COVID-19: What are the major

cardiovascular issues?
Acute viral myocarditis often confounds with
ischemic injury
Publish date: April 24, 2020 Author(s):  Bishnu H. Subedi, MD, FACC , Raghavendra
Tirupathi, MD, FACP , Swetha Areti Md , And Venkataraman Palabindala, MD, SFHM,
MBA
Frontline health care workers are facing escalating challenges with rapidly
spreading coronavirus disease 2019 (COVID-19) caused by severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) infection. 1 Hospitalists will often deal with
various manifestations of acute cardiac injury, controversial withholding of ACE
inhibitors (ACEI) or angiotensin receptor blockers (ARBs), arrhythmic toxicities
from such drug therapies as hydroxychloroquine.

Dr. Bishnu H. Subedi

Presentation and cardiac risks from COVID-19

Patients with COVID-19 often have presented with noncardiac symptoms, usually a
febrile illness associated with cough or shortness of breath. Recent reports from
Italy and New York have suggested patients also can present with isolated cardiac
involvement without any other symptoms that can portend a grim
prognosis.2 Cardiac effects include myocarditis, acute coronary syndrome,
malignant arrhythmias ultimately cardiogenic shock and cardiac arrest. 3

The mortality rate correlates with older age, preexisting health conditions, and
availability of medical resources. A recent meta-analysis including 53,000 COVID-
19 patients found the most common comorbidities were hypertension (19%),
diabetes (8 %) and cardiovascular disease (CVD) (3%). 4 Half of the cases died from
respiratory failure and one-third have died from concomitant respiratory and heart
failure. Acute heart failure alone accounted for about 7% of cases.5

Overall mortality rate can be better understood with the largest case series to-date
of COVID-19 in mainland China published by the Chinese Center for Disease
Control and Prevention. The overall case-fatality rate was 2.3% (1,023 deaths
among 44,672 confirmed cases), but the mortality reached 10.5% in patients with
underlying CVD.6

Acute cardiac injuries in COVID-19

Acute cardiac injury (ACI) is defined as troponin elevation above the 99th
percentile of the upper reference limit. 7 A practical description of ACI in COVID-19
patients should also include broader definition with new abnormalities in ECG
since not all patients with acute cardiac effects have developed troponin
elevation.3 More recent reports showed up to 28% of hospitalized patients had a
myocardial injury.3

It is not uncommon to see a patient with COVID-19 myocarditis as a mimicker of

acute ST-elevation myocardial infarction (STEMI). The mechanism of ACI is
unknown, though several hypotheses have been proposed based on case series and
retrospective reviews. These include direct viral invasion into myocardial cells
leading to myocarditis, oxygen demand-supply mismatch, acute coronary
syndrome from plaque rupture, stress, or cytokine-mediated cardiomyopathy. 3 The
exact incidence of true MI from occlusive coronary disease in the COVID-19
population is yet unknown.

In some cases, troponin elevation may be a late manifestation of COVID-19. As

coronavirus disease progressed slowly, a rapid rise of troponin was noted when
patients developed acute respiratory failure after 10 days of illness. Among
nonsurvivors, a steady rise in troponin was observed from day 4 through day 22. 8

ACI is associated with ICU admission and mortality. Both troponin and BNP levels
increased significantly during the course of hospitalization in those who ultimately
died, but no such changes were evident in survivors. 3 ACI was higher in
nonsurvivors (59%) than in survivors (1%). 8 ACI was higher in ICU patients (22%),
compared with non-ICU patients (2%).9 Patients with CVD were more likely to
exhibit elevation of troponin levels (54%), compared with patients without CVD
(13%).3

Higher troponin levels and the presence of CVD are directly proportional to severe
disease and death. Patients with elevated troponin developed more frequent
complications including acute respiratory distress syndrome, malignant
arrhythmias including ventricular tachycardia/ventricular fibrillation, acute
coagulopathy, and acute kidney injury.3,8 Death was markedly higher in patients
with elevated troponin, compared with normal levels: 60% versus 9%. Only 8%
with no CVD and normal troponin died, whereas 69% of people with underlying
CVD and elevated troponin died.3

The median duration from illness onset to death was 23 (8-41) days in the group
with elevated troponin. Patients with CVD and escalation of troponin levels had the
shortest survival of 1-5 days. The dynamic rise of cardiac biomarkers and increased
incidence of malignant arrhythmias during the course of illness shows that
myocardial injury played a greater role in the fatal outcome of COVID-19 than the
presence of preexisting CVD itself.3

Management of acute cardiac issues in COVID-19

There are no established therapeutic options with randomized, clinical trials
specific to the management of COVID-19 patients at this point. Standard
supportive care and individualized treatment plan based on existing guidelines is
probably the best approach. Disposition of cases and cardiac testing should be
tailored, based on local protocols, availability of resources and expertise. 10

Dr. Raghavendra Tirupathi

There seems to be a consensus that baseline troponin levels should be obtained in

all admitted patients. Repeat troponin levels can be obtained based on the severity
of illness, for example, daily troponin checks are reasonable in ICU patients and
every-other-day troponin testing may be reasonable in general inpatients. Routine
troponin testing in minimally symptomatic or asymptomatic patients will likely not
change any outcome.3,11,12

Daily ECG is reasonable in severe COVID-19. However, routine transthoracic ECGs

are not reasonable, unless it will change further treatment plans. Transthoracic
electrocardiograms (TTE) are reasonable in patients with significant troponin
elevation, a decline in central venous oxygen saturation, new heart failure, shock,
new persistent arrhythmias, or significant new ECG changes. 12

Limited TTEs for a focused exam enough to answer the clinical question should be
ordered to minimize the risk of viral exposure to the sonographers.
Transesophageal echo will rarely be needed, and its use should be minimized to
reduce direct contact exposure and because of anesthesia risks. 13 Routine stress
testing should not be ordered in active COVID-19 and should be deferred for
outpatient evaluation, if clinically indicated, once the patient recovers from the
infection.12

Myocarditis and pericarditis are potential manifestations of acute cardiac injury.

Recent case reports have suggested evidence of myocarditis confirmed with cardiac
MRI.11 Because of high fatality rates with cardiac involvement and no proven
therapies yet, the role of routine advanced cardiac imaging such as cardiac CT,
cardiac MRI, or cardiac biopsy is unclear.

Myocarditis can likely be caused either by the virus itself, or the body’s immune
and inflammatory response (cytokine storm) to the virus. 2,3 The use of anti-
inflammatory drugs like colchicine, ibuprofen, steroids, or statins is not yet
established.10,12 Drugs like remdesivir, lopinavir-ritonavir, hydroxychloroquine,
chloroquine, and anti-interleukin-6 agents have been invariably used with some
anecdotal success and randomized clinical trials for some of these drugs are
presently undergoing.
Physicians may encounter situations to call a STEMI code or not in COVID-19
patients.2,11 Patients may have substernal pain, diffuse or regional ST elevations in
ECG and reduced left ventricular dysfunction with regional wall motion
abnormalities on ECG. These findings may be casued by myocarditis, acute type 1
MI, or stress-induced cardiomyopathy. Clinicians should make their judgment
based on the overall pretest probability for type 1 MI, incorporating risk factor
profiles and the presence of typical symptoms.

Treatment practice for questionable STEMI cases will likely vary across the country
as we are learning more about the virus. Cath lab operators are at risk for COVID-
19 infection through direct contact with patients. Few cardiologists were admitted
after COVID-19 infections in the ICU at a New York hospital after they were
involved in a acute MI case in a cath lab. 14 Based on the Chinese experience, some
have suggested the idea of lytic therapy first with follow-up cardiac CT to assess the
recanalization of perfusion status, but at this point, this strategy remains
controversial in the United States. In addition, if the patient has myocarditis
instead, there will be a risk for pericardial effusion and hemorrhagic complications
with lytic therapy.

Case examples
1. A 70-year-old male presents with fevers, chest pain, cough, shortness of breath.
He has a history of metabolic syndrome and 30 pack-years of smoking. His ECG
showed 1.5 mm ST elevation in inferior leads with reciprocal ST depressions in
lateral leads, and his initial troponin is 2. Echocardiogram showed reduced left
ventricle ejection fraction of 32% and inferior wall hypokinesis. He is suspected
COVID-19 and his PCR result is pending. How would you manage this patient?

This patient presented with febrile illness and, but he had a very high pretest
probability for obstructive coronary artery disease based on his age, male sex, and
multiple risk factors. He may have a viral syndrome and it is a stressful situation
for him. This may have precipitated plaque rupture causing acute MI.

Activating the STEMI pathway for emergent left heart catheterization is likely
appropriate in this case. Coronary angiogram in this patient showed a 100%
occluded mid-right coronary artery with a fresh thrombus. Delaying cardiac cath
would have possibly led to malignant arrhythmias and death from ischemic injury.
We need to be cognizant patients can die from non–COVID-related emergencies
also.

2. An 18-year-old healthy male presents with cough and chest pain and has
bilateral lung infiltrates. ECG showed anterolateral 2 mm ST elevations and no
reciprocal ST changes. Stat TTE showed anterior wall hypokinesis and LV function
30% and his initial troponin are 0.6 (normal is < .05). The nasopharyngeal swab is
sent out and his COVID result is pending. How would you manage this patient?
A young patient with no cardiovascular risk factors has a very low pretest
probability for obstructive coronary disease and the likelihood of having a true
ischemic MI is low even though he has significant new ST elevations. Especially
with presumed COVID-19 and risk of virus exposure to the cath lab personnel, it
will be prudent to manage this patient with supportive therapy including beta-
blockers, ACEIs, etc. Repeat echo in 7 days before discharge showed improved
LVEF 45%.

Controversy on ACEI/ARB
The SARS-CoV-2 virus enters via cell-entry receptor namely angiotensin-
converting enzyme 2 (ACE2). SARS-CoV-2 is thought to have a higher affinity for
ACE2 than other SARS-viruses.15

ACE2 is expressed in the heart, lungs, vasculature, and kidneys. ACEI and ARBs in
animal models increase the expression of ACE2, 16 though this has not been
confirmed in human studies. This has led to the hypothesis that ACEI and ARBs
might worsen myocarditis or precipitate the acute coronary syndrome. It has also
been hypothesized that the upregulation of ACE2 is therapeutic in COVID-19 and
that ARBs might be protective during infection. 17

The increased ACE2 expression induced by ACEI or ARB would aggravate lung
injury of patients with COVID-19. However, a previous study showed a beneficial
effect of ACEI/ARB in patients admitted with viral pneumonia, as it significantly
reduced the pulmonary inflammatory response and cytokine release caused by
virus infection.18

Therefore, this remains an area of investigation and it is unclear how these

medications affect patients with COVID-19. In a recent review, with a limited
number of patients, the mortality of those treated with or without the use of
ACEI/ARB did not show a significant difference in the outcome.3

Both American and European cardiology societies recommend against routine

discontinuation of ACEI and ARBs in patients with COVID-19 because of risks of
uncontrolled hypertension and heart failure, stroke, or heart attack. 19 However, it
will be reasonable to hold off in inpatients in cases of acute kidney injury,
hypotension, shock, etc.12

Cardiac concern about hydroxychloroquine and

chloroquine
Hydroxychloroquine (HCQ) is an antimalarial drug shown to have in vitro (but not
yet in vivo) activity against diverse RNA viruses, including SARS-CoV-1. 20 An expert
consensus group from China suggests that chloroquine improved lung imaging and
shortened disease course.21 HCQ was found to be more potent than chloroquine in
inhibiting SARS-CoV-2 in vitro.22

Based on limited in vitro and anecdotal clinical data from other countries, the U.S.
Food and Drug Administration recently authorized emergency use of chloroquine
and HCQ in hopes of slowing the progression of the disease when a clinical trial is
not available, or participation is not feasible for use of these drugs in hospitalized
patients. However, with no clear benefit, there is a concern for possible risks with
cardiac toxicity.

HCQ is known to cause cardiomyopathy in a dose-dependent manner over several

years. Given the anticipated short duration in COVID-19, it is not an expected risk.
QT-segment prolongation and torsades de pointes, especially if administered in
combination with azithromycin, is possible even in short term use.23

Dr. Raman Palabindala

Given above, frequent ECG monitoring is indicated for patients being treated with
chloroquine or HCQ. All other QT-prolonging drugs should be discontinued.
Continuous telemetry monitoring while under treatment is reasonable. HCQ
should not be started if baseline QTc is > 500 msec and it should be stopped if the
patient develops ventricular arrhythmias. 12

Dr. Subedi is a noninvasive cardiologist for Wellspan Health System in Franklin

and Cumberland counties in south central Pennsylvania. He is a clinical assistant
professor of medicine at Penn State College of Medicine, Hershey, Pa. He is an
active member of the critical care committee at Wellspan Chambersburg (Pa.)
Hospital. Dr. Tirupathi is the medical director of Keystone Infectious
Diseases/HIV in Chambersburg and currently chair of infection prevention at
Wellspan Chambersburg and Waynesboro Hospitals, all in Pennsylvania. He also
is the lead physician for antibiotic stewardship at these hospitals. Dr. Areti is
currently working as a hospitalist at Wellspan Chambersburg Hospital and is a
member of the Wellspan pharmacy and therapeutics committee. Dr.
Palabindala is hospital medicine division chief at the University of Mississippi
Medical Center, Jackson.

Key points
 Acute cardiac injury or myocarditis is common among patients infected with
COVID-19. Often, COVID myocarditis can mimic acute MI or stress
cardiomyopathy and will present diagnostic and therapeutic challenges. On
the other hand, isolated cardiac involvement can occur, even without
symptoms and signs of interstitial pneumonia.
  A most important indicator of worse prediction is the degree of myocardial
injury, regardless of preexisting conditions or underlying cardiovascular
disease.
 Early recognition of cardiac involvement will be helpful in targeting more
aggressive supportive therapies. Commonly available clinical tools like
bloodwork, ECG, or echocardiogram should be adequate to diagnose carditis
in most cases.
 Advanced cardiac imaging tests or cardiac biopsy are of uncertain benefits.
Meticulous evaluation is needed for possible ischemic changes before taking
the patient to the cardiac cath lab in order to reduce unnecessary virus
exposure to the operators.
 ACEI/ARB should be continued in most cases in COVID patients based on
cardiology societies’ recommendations.
 With the widespread use of antimalarial drugs like chloroquine or
hydroxychloroquine, frequent ECG and continuous telemetry monitoring is
reasonable to rule out ventricular arrhythmias like torsades.
 There is no specific treatment to date for acute cardiac injuries. Since there
are no specific guidelines and information about the virus is rapidly
changing, it will be prudent to follow common-sense approaches outlined by
institutions like the Brigham and Women’s Hospital COVID-19 Critical
Care clinical guidelines, which incorporate new clinical information on a
daily basis ().

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