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hyperinflammatory syndrome with features of Kawasaki might be asymptomatic, routine screening of donor
disease, five of whom tested positive for SARS-​CoV-2 or tissues is necessary during the pandemic. Screening of
were potentially exposed to SARS-​CoV-2 from family recipients before transplantation will also be required to
members26. Clinical presentations included fever, variable avoid worsening of subclinical infection after starting
rash, conjunctivitis, peripheral oedema, extremity pain immunosuppression.
and severe gastrointestinal symptoms. A common find- As with patients with CVD, patients with cancer are
ing on echocardiography was echo-​bright coronary ves- thought to be at higher risk of severe COVID-19 symp-
sels, which progressed to a giant coronary aneurysm in toms than the general population97–99. This high risk
one patient. Furthermore, researchers in Bergamo, Italy, of poor outcomes might be attributable to suppressed
found a 30-​fold increase in the incidence of Kawasaki-​ immunity by chemotherapy, the presence of cardiovas-
like disease among children during the peak of the cular risk factors (such as hypertension and diabetes),
pandemic92. These paediatric patients were older and cardiotoxicity of cancer treatment and/or cardiovascular
had a higher rate of cardiac involvement than patients damage by COVID-19, combined with their impaired
diagnosed with Kawasaki disease before the pandemic. baseline condition97. Therefore, a major considera-
Together, these early clinical findings are suggestive of tion in the delivery of care to these patients during the
a new phenomenon caused by SARS-​CoV-2 infection pandemic is to balance the risk of SARS-​CoV-2 infec-
in children that can lead to a hyperinflammatory syn- tion with the need to provide timely cancer treatment.
drome with features that are similar to those of Kawasaki Clinicians need to determine the optimal timing of treat-
disease, including coronary artery abnormalities. ment in patients with cancer and cardiovascular comor-
bidities, especially if they are infected with or exposed to
Immunocompromised patients SARS-​CoV-2. Routine COVID-19 screening might be
In general, patients with depressed immunity are at a necessary before cancer treatment to avoid worsening
higher risk of infectious diseases. The effect of COVID-19 of a subclinical infection.
on the cardiovascular system in immunocompromised
patients, such as those with cancer or those who have ACE2 and cardiovascular manifestations
undergone organ transplantation, is largely unknown. The mechanisms underlying the development of
Heart transplantation recipients might be at higher COVID-19-related cardiovascular injury are not
risk of COVID-19 owing to their immunosuppressed known. ACE2 expression is thought to be one of the
state combined with their baseline cardiovascular major factors involved in the biological mechanism
disorders14,93. COVID-19 has been reported in two underlying tissue-​specific infection. As with SARS-CoV,
heart transplantation recipients from China, both of SARS-CoV-2 infection is triggered by binding of viral
whom made a full recovery94. The clinical presenta- S protein to human ACE2, whereas TMPRSS2 induc­
tions of these two patients were not distinct from those es S protein priming4. The interaction between S protein
of non-​immunosuppressed patients. In a retrospec- and ACE2 has gained much research interest given that
tive case series of heart transplantation recipients with ACE2 is known to have crucial roles in both the cardi-
COVID-19 admitted to hospitals in Michigan, USA, ovascular system and the immune system61,100. ACE2 is
between 21 March 2020 and 22 April 2020, 13 patients a part of the RAAS and is involved in the development
were identified, all of whom were African American of diabetes, hypertension and heart failure. At the tissue
men95. Six patients required admission to the ICU and level, ACE2 is highly expressed in the lungs, kidneys,
two patients died during hospitalization. Of note, the heart and blood vessels61,100. According to bulk RNA
clinical presentation and laboratory markers of disease sequencing data in the Genotype-​Tissue Expression
severity of these patients were not distinct from those (GTEx) project V8, the expression of ACE2 in the heart
of the general population, despite immunosuppression and coronary arteries is even higher than in the lungs101.
use to preserve allograft function. However, another case At the single-​cell level, ACE2 is highly ex­pressed in
series involving 28 heart transplantation recipients with pericytes of adult human hearts102. Single-​cell RNA
COVID-19 in New York reported higher mortality and sequencing data have also revealed that cardiomyocytes
an increased incidence of severe complications in these (especially those in the right ventricle) express ACE2 at
individuals than in the general population96. A total of a lower level than pericytes and that neither pericytes
22 patients were hospitalized, of whom 7 patients required nor cardiomyocytes express TMPRSS2 (ref.103). However,
mechanical ventilation and 7 patients died (case fatality both cell types have a high expression of cathepsin B
rate 25%). Moreover, 13 out of 17 patients had myocar- and cathepsin L, which facilitate S protein priming and
dial injury, as evidenced by elevated levels of troponin T might promote entry of the virus into the cell via the
(>0.022 ng/ml). endocytic pathway. Therefore, SARS-​CoV-2 might be
These findings suggest that recipients of heart trans- capable of directly infecting multiple cardiovascular cell
plantation are at high risk of severe complications from types, including cardiomyocytes, endothelial cells and
COVID-19. Whether organ transplantation recipients are pericytes. Importantly, however, expression of ACE2 is
more susceptible to COVID-19 and whether immuno­ not in itself sufficient for entry of the virus into a cell,
suppressive treatments have harmful (or protective) and the efficiency of viral replication and release might
effects on disease progression needs to be assessed in also have a role in host cell infection. To date, clinical
large-​scale studies. Another important point regarding evidence of direct viral infection of cardiomyocytes
heart transplantation is the need to screen for COVID-19. has not been found. Given that myocarditis related
Given that individuals with SARS-​C oV-2 infection to SARS-​C oV-2 infection is rare23,53, the interaction

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between SARS-​C oV-2 and ACE2 might affect the histological evidence of direct viral infection in
cardiovascular system in an indirect manner 61,100. non-​respiratory organs such as the heart, brain, liver
Genome-​wide association studies would help to facil- and kidney59,69,118.
itate the identification of novel pathways involved in In an autopsy case series involving 12 patients with
SARS-​CoV-2 pathogenesis104,105. COVID-19, in which SARS-​CoV-2 RNA was detected
by quantitative reverse transcription PCR in the lungs
Potential downregulation of ACE2 by SARS-​CoV-2. at high concentrations in all patients, 5 patients also
SARS-​CoV entry into cells has been shown to downregu­ had high viral RNA titres in the heart, liver or kidney59.
late ACE2 expression62,106,107. In a mouse model of SARS, Similarly, SARS-​CoV-2 RNA was detected in the lungs,
ACE2 levels in the heart were significantly reduced heart, brain, liver or kidneys in an autopsy analysis of
after SARS-​C oV infection62. In addition, a separate 27 patients who died with COVID-19 (ref.118), indicat-
study reported that knockout of Ace2 in mice resulted ing a broad organotropism of SARS-​CoV-2. Although
in a significant reduction in cardiac contractility108. the specific cell types infected by SARS-​CoV-2 in each
Furthermore, Ace2–/–Apoe–/– mice had greater atheroscle- organ are unknown, these preliminary data support
rotic plaque accumulation and upregulated expression of the possibility that the extrapulmonary manifestations
genes encoding adhesion molecules and inflammatory and multiorgan failure observed in patients who died
cytokines such as IL-6 and CCL2 compared with Apoe–/– with COVID-19 are not just a consequence of systemic
mice109. These results support a cardioprotective role of inflammation or cytokine storm, but might also be
ACE2 (ref.61). caused by direct infection of numerous organ systems by
Similarly, ACE2 has a protective effect in the lungs. SARS-​CoV-2. Mechanistically, the broad tissue tropism
ACE2 is expressed primarily in alveolar epithelial type II of SARS-​CoV-2 might be a result of the instability of the
cells in the normal adult lung110–112. These cells produce S protein of SARS-​C oV-2 related to the presence of
surfactant proteins that reduce surface tension, pre- the novel furin cleavage site, as mentioned above4.
venting the alveoli from collapsing. In a mouse model
of ARDS, Ace2 knockout exacerbated acute lung injury, Viral targeting of endothelial cells
whereas treatment with recombinant ACE2 rescued Preliminary histological data from a case series of three
lung damage106. Therefore, like SARS-​CoV, SARS-​CoV-2 patients with COVID-19 have shown that endothelial
infection might result in the downregulation of ACE2, cells might be a direct target of SARS-​CoV-2 infection69.
which can lead to cardiac dysfunction and progression In a patient with a history of renal transplantation who
of atherosclerosis, as well as exacerbated lung damage. died from COVID-19-​induced multiorgan failure,
viral particles were detected by electron microscopy in
ACE2 as a therapeutic target. Angiotensin II, the main endothelial cells in the kidney69. A prominent endotheli-
effector molecule in the RAAS, is upregulated in many itis (inflammation within the endothelium) with recruit-
diseases and is a common treatment target for various ment of inflammatory cells was identified on histological
cardiovascular disorders61,100,113. ACE2 inactivates angi- assessment, as well as an unusually high concentration of
otensin II by converting angiotensin II to angioten- apoptotic bodies in numerous organs including the lungs,
sin (1–7)61,100. Cryogenic electron microscopy studies small bowel and heart69. In another patient who died from
have demonstrated that the S protein of SARS-​CoV-2 COVID-19-​related multiorgan failure and ST segment
can directly bind to human ACE2 with a similar or elevation myocardial infarction, lymphocytic endotheli-
even higher affinity than the binding of the S protein itis was observed in the lungs, heart, liver and kidneys69.
of SARS-​CoV to human ACE2 (refs9–11). In this con- In the third patient who had mesenteric ischaemia and
text, a study has shown that exogenous administration underwent resection of the small intestine, histological
of recombinant human ACE2 (rhACE2) can prevent assessment of the small intestine revealed prominent
SARS-​C oV-2 infection by acting as a decoy114. The endotheliitis of the submucosal vessels in addition to a
investigators demonstrated that clinical-​grade rhACE2 large concentration of apoptotic bodies69. Findings from
can reduce SARS-​CoV-2 infection in cell culture and in this case series suggest that SARS-​C oV-2 can infect
engineered human blood vessel organoids and kidney endothelial cells directly, which can lead to inflammation
organoids114. Given that rhACE2 has been shown to be in the endothelium69. Given that endothelial cells are an
protective against various CVDs61,115,116, rhACE2 therapy important component of every organ and have a high level
might be a promising approach to treat patients with of ACE2 expression, inflammation in the endothelium
COVID-19-​related cardiovascular disorders114. caused by infection with SARS-​CoV-2 might underlie the
diverse clinical manifestations of COVID-19.
Broad tissue tropism of SARS-​CoV-2
Although SARS-​CoV-2 preferentially infects the lungs Potential drug–disease interactions
and respiratory tract like other respiratory viruses, The potential drug–disease interactions in patients with
COVID-19 can cause a diverse range of extrapulmo- COVID-19 have become a highly researched topic12–14
nary manifestations including CVD, stroke, seizures, (Fig. 2). First, whether antihypertensive agents such as
liver damage, renal dysfunction and gastrointestinal ACE inhibitors and angiotensin II receptor blockers
symptoms117. Systemic hyperinflammation induced (ARBs) are involved in the progression or prevention of
by viral pneumonia is likely to have an important role COVID-19 is unknown113,119. Second, some of the poten-
in the development of these varied manifestations of tial antiviral drugs used to treat patients with COVID-19
COVID-19, but numerous studies have also reported are known to induce cardiotoxicity41.

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Main effector of angiotensin II61,113. Therefore, neither class of drugs

affects ACE2 directly. Although some animal studies have
shown that treatment with ACE inhibitors or ARBs can
increase the expression of Ace2 (refs121,129), findings from
Angiotensin I Angiotensin II Angiotensin (1–7)
other preclinical studies were more mixed113,119,120,130–132. In
clinical studies, long-​term exposure to the ACE inhibitor
Protective Harmful captopril133 or the ARB olmesartan134 was associated with
increased plasma levels of angiotensin (1–7) or urinary
ACE inhibitors ARBs levels of ACE2, respectively, indicating increased ACE2
ACE ACE2
activity. However, other studies have not shown evidence
Plasma Angiotensin II
membrane receptor type 1
of upregulated ACE2 by RAAS inhibitors in patients with
Cytoplasm heart failure135, aortic stenosis136, atrial fibrillation137 or cor-
No direct effect
onary artery disease138. These inconsistent results are likely
to be attributable to the indirect effects of ACE inhibitors
Downregulation of ACE2 Cardiovascular diseases or ARBs on ACE2, which depend on conditions such as
by SARS-CoV-2 infection and lung injury baseline expression levels of ACE2, dosing and treatment
periods. Second, whether potential upregulation of ACE2
Fig. 3 | aCE2 as a part of the raaS. Angiotensin II, the main effector molecule in the is harmful or protective is uncertain. Even if ACE inhib-
renin–angiotensin–aldosterone system (RAAS), is upregulated in many pathological itors or ARBs can upregulate ACE2, no direct evidence
conditions, for which inhibition of angiotensin II by RAAS inhibitors is a common
has been found to show that upregulation of ACE2 affects
therapeutic strategy.Angiotensin-​converting enzyme (ACE) produces angiotensin II
from angiotensin I, whereas ACE2 inactivates angiotensin II by converting it to susceptibility to viral infection113. Furthermore, as shown
angiotensin (1–7). Therefore, ACE2 has a protective effect against cardiovascular in Ace2-​knockout mice106–109 and rhACE2 studies114–116,
disease and lung injury. In the setting of coronavirus disease 2019, downregulation ACE2 is considered to be protective rather than harm-
of ACE2 by severe acute respiratory syndrome coronavirus 2 (SARS-​CoV-2) infection ful in settings of lung injury and CVDs61,100. Together,
might be involved in mediating cardiovascular damage. ARB, angiotensin II receptor these findings indicate no benefit of withdrawal of ACE
blocker. inhibitors or ARBs in protecting against COVID-19.

Effect of RAAS inhibitors on COVID-19 Cardiovascular effects of antiviral drugs

Given that ACE2 is a receptor for SARS-​CoV-2, clini- At present, many research teams worldwide are focused
cians have expressed concern that medications that on the development of drugs for the prevention and treat-
upregulate the cell surface expression of ACE2 might ment of COVID-19 (ref.41). Of note, the development and
be harmful113,119,120. ACE inhibitors and ARBs have been testing of new drugs are time-​consuming processes139
shown to increase the expression of ACE2 in animal and not a viable strategy during this COVID-19
models121. Given that both ACE inhibitors and ARBs are pandemic. Drug repurposing139, in which existing med-
commonly used worldwide for the treatment of hyper- ications that have already been approved for a disease
tension and other CVDs, whether these drugs should are tested for a new condition, is currently the main
be discontinued during the COVID-19 pandemic has approach in the search for new drugs for COVID-19
become a pertinent question. Importantly, indiscrim- (refs 41,42,140,141) . However, some of the drugs under
inate withdrawal of these drugs could harm high-​risk investigation have known or unknown cardiovascular
patients. Several medical societies including the ACC, adverse effects142 or might be involved in drug–drug or
AHA, Chinese Society of Cardiology, ESC and the Heart drug–disease interactions41,140 (Table 2).
Failure Society of America have issued statements rec-
ommending continuation of RAAS antagonists for those Hydroxychloroquine and azithromycin. Chloroquine
who are currently prescribed these agents122–124. Findings and hydroxychloroquine have been widely touted as
from clinical studies support this recommendation. In potential treatment strategies for COVID-19 (refs143–145).
four studies from Spain (n = 1,139)125, Italy (n = 6,772)126 Chloroquine and hydroxychloroquine can poten-
and the USA (n = 5,894 and 1,735)127,128, the use of RAAS tially block virus entry into cells, particularly via the
inhibitors was not associated with a positive COVID-19 endosomal pathway, by inhibiting the glycosylation of
test, suggesting that these agents do not affect suscep- host receptors, proteolytic processing and endosomal
tibility to SARS-​C oV-2 infection. Furthermore, the acidification41,145. These agents can also mediate immuno­
use of these agents was not associated with a substan- modulatory effects through attenuation of cytokine
tial increase in the risk of severe or fatal illness among production and inhibition of autophagy and lysoso-
patients with COVID-19 (refs126,127). mal activity41. Both drugs are used in the treatment of
Two main points need to be discussed on this malaria and chronic inflammatory diseases such as sys-
topic. First, the effect of RAAS inhibitors on ACE2 is temic lupus erythematosus and rheumatoid arthritis41,146.
controversial113. As shown in Fig. 3, the targets of ACE A French observational study involving 36 patients
and ACE2 are different despite high structural similarity with COVID-19 reported improved virus clearance with
between the two enzymes. ACE converts angiotensin I to hydroxychloroquine treatment144. Furthermore, com-
angiotensin II, whereas ACE2 degrades angiotensin II bining hydroxychloroquine with azithromycin in six
to angiotensin (1–7). ACE inhibitors prevent the conversion patients resulted in even better virus clearance than with
from angiotensin I to angiotensin II, whereas ARBs inhibit the use of hydroxychloroquine alone144. Importantly,
the angiotensin II receptor type 1, which is downstream however, several concerns have been raised regarding

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the characteristics of the control group (which consisted hydroxychloroquine (with or without azithromycin),
of patients recruited from a separate hospital) and ethics those who received a combination of hydroxychloro­
approval147. In a randomized study involving 62 patients quine and azithromycin had greater QT interval prolon-
with COVID-19 in China, patients in the treatment group gation than those taking hydroxychloroquine alone151.
received hydroxychloroquine (400 mg per day) for 5 days, Furthermore, in a retrospective cohort study of 1,438
whereas patients in the control group received standard patients hospitalized with COVID-19 in New York,
treatment (oxygen therapy, antiviral agents, antibacterial treatment with hydroxychloroquine, azithromycin or
agents and immunoglobulin, with or without corticos- both was compared with neither treatment153. None
teroids)143. Hydroxychloroquine improved the time to of the groups had an increase in in-​hospital mortality,
clinical recovery, body temperature recovery time, cough but the secondary outcome of cardiac arrest was more
remission time and pneumonia-​related symptoms com- likely in patients receiving both hydroxychloroquine and
pared with standard treatment alone. Furthermore, in a azithromycin than in patients receiving neither drug153.
retrospective study from Wuhan involving 550 critically Given that some patients with COVID-19 might have
ill patients with COVID-19, mortality was significantly impaired renal function owing to systemic illness, fre-
lower among patients treated with hydroxychloroquine quent electrocardiographic evaluation should be strongly
plus standard treatment (which included other anti- considered in patients treated with hydroxychloroquine
viral drugs and antibiotics) compared with standard and/or azithromycin.
treatment alone (18.8% versus 47.4%)148. However, in a
large observational study involving 1,376 patients from Remdesivir. Remdesivir is a promising investigational
New York City, hydroxychloroquine treatment did not nucleotide analogue for the treatment of COVID-19 that
alter the risk of the composite end point of intubation or has broad-​spectrum antiviral activity and functions by
death149. These inconsistent results show that the efficacy targeting RdRP27,154,155. Remdesivir was originally devel-
of hydroxychloroquine is still controversial and needs to oped for the treatment of Ebola virus disease. Prophylactic
be validated in large, randomized studies150. and therapeutic administration of remdesivir has been
Although chloroquine and hydroxychloroquine have shown to improve pulmonary function and to decrease
a long history of clinical use for numerous conditions, viral load in a mouse model of MERS156. In a rand-
these agents are also known to induce arrhythmias41,142,151. omized, double-​blind, placebo-​controlled trial involving
Azithromycin, which has been assessed in combination 237 patients with COVID-19 in China, remdesivir was
with hydroxychloroquine as a treatment for COVID-19, associated with a numerically (but not statistically signif-
is also known to prolong the QT interval152. In a cohort icant) faster time to clinical improvement than was the
study of 90 patients with COVID-19 who received placebo155. Preliminary results from a double-​blind, ran-
domized, multicentre, placebo-​controlled trial involving
1,063 patients with COVID-19 indicate that those who
Table 2 | adverse cardiovascular effects of potential drugs to treat CoVid-19 received remdesivir had a 31% faster time to recovery
drug Mechanism of action Cardiovascular adverse than those who received placebo (median time to recov-
effects ery 11 days versus 15 days)157. Of note, in light of these
Inhibitors of endocytosis
preliminary findings, the FDA granted emergency use of
remdesivir for COVID-19 in May 2020 to meet the urgent
Camostat mesylate Inhibition of TMPRSS2 Not common demand for treatment of hospitalized patients158. The
Chloroquine and Blockade of virus entry by QT interval prolongation optimal dosing and duration of treatment is still under
hydroxychloroquine multiple mechanisms investigation. Under the emergency use authorization, a
Umifenovir Inhibition of S protein–ACE2 Not common, but limited 10-​day treatment regimen (200 mg on day 1 followed by
interaction and membrane fusion clinical data 100 mg per day for 9 days) is suggested for patients requir-
Inhibitors of synthesis of non-​structural proteins ing invasive mechanical ventilation and/or extracorporeal
membrane oxygenation, and a 5-​day treatment course is
Lopinavir–ritonavir Inhibition of 3-​chymotrypsin-​like Atrioventricular block
protease and cytochrome P450 suggested for patients with milder symptoms. Although
3A4-​related drug–drug prominent cardiovascular adverse effects associated with
interaction remdesivir have not been reported so far, these might
Inhibitors of viral RNA replication become apparent with more widespread use158.
Favipiravir Inhibition of RdRP Not common, but limited
clinical data Lopinavir–ritonavir. Lopinavir–ritonavir is a fixed-​dose
drug combination used for the prevention and treat-
Remdesivir Inhibition of RdRP Not common, but limited
clinical data
ment of HIV infection and works by inhibiting protease
activity159. Lopinavir is available only in combination
Ribavirin Inhibition of RdRP Not common with ritonavir, which functions to slow the breakdown
Others of lopinavir by inhibiting cytochrome P450 3A4 (ref.41).
Azithromycin Macrolide antibiotic; used in QT interval prolongation In a randomized, controlled, open-​label trial involving
combination with chloroquine 199 patients with COVID-19, no benefit was observed
or hydroxychloroquine with lopinavir–ritonavir treatment compared with
Tocilizumab IL-6 inhibition Hypertension standard care159. Gastrointestinal adverse effects were
ACE2, angiotensin-​converting enzyme 2; COVID-19, coronavirus disease 2019; RdRP, more frequently reported in the lopinavir–ritonavir
RNA-​dependent RNA polymerase; S protein, spike protein. treatment group than in the standard group, but adverse

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 Reviews

Box 1 | Useful web links for CoVid-19 information understand the disease processes involved in COVID-19.
Mechanistically, the interaction between the S protein
genetics and ACE2 is likely to have a central role in disease patho-
The COVID-19 Host Genetics Initiative: https://www.covid19hg.org/ genesis, especially in cardiovascular manifestations of
Single-​cell rNa sequencing data this disease, and this interaction is a potential target for
COVID-19 Cell Atlas: https://www.covid19cellatlas.org/ the prevention and treatment of COVID-19.
Virus genome Several hurdles need to be overcome in the study of
GenBank severe acute respiratory syndrome coronavirus 2 sequence: https:// the mechanisms underlying COVID-19. First, biological
www.ncbi.nlm.nih.gov/genbank/sars-​cov-2-​seqs/ experiments using SARS-​CoV-2 can be performed only in
China National Center for Bioinformation: https://bigd.big.ac.cn/ncov?lang=en laboratories with a biosafety level 3 rating161,162. Second, the
Virus protein data use of animal models to mimic the disease process is asso-
ViralZone: https://viralzone.expasy.org/ ciated with numerous challenges163–165. Given that cellular
COVID-19 Molecular Structure and Therapeutics Hub: https://covid.molssi.org/ or tissue tropism is likely to be an important factor con-
literature tributing to the diverse phenotypes of COVID-19 (ref.4),
LitCovid: https://www.ncbi.nlm.nih.gov/research/coronavirus/ mouse or rat models are not ideal to study host tropism
COVID-19-related preprints (medRxiv and bioRxiv): https://connect.biorxiv.org/relate/ because they are not as susceptible to SARS-​CoV-2 as
content/181 humans owing to differences in the amino acid sequence
Materials of ACE2 (ref.166). To use mice or rats, human ACE2 needs
Addgene COVID-19 and Coronavirus Plasmids & Resources: https://www.addgene.org/ to be introduced artificially. Transgenic mice expressing
collections/covid-19-​resources/ ACE2 infected with SARS-​CoV-2 have been reported
ATCC Coronavirus Resources: https://www.atcc.org/Landing_Pages/Coronavirus_ to show signs of pneumonia, but the overall symptoms
Resources.aspx experienced by these mice are much milder than those in
other resources humans163. Therefore, alternative platforms might involve
NIH COVID-19 webpage: https://www.nih.gov/health-​information/coronavirus genome-edited mouse or rat models in which Ace2 is
CDC COVID-19 webpage: https://www.cdc.gov/coronavirus/2019-​nCoV/hcp/ replaced by human ACE2, other animal species that are
index.html naturally susceptible to SARS-​CoV-2 infection (such as
Johns Hopkins Coronavirus Resource Centre: https://coronavirus.jhu.edu/map.html ferrets, hamsters and non-​human primates)164,165,167–170
AHA COVID-19 Professional Resources: https://professional.heart.org/professional/ or in vitro models such as induced pluripotent stem
General/UCM_505868_COVID-19-​Professional-​Resources.jsp cells171–173 and organoids114,174,175.
ACC COVID-19 hub: https://www.acc.org/latest-​in-​cardiology/features/ The COVID-19 pandemic is changing our lives in
accs-​coronavirus-​disease-2019-​covid-19-​hub
unprecedented ways. Given the lack of safe and effec-
ESC COVID-19 and cardiology: https://www.escardio.org/education/
COVID-19-​and-​Cardiology
tive vaccines or proven treatments for COVID-19,
our main strategy to combat the pandemic is social
COVID-19, coronavirus disease 2019. distancing. The capacity of health-​care systems glob-
ally has been severely tested (and in some countries
cardiovascular effects were not reported in either completely overwhelmed), and the effect of this pan-
group159. Nevertheless, lopinavir–ritonavir should be demic on social interactions, health-​care delivery and
used with caution in patients with COVID-19 because the global economy continues to mount. Reduced
this drug combination might interact with common car- physical activity owing to lockdown measures might
diovascular drugs that are metabolized by cytochrome also contribute to poor control of cardiovascular
P450 3A4, including antiarrhythmic agents, antiplatelet risk factors. Vaccine development is expected to take
drugs and anticoagulants41,160. 12–18 months34. To meet the urgent need for effective
treatment and preventative strategies, a concerted effort
Conclusions must be made by researchers globally to investigate
Given that numerous studies have demonstrated and integrate biological and clinical findings related to
that SARS-CoV-2 shares many biological features COVID-19 (Box 1).
with SARS-CoV, our knowledge of the pathophysio-
logical mechanisms underlying SARS can be used to Published online xx xx xxxx

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