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SCIENCE SERIES

ABSTRACT
Coronavirus disease 2019 (COVID-19), caused by the severe 

acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has 

far-reaching impacts on human health. First identified as a dis-

ease of the respiratory system, COVID-19 also causes gastroin-

testinal, renal, neurological, and/or cardiovascular symptoms. 

This article elucidates biological relationships between COVID-

19 and the cardiovascular system. It postulates molecular and 

physiological mechanisms behind COVID-19–related cardiovas-

cular ailments and examines intersections among the cardiovas-

cular system, SARS-CoV-2, COVID-19, and certain medications. 

New scientific information on COVID-19 and the cardiovascu-

lar system accumulates weekly. In recognition of such rapidity, 

this paper offers a framework in which the reader will be able to 

place the growing and evolving field of knowledge.

EFFECTS OF SEVERE ACUTE RESPIRATORY 
SYNDROME CORONAVIRUS 2 INFECTION ON 
THE CARDIOVASCULAR SYSTEM
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 

infects cells through an interaction between the virus’s spike 

(S) protein and angiotensin-converting enzyme (ACE) 2 in host 

cells.1-5 Within the cardiovascular system, ACE2 is reportedly 

located on heart muscle cells,6-11 endothelial cells (ECs) that 

line the interior of blood vessels and regulate blood clotting 

and blood pressure,12,13 pericytes that surround and aid ECs,6-8 

and arterial smooth muscle cells (SMCs) that control vascular 

diameter and thereby blood pressure and flow.7,12,13 SARS-CoV-2 

infection of these cells hinders their health-promoting work.

 Cardiovascular health is also threatened when SARS-CoV-2 

invades noncardiac areas and triggers immune responses. To 

fight the “intruder,” local white blood cells activate, recruit 

other white blood cells, and produce pro-inflammatory chemi-

cals, which increases inflammation. Interestingly, a source of 

these chemicals may be direct SARS-CoV-2 infection of mac-

rophages—a type of white blood cell that expresses ACE2.14 As 

the immune system battles the virus, the affected body organ 

may (temporarily) malfunction. These malfunctions and the 

pro-inflammatory chemicals released into the blood may elicit 

negative effects on blood vessels and the heart.15

 Cardiovascular conditions induced by these direct and 

indirect effects of SARS-CoV-2 infection include myocarditis 

(inflamed heart tissue), blood pressure irregularities, abnor-

mal blood clot (thrombus) formation, hypoxia, arterioscle-

rotic heart disease (ASHD), myocardial infarctions (MIs; heart 

attacks), arrhythmias, and heart failure (Figure 1).16-29 If left 

unchecked or if severe enough, these ailments could be fatal.

Myocarditis
Myocarditis compromises contractility of the heart muscle. As 

a result, the heart compensates in order to insure proper deliv-

ery of blood (and O2) to the body. Compensation occurs by one 

of at least 2 methods: (1) thickening of the heart muscle layer 

(hypertrophy), and (2) heart rate elevation (tachycardia). Both 

choices could progressively worsen the heart’s already precari-

ous condition.

Blood Pressure Irregularities
Some patients with coronavirus disease 2019 (COVID-19) pres-

ent with hypertension.19 The causal link between this elevated 

blood pressure and SARS-CoV-2 may be ACE2. Besides being 

the binding target of SARS-CoV-2’s S protein, ACE2 is part of 

the renin–angiotensin system (RAS) pathway (Figure 2). The 

RAS pathway controls SMC contraction and relaxation and 

thereby influences blood pressure. SMC contraction narrows 

vessels’ diameter (vasoconstriction) and raises blood pres-

sure. SMC relaxation widens vessels’ diameter (vasodilation) 

and lowers blood pressure. SMC contraction and relaxation are 

controlled by the RAS pathway’s angiotensin II and angiotensin 

(1-7), respectively. ACE1 converts relatively inactive angioten-

sin I into angiotensin II, a highly active vasoconstrictor. ACE2 

converts angiotensin II into angiotensin (1-7), a vasodilator 

(Figure 2).30 ACE2 levels likely decline in SARS-CoV-2–infected 

Jennifer L. Busch, PhD  / Associate Professor of Biology, Wheaton College, Wheaton, IL

Intersections of Severe Acute Respiratory Syndrome 
Coronavirus 2, Coronavirus Disease 2019, and the  
Cardiovascular System



      AMWA Journal / V36 N2 / 2021 / amwa.org    73

Figure 1. Confirmed and plausible mechanisms by which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infec-
tion causes cardiovascular symptoms. Several cell types and organs (indicated by the spiked star symbol) are reported targets for 
SARS-CoV-2 infection. Some of these host cells are part of the cardiovascular system, macrophages may lie within or outside of 
the cardiovascular system, and other sites lie outside of the cardiovascular system. (The cardiovascular system is defined by the 
thin-dashed enclosure.) Infections initiate a variety of cardiovascular symptoms (shaded boxes) that, if prolonged and severe 
enough, cause arrhythmias and heart failure (shaded boxes with thick outline). Viral infection of other organs may also affect 
the cardiovascular system in ways not specified here. Related schematics can be found in Guzik et al17 and Atri et al.16 ASHD, 
arteriosclerotic heart disease.

Figure 2. The renin–angiotensin system (RAS) pathway and sites of angiotensin-converting enzyme (ACE) inhibitor (ACEI) and an-
giotensin receptor blocker (ARB) inhibition. In the RAS pathway, renin (produced by the kidneys) converts angiotensinogen (produced 
by the liver) into angiotensin I. Angiotensin I is modified into angiotensin II, an active vasoconstrictor, by ACE1. ACE2 (the target 
for SARS-CoV-2 infection) produces the vasodilator angiotensin (1-7) from angiotensin II. The ACEI and ARB high-blood-pressure 
medications work by preventing vasoconstriction. They inhibit ACE1 and binding of angiotensin II to its receptors, respectively. 



74    AMWA Journal / V36 N2 / 2021 / amwa.org        

cells.31-33 Without ACE2, levels of angiotensin (1-7) would 

decrease, and angiotensin II levels would likely increase. These 

events would tip the scales toward vasoconstriction and ele-

vated blood pressure. This mechanistic explanation for hyper-

tension, although plausible, needs to be strengthened with 

additional research.

 Another explanation for hypertension development in 

patients with COVID-19 lies in direct viral infection of ECs and 

perhaps pericytes. Both of these cell types impact blood vessel 

diameter (Figure 1).34-36 A deficit of vasodilation or a prevalence 

of vasoconstriction likely causes hypertension.

 Some patients with COVID-19 develop low blood pressure 

(hypotension) rather than high blood pressure.22 Hypotension 

is a symptom of acute respiratory distress syndrome (ARDS),37 

so it is likely the result of SARS-CoV-2 infection of lung cells.

Thrombi Formation and Hypoxia
Another blood-related condition found in some patients with 

COVID-19 is the presence of thrombi.23-25 These abnormal 

blood clots form in arteries or veins. Interference of arterial 

blood flow jeopardizes delivery of O2 and nutrients to areas 

downstream of the blockage, whereas impedance of blood  

flow through a vein may cause swelling in the body upstream of 

the clot.

 Besides blood-flow alteration, thrombi pose an addi-

tional risk to patients: pieces may break off the clot, travel 

through the bloodstream, and lodge in another blood vessel. 

These traveling clots (emboli) endanger other organs. When 

an embolus in a large systemic artery flows to a narrower 

artery within an organ, it may get stuck, hinder blood flow, and 

deprive downstream organs—or areas within an organ—of O2.

 Emboli in veins pose a significant risk to the lungs. Such 

emboli could migrate through the right heart chambers, lodge 

in the lungs’ narrow arterial branches, and impede blood 

flow to the pulmonary capillaries. Complications of pulmo-

nary emboli include right ventricular hypertrophy, swelling 

(edema), and low O2 levels in the blood (hypoxia) (Figure 1).

 Right ventricular hypertrophy and edema are indirect 

effects of a pulmonary embolism. To force blood past the pul-

monary embolism, the heart’s right ventricle hypertrophies 

in an attempt to strengthen its pumping power. At best, this 

adjustment is a temporary fix. Persistence of the embolism 

increases blood pressure in the right side of heart, and by 

extension, in the body’s veins. This elevated vascular pressure 

induces edema. Gravity causes the swelling to be most promi-

nent in the lower limbs.

 Such edema also occurs in the lungs. This fluid buildup 

impedes the diffusion of O2 from the lungs’ alveoli to the blood 

in the pulmonary capillaries. It also reduces alveolar ventila-

tion (O2 entry into the alveoli), as fluid-filled sacs fail to remain 

open. Diminished blood flow to alveoli on account of pulmo-

nary emboli may also prevent the blood from picking up  

adequate O2. Collectively, these emboli-initiated events  

cause hypoxia.

 Two culprits induce thrombi formation: injured ECs and 

pro-inflammatory chemicals (Figure 1). ECs may be damaged 

by direct SARS-CoV-2 infection.38 Such damaged cells activate 

platelets and make them more “sticky”; thus, they adhere to 

the vessel wall and to each other. Clotting factors in the blood 

set off a chain reaction that culminates in the modification of 

fibrinogen to fibrin. Fibrin threads attach to the mass of plate-

lets to form the clot. If ECs are undamaged, a clot may still 

form: pro-inflammatory chemicals may activate platelets and 

clotting factors (Figure 1).39

ASHD, MIs, and Arrhythmias
Thrombi may form in the coronary arteries of some patients 

with COVID-19, a condition known as ASHD.26-28 Coronary 

arteries carry O2-rich blood to the heart tissue. Such O2 helps 

fuel the heart’s vital blood-pumping actions. Partial or com-

plete blockage of these coronary vessels is life-threatening. 

Whether through blocked delivery or through hypoxia, insuf-

ficient O2 causes heart muscle cells to malfunction and die. The 

likelihood of MIs increases (Figure 1). MIs in a small number of 

patients with COVID-19 have been reported.26-28

 Arrhythmias have also been reported in some patients with 

COVID-19.16,18,29 In the general population, these altered heart 

rhythms are caused by ASHD, MIs, myocarditis, and heart 

hypertrophy. Therefore, these cardiovascular conditions are 

the current “suspects” for reported arrhythmias in COVID-19–

related cases.16,18,29

Heart Failure
Persistence of these aforementioned cardiovascular problems 

gradually weakens the heart, compromises its pumping ability 

and effectiveness, and can lead to heart failure (Figure 1). The 

heart becomes progressively more incapable of delivering O2- 

and nutrient-rich blood to the body. Preexisting heart failure 

appears to increase the likelihood of death from the disease in 

patients with COVID-19.40

Preexisting hypertension, ASHD, 

arrhythmias, MIs, and heart failure  

seem to increase the severity of 

COVID-19 symptoms in patients.



AMWA Journal / V36 N2 / 2021 / amwa.org    75

MEDICATIONS AND HEALTH (COVID-19 AND 
CARDIOVASCULAR) RISKS
COVID-19 impacts the cardiovascular system, but the inverse 

may also be true. Percentages of patients with COVID-19 and 

cardiovascular conditions are not higher than the prevalence of 

these conditions in the general population.18-20,40-46 Therefore, 

these cardiovascular illnesses do not appear to increase one’s 

risk of developing COVID-19. However, preexisting hyperten-

sion,18-20,40,41 ASHD,18,19,40,41 arrhythmias,19,20,41 MIs,20 and heart 

failure19,20,41 seem to increase the severity of COVID-19 symp-

toms in patients. This observation led scientists to examine 

whether certain cardiovascularly related medications alter 

patients’ risk of SARS-CoV-2 infection and/or COVID-19  

severity. (It is worth noting that classifications of “severity” vary 

among studies. Distinctions include normal vs high protein 

[troponin] concentrations in the blood, nonsevere vs severe 

disease, nonhospitalized patients vs hospitalized patients, 

non–intensive care unit [ICU] patients vs ICU patients, and 

survivors vs nonsurvivors.17,29)

ACE Inhibitors and Angiotensin Receptor Blockers
Some antihypertensive medications are the focus of such 

research. Many Americans (13% to nearly 50%, depending on 

definitions and the data source) have hypertension.42,45,46 This 

percentage increases as one ages.45 To lower high blood pressure, 

physicians may prescribe ACE inhibitors (ACEIs) and/or angio-

tensin receptor blockers (ARBs). These medications minimize 

production of angiotensin II and block angiotensin II’s interac-

tion with receptors, respectively (Figure 2), thereby preventing 

the vasoconstriction that elevates blood pressure (Figure 2).

 However, certain ACEIs and ARBs likely increase levels 

and activity of ACE2 throughout the body.47-49 Because ACE2 is 

the receptor for SARS-CoV-2 binding, it is important to ascer-

tain whether ACEIs and ARBs alter patients’ risk of contract-

ing SARS-CoV-2 and/or developing COVID-19. Mackey et al50 

provide regular updates on newly published research articles 

pertaining to this topic. Articles sampled from this compila-

tion show wide variability in the study design.44,50-54 Differences 

include variations in comparison groups, ethnic groups, sta-

tistical analyses, sample sizes, dates of studies (before or after 

widespread COVID-19 testing), lengths of time on ACEIs or 

ARBs, attention levels paid to confounding health issues, and 

definitions of “severe COVID-19.” Some articles are retrospec-

tive observational studies. Such studies are subjective to selec-

tion bias; for example, a cohort of hypertensive patients tested 

for COVID-19 leaves out hypertensive patients who did not 

get tested because they were asymptomatic. Identification 

of patients prescribed ACEIs or ARBs also assumes that the 

patients take these medications as prescribed, which may not 

be the case.

 Nevertheless, most studies come to the same conclusion: 

use of ACEIs or ARBs does not increase one’s risk of SARS-CoV-2 

infection or development of severe COVID-19.55,56 Currently, 

the Centers for Disease Control and Prevention (CDC) and 

other cardiovascular health organizations advise patients to 

continue their ACEI or ARB prescriptions, unless advised oth-

erwise by a physician.57,58 Clinical trials concerning ACEIs, 

ARBs, and COVID-19 are ongoing.59

 Interestingly, the ACEI- and ARB-induced increase in  

ACE2 expression levels may be advantageous to patients.52,54  

It may counteract virally induced reduction of ACE2 levels and 

thereby preserve the production of angiotensin (1-7), which 

lowers elevated blood pressure, promotes structural health of 

blood vessels and ECs, protects against cardiac hypertrophy, 

and may enhance blood cell production.60,61

COVID-19 Treatments and Cardiac Health Risks
Some medications—lopinavir/ritonavir, hydroxychloroquine 

(HCQ), favipiravir, remdesivir, and tocilizumab—were origi-

nally developed for other uses but demonstrate various levels 

of efficacy in treating patients with COVID-19. Lopinavir/rito-

navir and HCQ reportedly disrupt SARS-CoV-2’s entry into host 

cells.62 Favipiravir and remdesivir likely prevent the replication 

of the virus’s genome.62 Tocilizumab reduces inflammation by 

limiting the effectiveness of pro-inflammatory chemicals.62 

Last year, a multinational study of more than 10,000 patients 

examined the effects of some of these drugs on the mortality of 

patients with COVID-19.63 The tests using HCQ (low doses) and 

lopinavir/ritonavir were halted prematurely, as no improve-

ments were seen.64 Currently, the National Institutes of Health 

(NIH) recommends against their use as a treatment for  

COVID-19.65,66

 These drugs have been linked to cardiovascular side effects. 

Lopinavir/ritonavir, HCQ, favipiravir and remdesivir may 

cause arrhythmias.29,67-69 Lopinavir/ritonavir may trigger MIs.70 

Furthermore, lopinavir/ritonavir and tocilizumab may com-

promise the effectiveness of cardiovascular medications.29,71 

These cardiovascular risks are inferred primarily from a small 

number of studies with a small number of subjects without 

COVID-19. A more robust examination of these drugs’ cardio-

vascular effects in patients with COVID-19 has begun in several 

clinical trials funded by the NIH.29

CONCLUSION
Approximately 1.5 years have passed since SARS-CoV-2 and 

COVID-19 were identified.1,72,73 In this time, much scientific 

understanding of SARS-CoV-2 infection patterns and COVID-

19 comorbidities has been acquired. Improved treatment pro-

cedures enhance patients’ prognoses, and awareness of drug 

side effects likely reduces health complications. This article 



76 AMWA Journal / V36 N2 / 2021 / amwa.org 

illuminates the landscape of SARS-CoV-2 and COVID-19 in 

relationship with the cardiovascular system and provides a 

biological foundation to support readers as they engage with 

the burgeoning quantity of scientific studies on this topic. 

Indeed, the necessity of continued research remains. Some 

current information is conjecture, drawn from studies on 

the first severe acute respiratory syndrome coronavirus or in 

patients without COVID-19. Other knowledge is based on only 

a few small studies and needs stronger support. Longitudinal 

studies are necessary to determine the long-term effects of 

SARS-CoV-2 and COVID-19 on human health. Regardless, the 

approval of effective SARS-CoV-2 vaccines,74,75 enhancements 

to patient care, and funded clinical trials provide hope for a 

future in which SARS-CoV-2 infection rates decline, patient 

mortality decreases, and life without social-distancing restric-

tions resumes.

Author declaration and disclosures: The author notes no commercial 
associations that may pose a conflict of interest in relation to this article.

Author contact: jennifer.busch@wheaton.edu

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