JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO.

-, 2021
ª 2021 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER

THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).

STATE-OF-THE-ART REVIEW

The Pathogenesis and Long-Term

Consequences of COVID-19 Cardiac Injury
State-of-the-Art Review

Bhurint Siripanthong, BA,a,* Babken Asatryan, MD, PHD,b,* Thomas C. Hanff, MD, MSCE,c
Salman R. Chatha, MBBS, MSC,d,e Mohammed Y. Khanji, MBBCH, PHD, MRCP,d,f,g Fabrizio Ricci, MD, PHD, MSC,h,i,j
Daniele Muser, MD, PHD,k Victor A. Ferrari, MD,l,m Saman Nazarian, MD, PHD,n Pasquale Santangeli, MD, PHD,n
Rajat Deo, MD, MTR,n Leslie T. Cooper, JR, MD,o Saidi A. Mohiddin, MBCHB, MD, MRCP,d,g
C. Anwar A. Chahal, MBChB, PHD, MRCPd,n,p,q

HIGHLIGHTS

COVID-19 myocardial injury results from immune and hypercoagulability responses.

Long-term cardiac consequences of COVID-19 include structural and functional changes.

Myocarditis after COVID-19 vaccination is uncommon (highest risk in teenage males).

Larger population-based studies are necessary to validate these early results.

SUMMARY

The mechanisms of coronavirus disease 2019 (COVID-19)–related myocardial injury comprise both direct viral invasion
and indirect (hypercoagulability and immune-mediated) cellular injuries. Some patients with COVID-19 cardiac involve-
ment have poor clinical outcomes, with preliminary data suggesting long-term structural and functional changes. These
include persistent myocardial fibrosis, edema, and intraventricular thrombi with embolic events, while functionally, the
left ventricle is enlarged, with a reduced ejection fraction and new-onset arrhythmias reported in a number of patients.
Myocarditis post-COVID-19 vaccination is rare but more common among young male patients. Larger studies, including
prospective data from biobanks, will be useful in expanding these early findings and determining their validity.
(J Am Coll Cardiol Basic Trans Science 2021;-:-–-) © 2021 The Authors. Published by Elsevier on behalf of the
American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

From the aSchool of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom; bDepartment of Cardiology,
Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; cUniversity of Utah Health, Salt Lake City, Utah, USA;
d
Barts Heart Centre, St Bartholomew’s Hospital, Barts Health NHS Trust, London, United Kingdom; eUniversity Hospital of North
Midlands NHS Trust, Stoke-on-Trent, United Kingdom; fNewham University Hospital, Barts Health NHS Trust, London, United
Kingdom; gNIHR Barts Biomedical Research Centre, William Harvey Research Institute, Queen Mary University of London,
London, United Kingdom; hDepartment of Neuroscience, Imaging and Clinical Sciences, “G. d’Annunzio” University of Chieti-
Pescara, Chieti, Italy; iCasa di Cura Villa Serena, Città Sant’Angelo, Pescara, Italy; jDepartment of Clinical Sciences, Lund Uni-
versity, Malmö, Sweden; kDipartimento Cardiotoracico, U.O.C. di Cardiologia, Presidio Ospedaliero Universitario “Santa Maria
Della Misericordia,” Udine, Italy; lPerelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA;
m
Penn Cardiovascular Institute, Philadelphia, Pennsylvania, USA; nElectrophysiology Section, Division of Cardiovascular Medi-
cine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA; oMayo Clinic, Jacksonville,
Florida, USA; pDepartment of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA; and the qWellSpan Center for
Inherited Cardiovascular Diseases, WellSpan Health, Lancaster, Pennsylvania, USA. *Siripanthong and Dr Asatryan contributed
equally to this work and are joint first authors.

ISSN 2452-302X https://doi.org/10.1016/j.jacbts.2021.10.011

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Long-Term Consequences of COVID-19 Cardiac Injury - 2021:-–-

ABBREVIATIONS BACKGROUND IMAGING AND HISTOLOGICAL EVIDENCE OF

AND ACRONYMS SARS-CoV-2-RELATED MYOCARDIAL INJURY AND THE
BIOCHEMICAL CUES TO CARDIAC CONTROVERSIAL DIAGNOSIS OF MYOCARDITIS. As
CMR = cardiovascular magnetic
resonance
INVOLVEMENT IN CORONAVIRUS DISEASE mentioned, elevated cardiac biomarkers in patients
2019. Approximately 15 months after the with COVID-19 are common, but this does not
COVID-19 = coronavirus
disease 2019 World Health Organization declared corona- necessarily indicate clinically significant cardiac
CT = Computerized virus disease 2019 (COVID-19) a pandemic, involvement. When coronary angiography fails to
Tomography the global case load exceeds 217 million, with indicate an ischemic cause of the myocardial injury, it
LGE = late gadolinium more than 4.5 million deaths worldwide as of cannot be assumed that the elevated cardiac enzymes
enhancement September 2021. 1 Although severe respira- result from myocardial inflammation.15 Additional
MI = myocardial infarction tory failure is considered the main cause of investigations are therefore required to ascertain the
SARS-CoV-2 = severe acute death, 2 cardiovascular symptoms such as existence of myocardial injury.
respiratory syndrome
palpitations, dyspnea, fatigue, and chest Cardiovascular magnetic resonance (CMR) imaging
coronavirus-2
pain are common both in the subacute and has been used to assess cardiac involvement in
chronic stages of the disease.3-6 Additionally, a sig- recovered patients with COVID-19.16,17 In general, a
nificant proportion of patients with COVID-19 were positive correlation is found between abnormal CMR
found to have biochemical evidence of myocardial findings (eg, increased T1 or late gadolinium
injury. Myocardial injury is common in patients with enhancement [LGE]) and increased troponin levels,
COVID-19, its frequency increases with greater suggesting that the cardiac biomarker is sensitive but
severity of illness, and it carries relevant prognostic not specific to myocardial injury found in recovered
7
information. The first case series reported on clinical patients with COVID-19. Studies to date indicate that
outcomes and cardiac involvement in COVID-19 sug- cardiac involvement, as measured by CMR, is fairly
gested that up to 28% of hospitalized patients had common among recovered patients with COVID-19
8
elevated troponin levels. Subsequent studies have (range: 30%-78%), even when these patients were
reported an association between biochemical evi- included nonselectively for cardiovascular pre-
dence of myocardial injury and increased risk for sentations during their acute illness. Furthermore,
arrhythmic events, extracardiac complications (acute the nonischemic LGE patterns found among partici-
respiratory distress syndrome, mechanical ventila- pants suggest a non-MI cause of cardiac injury.
tion), and mortality in hospitalized patients. 9,10 More controversial, however, is the diagnosis of
However, the majority of patients with COVID-19 myocarditis ascribed to patients with COVID-19 with
with elevated cardiac enzymes have no underlying cardiac symptoms. Many case reports of myocarditis
epicardial coronary artery occlusion (effectively in patients with COVID-19 rely on clinical diagnoses,
excluding type 1 myocardial infarction [MI]) or clin- and several lack robust advanced imaging and/or
ical symptoms of a cardiac pathology. 11 This promp- biopsy-derived evidence (including conventional and
ted some to propose that COVID-19 predisposes to a immunohistochemistry and polymerase chain reac-
nonspecific myocardial injury biomarker leak not tion) to help establish the diagnosis. This has led
indicative of a type 2 MI. 12 Nevertheless, recent au- some to suggest that myocarditis is a rare complica-
topsy series of patients with COVID-19 have demon- tion of COVID-19; nevertheless, a recent study
strated venous thromboembolism and pulmonary showed that 4.5% of COVID-19-related cases exam-
embolism as frequent findings.13 The underlying hy- ined with autopsy or endomyocardial biopsy showed
percoagulability may contribute to hypoxia or histologic evidence of myocarditis.18 However, with
thrombosis, which precipitate organ failure, elevated cardiac enzymes, the priority is to exclude
including sudden ventricular dysfunction and cor an acute coronary syndrome, and in cases in which
pulmonale. 14 Potential mechanisms for myocardial culprit occlusions cannot be found, other in-
injury engendered by severe acute respiratory vestigations are used to refine the diagnosis. The di-
syndrome coronavirus-2 (SARS-CoV-2) are discussed agnoses of myocarditis and other cardiovascular
in detail under “SARS-CoV-2-Related Myocar- involvement of COVID-19 are discussed in the next
dial Injury.” section.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received July 12, 2021; revised manuscript received October 18, 2021, accepted October 20, 2021.
JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2021 Siripanthong et al 3
- 2021:-–- Long-Term Consequences of COVID-19 Cardiac Injury

SARS-CoV-2-RELATED MYOCARDIAL INJURY indirect injury from hypercoagulability; 4) indirect

injury from cytokine storm; and 5) a form of cell-
PREVALENCE. The prevalence of myocardial injury as or antibody-mediated autoimmunity triggered
a consequence of COVID-19 remains uncertain. An following the host response to the virus in suscepti-
early case series of COVID-19-related mortalities ble individuals (Figure 1). 22 These suggestions have
attributed as much as 7% of all COVID-19 deaths to been refined according to the evolving evidence
myocarditis.2 However, the diagnosis of myocarditis gradually being made available from autopsy series
was loosely based on clinical presentation and cardiac reported from centers around the globe. One early
biomarkers, both of which have low specificity to the suggestion was direct cell injury by means of SARS-
disease. This likely contributed to an overestimation CoV-2 entry into the myocardium. This proposition
of the incidence of SARS-CoV-2-related myocarditis. A is based on the presence of angiotensin-converting
recent retrospective cohort study showed that new enzyme 2, a membrane protein, on cardiomyocytes.
heart failure was seen in 0.6% of patients with COVID- Angiotensin-converting enzyme 2 acts as a docking
19 (37 of 6,439), and among these patients, 22% (8 of site for SARS-CoV-2 to gain cell entry.23 In an in vitro
37) had no predisposing risk factors or preexisting study using human induced pluripotent stem cell–
cardiovascular disease.19 The Centers for Disease derived cardiomyocytes, Sharma et al24 demon-
Control and Prevention revealed that the risk for strated that SARS-CoV-2 can infect and induce
myocarditis is 0.146% among inpatients and out- apoptosis in these cardiomyocytes. Direct viral
patients with COVID-19; this is 15.7 times the back- infection of human induced pluripotent stem cell–
ground risk in those without COVID-19, after matching derived cardiomyocytes was also shown to cause
for patient and hospital characteristics. 20 Although up-regulation of certain proteins, including brain
not all diagnoses had histologic or radiological proof of natriuretic peptide, interleukin-6, interleukin-8, and
myocarditis, a subset of these patients might have had tumor necrosis factor– a , to the detriment of
myocarditis secondary to SARS-CoV-2. Therefore, angiotensin-converting enzyme 2 expression. 25 The
when applying conventional diagnostic criteria for crucial flaw in these studies is that cardiac tropism of
myocarditis (ie, the updated Lake Louise criteria SARS-CoV-2 was forced in an artificial cellular model,
for CMR imaging or the [outdated] Dallas criteria for when in fact presence of the binding proteins does
endomyocardial biopsy), only a handful of case reports not always predict tropism,26 and so far, there is little
would be truly identified as myocarditis. 18 However, in vivo evidence to support this model. For example,
in this setting of acute myocardial injury of unknown direct detection of SARS-CoV-2 in the heart is rare but
mechanism(s), the validity of these criteria is ques- reported; 27 among these highly selected cases, local-
tionable, as is the attribution to myocarditis (rather ization of SARS-CoV-2 has been confined principally
than to another noncoronary pathological process) of to interstitial cells or macrophages, rather than the
abnormalities detected. Additionally, a prospective cardiomyocytes. 18,28
multicenter cohort study of cardiac involvement in An alternative proposal is that SARS-CoV-2 infects
young athletes with COVID-19 revealed a low preva- the endothelial cells, which in turn mediates cellular
lence of cardiac involvement.21 In the study, only injury to the tissues supplied by the affected vascu-
12.6% of patients who were clinically indicated for lature. Endotheliitis, an inflammatory capillary injury
CMR were found to have findings that satisfied Lake with fibrin deposition and activation of the terminal
Louise criteria for myocarditis. CMR and endomyo- portion of the complement cascade, was histologi-
cardial biopsy were underused in these early patients, cally confirmed in autopsies of patients with COVID-
in part because of restrictions from infection control 19. 29 The investigators reported direct involvement of
measures, redeployment of staff, and lack of staff and SARS-CoV-2 in the endothelium in addition to the
equipment to justify these tests in infectious and proposed immune-mediated inflammation. However,
critically ill patients. Nevertheless, it is reasonable to the study did not address the pattern of tissue injury
suggest that even within the select group of patients beyond the endothelium (ie, the suggestion that
with COVID-19 with the clinical presentation of endotheliitis was responsible for local hypoxia and
myocarditis, radiologically or histologically confirmed tissue ischemia is speculative, as other plausible
myocarditis remains an uncommon diagnosis. causes of organ failure, including cytokine storm and
COVID-19-RELATED MYOCARDIAL INJURY: THE PROPOSED type I/II respiratory failure, cannot be negated).
MECHANISMS. Various mechanisms have been Another hypothesis is that SARS-CoV-2 causes
proposed for SARS-CoV-2-mediated cardiac injury: myocardial injury indirectly, as there is often a tem-
1) direct injury to cardiomyocytes; 2) direct damage poral delay between the cardiac presentations and
to endothelial cells and endotheliitis; 3) SARS-CoV-2 infection. 27,30,31 A handful of
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F I G U R E 1 Summary of the Proposed Mechanisms for Myocardial Cell Injury by SARS-CoV-2 Infection

Direct injury might be caused by cell entry via the angiotensin-converting enzyme 2 (ACE2) protein expressed naturally on cardiomyocytes or
endothelial cell damage (endotheliitis) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Indirect damage
might be brought on by the hypercoagulability state of coronavirus disease 2019 (COVID-19), which engenders microthrombus formation,
disrupting cardiac capillary flow or by means of T lymphocyte–mediated cytotoxicity as part of the phenomenon called cytokine storm. *Since
April 2021, there have been case reports of myocarditis and pericarditis following COVID-19 vaccination across all vaccine types, especially
in young male subjects. The mechanism remains unknown. IL ¼ interleukin.

mechanisms may be relevant and may coexist in some possible mechanism of myocardial injury secondary
patients, such as, venous thromboembolism, with to SARS-CoV-2 infection.
pulmonary embolism being an important cause of Nevertheless, the most likely pathophysiology for
adverse outcomes associated with COVID-19. 32 An SARS-CoV-2-related myocardial injury is based on a
autopsy report from Germany reported deep venous phenomenon known as cytokine storm. Proin-
thrombosis in 58% of patients (7 of 12) in whom flammatory cytokines, released by innate and adap-
venous thromboembolism was not suspected before tive immune cells, result in hyperactive and
death,13 and the incidence of alveolar capillary dysregulated immune responses. These responses are
microthrombi was significantly higher than following pleiotropic and complex but may include polarization
H1N1 influenza.12 Microthrombi have also been iden- toward cardiotropic CD4 and CD8 T cells and sup-
tified in the cardiac vasculature of patients with pression of T regulatory cells. Evidence supporting
COVID-19; nevertheless, the study lacks cardiac im- this hypothesis includes elevated proinflammatory
aging and clinical correlation to corroborate the cytokines, such as interleukin-6 and interferon-g in
postmortem findings, which may well be incidental patients with COVID-19,35 as well as documented
33
rather than causal of the myocardial injury. The cases of cytokine storm syndrome in severely ill in-
reasons for greater thrombosis risk in patients with patients. 36 Elevated interleukin-6, which was found
COVID-19, compared with other infectious diseases, to be one of the predictors of more rapid COVID-19
remain unknown. Additionally, it is unclear whether deterioration, may partly explain the acute and
the microthrombosis was due to the procoagulable long-term consequences of COVID-19, including
state of COVID-19 or the endothelial injury brought on myocardial inflammation, as it is known to be a
by SARS-CoV-2 or both. However, the high throm- mediator of the prothrombotic state, platelet func-
bosis burden among patients with COVID-19 may tion, and antibody production. 37 Other interleukins
predispose them to poorer health outcomes, espe- may also be involved in acute heart failure and
cially in patients with concurrent ST-segment eleva- myocarditis. For instance, intense NOD-, LRR-, and
tion myocardial infarction.34 Figure 1 summarizes the pyrin domain-containing protein 3 inflammasome
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F I G U R E 2 Acute Cardiac Injury in Coronavirus Disease 2019

In the acute setting, both direct (viral) and indirect (immune-mediated) damage to the myocardial and other heart tissues can give rise to
perimyocarditis or myocarditis. Moreover, endothelial tissue injury, by means of endotheliitis and microthrombus formation, leads to type 2
myocardial infarction. TF ¼ tissue factor; TNF-a ¼ tumor necrosis factor-a; other abbreviations as in Figure 1.
6 Siripanthong et al JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2021
Long-Term Consequences of COVID-19 Cardiac Injury - 2021:-–-

formation in the heart is observed in myocarditis, inotropes or vasopressors to improve perfusion. If

producing the proinflammatory cytokine interleukin- these modalities are insufficient to overcome shock or
1 which exacerbates the myocardial injury. 38 Figure 2 normalize cardiac filling pressures, temporary me-
shows the proposed molecular mechanism for the chanical circulatory support may be required with an
indirect and indirect myocardial injury due to SARS- intra-aortic balloon pump, a percutaneous left ven-
CoV-2. tricular assist device, or extracorporeal membrane
CLINICAL CHARACTERISTICS OF THE REPORTED oxygenation.56 In patients with severe COVID-19
CASES OF SARS-CoV-2-RELATED MYOCARDITIS. pneumonia, often with signs of systemic infection,
The clinical presentation of SARS-CoV-2-related immunomodulatory treatments may be given to
myocarditis is, in general, highly variable and alleviate the respiratory symptoms. These include
nonspecific, partly because of a lack of definitive in- corticosteroids (eg, dexamethasone) and anti-
vestigations discussed under “Background.” The re- interleukin-6 receptor monoclonal antibodies (eg,
ported presenting symptoms range from relatively tocilizumab, sarilumab). Tocilizumab was shown in
mild (eg, fatigue and dyspnea) 39-42 to more severe the RECOVERY (Randomised Evaluation of COVID-19
(eg, chest pain on exertion and hemodynamic insta- Therapy) trial to be effective at improving survival
bility). 43-45 However, even in cases in which and clinical outcomes in patients with COVID-19 with
myocarditis is eventually confirmed, presenting hypoxia and systemic inflammation.57 Both the US
symptoms may not be cardiac specific. 46
In general, and UK guidelines recommend tocilizumab for pa-
the cardiac disease was suspected when abnormal tients with COVID-19 with hypoxia requiring venti-
electrocardiographic changes and elevated troponins latory support or high-flow nasal oxygen. 58,59
were identified, even when the patients had minimal Moreover, tocilizumab, at the dose recommended
cardiac symptoms at presentation.44,47 Conversely, (8 mg/kg intravenously, up to 800 mg), was success-
some patients without overt cardiac symptoms at fully used as a part of management for a patient with
presentation have gone on to develop acute heart COVID-19 with acute heart failure. 60 There have been
failure and cardiogenic shock, 48
demonstrating how some anecdotal reports in favor of interleukin-1 an-
variable COVID-19 myocarditis can be over the dura- tagonists (eg, anakinra) in myocarditis, recurrent
tion of illness. pericarditis, and heart failure, although not in the
In the most severe presentation, patients have context of COVID-19. 38,61 Corticosteroid treatment is a
developed fulminant myocarditis, defined as acute mainstay in the management of severe COVID-19;
ventricular dysfunction and heart failure within 2 to however, its use may complicate viral myocardial
3 weeks of contracting the virus. 49-53
Although most injury in the early phases when active inflammation is
of these patients are young and recovered fully after required to clear the pathogen. Acute management
pharmacologic management, some patients pro- modalities so far reported for COVID-19-related
gressed to require durable mechanical circulatory myocarditis are summarized in Supplemental Table 2.
support in response to persistent severe ventricular Long-term management is more complex, though
dysfunction. 54
Because of the nonspecificity of few patients thus far have had such severe persistent
COVID-19-related myocarditis reported to date, other disease as to require durable left ventricular assist
diagnoses should also be considered and a clear support or heart transplantation. Nevertheless, pa-
diagnostic algorithm used. 22
The clinical characteris- tients with persistent severe left ventricular systolic
tics of reported cases of COVID-19-related myocarditis dysfunction should be optimized on goal-directed
(as of September 2021) are summarized in medical therapy. This includes beta-blockers, angio-
Supplemental Table 1. tensin receptor-neprilysin inhibitors, mineralocorti-
coid receptor antagonists, and even sodium-glucose
MANAGEMENT. Management of the cardiac compli- cotransporter 2 inhibitors, though the direct benefit
cations of COVID-19 is still contentious. The general of any of these therapies after COVID-19 myocarditis
principle is to establish hemodynamic stability in a is only inferred from other populations with heart
stepwise manner, escalating to match the patient’s failure.
clinical needs. Detailed suggested management algo-
rithms can be found in other papers;22,55 however, we LONG-TERM CONSEQUENCES OF
aim to provide an update to this with our current un- COVID-19-RELATED INJURY AND MYOCARDITIS
derstanding of the disease and additional evidence
since reported regarding the long-term consequences. CLINICAL OUTCOMES OF COVID-19-RELATED
In short, patients presenting acutely with cardio- MYOCARDITIS. Most surviving patients with
genic shock or severe hypotension may require myocarditis have achieved full or significant recovery
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- 2021:-–- Long-Term Consequences of COVID-19 Cardiac Injury

of their systolic function. However, a small minority LONG-TERM EFFECTS ON THE HEART. In the setting
experienced catastrophic consequences, which ulti- of COVID-19, myocarditis and cardiac myocyte dam-
mately led to death. A search of published studies age can lead to residual morphologic and functional
(MEDLINE, PubMed Central, and NCBI Bookshelf) impact on the myocardium (Figure 4), particularly in
identified 77 case reports of SARS-CoV-2-related those with preexisting cardiac disease. Optimal
myocarditis published by the end of September assessment of long-term outcomes of COVID-19-
2021. In 1 case report, ventricular fibrillation was the related cardiac injury, whether myocarditis or other
cause of death, representing 1 of 10 deaths overall in injury, requires regular follow-up with clinical
the 77 cases reviewed.44 In 3 patients who made a full investigation, cardiac arrhythmia monitoring, and
recovery, new-onset arrhythmias developed (2 com- multimodality imaging. Thus far, however, there are
plete atrioventricular block and 1 atrial fibrilla- very few studies assessing the long-term effects and
tion).50,62,81 In 1 case, the patient developed septic complications after recovery from COVID-19-
shock and disseminated intravascular coagulation.64 mediated myocarditis. 22,72 In a study from Germany,
One patient had a stroke several days after being patients recently recovered from COVID-19 had lower
discharged in stable condition following a myocar- left ventricular ejection fraction, higher left ventric-
ditis episode.65 Other milder complications include ular volumes, and higher native T1 (suggestive of
reduced exercise tolerance and persistent reduction myocardial interstitial fibrosis 73) and T2 (suggestive
in systolic ejection fraction. 66,67
A full summary of the of myocardial edema 74) values compared with
77 case reports can be found in Supplemental Table 1. healthy control subjects and risk factor–matched
POST-COVID-19 SYNDROME. There is a distinct lack control subjects.17 Abnormal CMR findings were pre-
of data on the long-term sequelae and prognosis sent in 78% of patients and ongoing myocardial
following SARS-CoV-2-related myocardial injury and inflammation in 60%. Native T1 and T2 mapping
myocarditis, although a fuller picture is beginning to provided the best discriminatory ability to detect
emerge via observational case reports. Understand- COVID-19-associated myocardial disease. These find-
ably, the main focus of the medical response to the ings correlated with higher levels of high-sensitivity
pandemic has been on early recognition and treat- troponin T and active lymphocytic inflammation on
ment to reduce systemic inflammatory response and endomyocardial biopsy specimens. 17 In summary,
prevent multiorgan failure and multiorgan this study also highlights that myocardial inflamma-
dysfunction syndrome. A principle-based approach tion can be observed radiologically (on CMR) in pa-
on managing post-COVID-19 syndrome68 was based tients recovering from COVID-19, in both
on the experiences of critical care patients who asymptomatic and symptomatic patients.75
survived sepsis, the postsepsis syndrome. Postsepsis The long-term cardiac consequences of COVID-19
syndrome is well reported and seen in up to 50% of may also be dependent on the severity of initial
sepsis cases managed on critical care,69 but little is COVID-19 itself. A recent study of health workers
known about the frequency of post-COVID-19 syn- seropositive for SARS-CoV-2 and either mild or no
drome. Proposed mechanisms first require intro- symptoms detected no differences in the CMR find-
ducing a compensatory anti-inflammatory response ings or cardiac biomarkers (ie, N-terminal pro–B-type
syndrome.70 It is postulated that a systemic in- natriuretic peptide and troponin) between 74 positive
flammatory response with cytokine storm is and 75 matched seronegative participants. 76
balanced by the compensatory anti-inflammatory One multicenter study involved 148 COVID-19
response syndrome to prevent widespread multi- survivors with elevated troponin who underwent
organ dysfunction. Patients who may have a milder CMR after a median of 68 days (range: 30-103 days)
earlier phase of illness can enter persistent inflam- following hospital discharge. 11 The investigators re-
mation, immunosuppression, and catabolism syn- ported a myocarditis-like LGE pattern in 26% (39 of
drome, which is a hypothesized cause of persistent 148), evidence of occlusive coronary disease (MI-
post-COVID-19 syndrome. There have also been re- pattern LGE and/or abnormal stress perfusion) in 22%
ports of latent virus reactivation of SARS-COV-2 in (32 of 148), and dual pathology in 6% (9 of 148).
recovered patients with COVID-19. These patients Myocardial injury was limited to #3 of the 17 Amer-
can then develop various post-COVID-19 manifesta- ican Heart Association segments, and there was no
tions, including pulmonary fibrosis, with trans- measurable impact on left ventricular ejection frac-
forming growth factor–beta implicated as a key tion. Neither peak nor admission serum troponin was
factor. Transforming growth factor–beta is a known predictive of a diagnosis of myocarditis; of the 39
inducer of fibrosis and immunosuppres- patients with myocarditis-like LGE patterns, 8 (20%)
sion 71 (Figure 3). also had elevated native T1 and T2 values indicative
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F I G U R E 3 Timeline of the Immune Response to COVID-19

The diagram shows the proposed immunologic reaction to SARS-CoV-2 infection, in which the proinflammatory response predominates in the acute phase, which could
culminate in acute respiratory response syndrome (ARDS), multisystem inflammatory syndrome (MIS), or systemic inflammatory response syndrome (SIRS). Should
there be no counterbalancing anti-inflammatory response, these syndromes could lead to multiorgan failure (MOF) or multiorgan dysfunction (MOD) and/or death. With
adequate counteracting anti-inflammatory cytokines produced, the body is in the immune-suppressed phase, a process called compensatory anti-inflammatory
response syndrome (CARS). With prolonged immune suppression, persistent infection can occur (ie, in the form of persistent inflammation, immunosuppression, and
catabolism syndrome [PICS] or persistent post-COVID-19 syndrome [PPCS]). Abbreviations as in Figure 1.

of myocardial edema. In the absence of pre-COVID-19 and a low risk for cardiac events in short-term follow-
imaging, determining antecedence and prior up among young competitive athletes. Applying the
myocardial scar or structural abnormalities is diffi- current evidence, athletes with COVID-19-related
cult, despite the use of matched non-COVID-19 con- cardiac disease should be screened for cardiovascu-
trol subjects and healthy control subjects.77 lar abnormality as per each sport’s regulatory guide-
In a US study of 26 competitive athletes recovering line. CMR is recommended only when initial
from COVID-19, 4 male athletes (15%) had CMR find- screenings reveal significant abnormalities, and those
ings suggestive of myocarditis on the basis of the who clear the screening tests and/or CMR imaging
Lake Louise criteria. 75 Twelve athletes (46%) had should be able to return to play safely.
myocardial LGE (mean of 2 of the 17 American Heart Electrocardiographic and cardiac conduction ab-
Association segments), of whom 8 (30.8%) had LGE normalities are not uncommon among recovered pa-
without concomitant T2 elevation. However, this was tients with COVID-19 who had moderate to severe
a small study, and it is unclear whether these CMR disease during their acute illness. Liu et al79 reported
changes predated these patients’ COVID-19 illness. A that among 486 Chinese patients with COVID-19 fol-
recent multicenter cohort study of nearly 789 pro- lowed at 3, 6, and 12 months postdischarge, arrhyth-
fessional athletes referred for CMR according to the mias were present in 12.4%, 7.6%, and 16.3%,
American College of Cardiology’s return-to-play respectively. However, it is unclear how many of
guideline found that only 5 athletes (0.6%) ulti- these abnormal electrocardiographic findings pre-
mately had CMR findings suggestive of inflammatory dated these patients’ COVID-19 illness and, more
heart disease (myocarditis in 3 and pericarditis in 2) important, which of these resulted from COVID-19.
that resulted in restriction from play.78 Another pro- Among the cases of COVID-19-related myocarditis
spective multicenter observational cohort study with reviewed, however, the majority of new-onset ar-
data from 42 colleges and universities from the rhythmias resolved spontaneously before
United States identified SARS-COV-2 cardiac discharge 50,80 and rarely required a treatment. 63,81
involvement in 21 of 3,018 athletes (0.7%). 21 During a The true long-term arrhythmic burdens arising from
median clinical surveillance period of 113 days, no COVID-19 are likely clarified in large population-
COVID-19-related adverse cardiac events occurred, based prospective studies focusing on cardiovascu-
confirming a low prevalence of cardiac involvement lar monitoring 82 (Central Illustration).
JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2021 Siripanthong et al 9
- 2021:-–- Long-Term Consequences of COVID-19 Cardiac Injury

F I G U R E 4 Chronic Consequences of COVID-19 Infection on the Heart

Most patients with cardiac involvement do fully recover, either with or without scarring (as evident in some follow-up studies). Some patients
with persistent infection can develop post-COVID-19 syndrome. The cardiac presentation of this includes pericardial effusion, perimyocarditis
(early) or myocardial edema, embolism, and interstitial fibrosis with heart failure with preserved ejection fraction (HFpEF) (late). Abbreviations
as in Figure 1.

MYOCARDITIS AND PERICARDITIS AFTER of July 3, 2021, with more than 177 million people who
COVID-19 VACCINATION received at least 1 dose of COVID-19 vaccine in the
United States,83 the Vaccine Adverse Event Reporting
Recently, several cases of myocarditis-like illness in System received 780 reports of myocarditis or peri-
COVID-19 vaccine recipients have been reported. As carditis among people aged #30 years, with most
10 Siripanthong et al JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2021
Long-Term Consequences of COVID-19 Cardiac Injury - 2021:-–-

C E N T R A L IL L U ST R A T I O N Long-Term Consequences of Coronavirus Disease 2019–Related

Myocarditis Affecting the Structure and Function of the Heart

Siripanthong, B. et al. J Am Coll Cardiol Basic Trans Science. 2021;-(-):-–-.

Some persistent structural abnormalities, including on T1 and T2 sequences on cardiovascular magnetic resonance, were noted in asymp-
tomatic patients, indicating fibrosis and myocardial edema. Ongoing myocardial inflammation as shown by late gadolinium enhancement was
also observed in recovered patients. A number of patients with healed myocarditis also showed reduced left ventricular (LV) ejection fraction
and increased LV volume long after the episode. Functionally, in a small number of patients, new-onset arrhythmias, including atrial
fibrillation and complete heart block, occurred. Concerns regarding myocardial fitness remain to be addressed, especially in young adult
athletes considering return to play.

cases being reported after messenger ribonucleic acid medications. Mean length of hospital stay was 3  1
COVID-19 vaccination, particularly in male adoles- days, and symptoms had resolved in all patients by
cents and young adults. As of the end of May 2021, in hospital discharge. Despite the temporal association
the European Economic Area, the exposure was about with COVID-19 vaccination, causality of myocarditis
221 million doses of COVID-19 vaccine, and cases of in these patients cannot be assumed.
myocarditis and pericarditis reported from the Data from the US military health system 85 showed
EudraVigilance database were 176 and 192, respec- that the incidence of myocarditis among those who
tively.84 These events have been reported with all 3 of were fully vaccinated by the organization did not
the US Food and Drug Administration–approved exceed the expected incidence of myocarditis (w20
vaccines: messenger ribonucleic acid (Moderna and cases per 1,065,000). However, those affected are all
Pfizer/BioNTech) and adenovirus (Janssen, Johnson & male, with a median age of 25 years, and all received
Johnson). In a series of 7 adult patients presenting messenger ribonucleic acid–based vaccines (Pfizer/
with myocarditis-like illness temporarily associated BioNTech or Moderna). Among the fully vaccinated
with COVID-19 vaccination, CMR between 3 and male military members, the incidence of myocarditis
37 days showed multifocal subepicardial LGE in all 7 is significantly greater than the expected background
patients and additional midmyocardial LGE in 4 of 7 level (19 vs 8 per 436,000). Another large study
patients. Corresponding myocardial edema was among 2,000,287 individuals 86 who received at least
detected in 3 of 7 patients. Treatment varied and a single dose of COVID-19 vaccine (52.6% Pfizer/Bio-
included beta-blockers and anti-inflammatory NTech, 44.1% Moderna, and 3.1% Johnson & Johnson)
JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2021 Siripanthong et al 11
- 2021:-–- Long-Term Consequences of COVID-19 Cardiac Injury

revealed 20 cases of myocarditis (11 after Moderna, 9 using an implantable loop recorder and stress echo-
after Pfizer/BioNTech) a median of 3.5 days after cardiography in adult athletes, who are at least
vaccination. The majority of these patients were men 1 month after diagnosis of COVID-19. This study is
(15 of 20), with a median age of 36 years. Neverthe- particularly important in the context of the available
less, a higher incidence of myocarditis after COVID-19 knowledge, suggesting that monomorphic ventricular
vaccination was reported in Israel,87 especially after arrhythmias are frequent after recovery from the
the second dose. Compared with unvaccinated in- acute phase of myocarditis caused by other viral
dividuals, the rate ratio of myocarditis in the antigens.89,90
following 30 days after the second dose of the Pfizer/ Another study (NCT04794062) aims to perform
BioNTech vaccine was 2.35. Strikingly, among the repeat CMR with contrast enhancement at 6 months
highest risk demographic (male, 16-19 years of age), of dynamic follow-up in participants with established
the rate ratio is 8.96 compared with the unvaccinated, COVID-19-related myocardial injury at inclusion to
which translates into 1 case in 6,637 second vaccina- assess the percentage of participants with ongoing
tions (0.015%). This still compares favorably with the myocardial injury. The CO-Qo-ICU (One-Year Out-
incidence of myocarditis in patients with COVID-19 comes in Survivors of the Severe COVID-19 Pneu-
across all age groups (0.146%).20 Immunophenotyp- monia) study (NCT04401111), whose aim is to study
ing studies investigating potential mechanisms of 1-year outcomes in survivors of severe COVID-19
vaccine-associated myocardial injury are necessary to pneumonia, will study echocardiographic parame-
determine whether populations at higher risk for this ters of right and left ventricular function during the
potential outcome exist. Systematic evaluation of first year after intensive care unit discharge. The
patients who develop chest pain and/or fever should MOIST (Multi-Organ Imaging With Serial Testing in
be conducted with timing of doses and symptoms COVID-19 Infected Patients) study (NCT04525404)
noted to demonstrate temporal antecedence. will enroll participants with newly or recently
On the basis of the limited evidence to date, the diagnosed COVID-19 infection (inpatients and out-
rate of COVID-19 vaccine–associated myocarditis-like patients), who will undergo multiorgan magnetic
illness appears low overall in comparison with doses resonance imaging (heart, brain, lungs, liver), blood
administered, and its clinical course favorable, with work, and functional testing at 1 or more time points.
resolution of symptoms in all patients reported thus These studies will hopefully elucidate the puzzling
far. We are not aware of studies suggesting that issue of COVID-19-related myocardial injury and
vaccine-related myocarditis is associated with inflammation and aid in understanding its potential
increased an risk for death or heart failure. Moreover, long-term consequences.91
most studies are based on imaging findings, with no With the increased diagnosis of new COVID-19
clear clinical correlation or concrete endpoints.85,86 subtypes, our appreciation of cardiac involvement in
COVID-19 and its long-term consequences may
FUTURE DIRECTIONS change over time. Currently, it is unknown if the
myocardial damage and inflammation caused by new
Despite the wealth of data regarding COVID-19 car- COVID-19 subtypes are any different from the accu-
diac involvement hitherto reported, more informa- mulated knowledge. Whether a combination of viral
tion must be curated over a much longer period and subtypes can cause a more severe disease presenta-
in a systematic manner to allow us to fully appreciate tion, and whether such cases will have significantly
the full spectrum and prevalence of long-term cardiac more myocardial inflammation or damage, remains
consequences of COVID-19. A number of clinical trials unknown and should be investigated in future
have been initiated to collect the cardiovascular pa- studies.
rameters in post-COVID-19 patients using a variety of The logistical difficulties associated with acute
inclusion criteria. Several recently launched studies evaluation and follow-up using multimodality imag-
aim to use CMR and/or computed tomography, ing and/or endomyocardial biopsy present consider-
including cardiac functional evaluation and myocar- able obstacles to prospective studies. Furthermore,
dial tissue characterization, to assess the long-term the inclusion of only hospitalized patients in studies
outcome of COVID-19-related cardiac disease in adds a potentially profound source of bias, particu-
adult and pediatric patients.88 The CoViDEx (Effect of larly as it remains far from certain that the myocardial
COVID-19 (Coronavirusdisease-19) and Exercise on consequences of SARS-CoV-2-infection are associated
Myocardial Fibrosis and Ventricular Arrhythmias) with the severity of the acute illness. Some sources of
study (NCT04726150) is investigating the association inclusion bias may be addressed by the use of
of myocardial fibrosis and ventricular arrhythmias biobank-based studies. Biobanks are a type of
12 Siripanthong et al JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2021
Long-Term Consequences of COVID-19 Cardiac Injury - 2021:-–-

biorepository in which biological samples from infection. 11 Furthermore, the classic cellular distinc-
participating volunteers are stored for research use. tions of myocardial inflammation have thus far not
The value of biobanks may overcome the knowledge been reproduced in the few autopsy and biopsy re-
gaps in COVID-19-related cardiac disease because of ports. Studies have largely focused on left ventricular
their scale and wider participation from both in- function, but right ventricular function, ventricular
patients and outpatients. The UK Biobank, for thrombus and thromboembolic risk, arrhythmia, 95-97
example, has rapidly tackled the global pandemic by and autonomic dysfunction,98 are clinically
undertaking several major initiatives, including the apparent within this patient group and should also be
COVID-19 repeat imaging study, which aims to systematically evaluated.
perform repeat CMR in 3,000 subjects. 92
CONCLUSIONS
Large-scale investigations planned by Public
Health England through the Post-Hospitalisation
Myocardial involvement in SARS-CoV-2-mediated
COVID-19 national consortium (with its 2 magnetic
disease is a consequence of multiple pathophysio-
resonance imaging substudies, C-MORE and COVER-
logical mechanisms, including severe hypoxia-
SCAN) 93 and several other biobanks around the world
mediated injury, thromboembolic disease, systemic
have also started to collate data and to make available
inflammatory response, and direct myocardial
health information regarding COVID-19 from partici-
inflammation. Studies of human engineered heart
pating patients. 92
tissues confirm that SARS-CoV-2 can directly infect
The first holistic data of post–hospital discharge
cardiac myocytes, causing cytokine production and
patients with COVID-19 showed medium-term effects
cardiomyocyte death. Rigorous analyses of cardiac
of SARS-CoV-2 infection on multiple vital organs,
tissue obtained from affected patients are limited,
exercise tolerance, and mental, cognitive, and phys-
and most knowledge of myocardial inflammation in
ical health in a significant proportion of patients with
COVID-19 is based on autopsy findings that have
long-haul symptoms. Notably, serum biomarkers of
limited value for prognostication in patients with
inflammation and severity of acute illness correlated
mild or moderate COVID-19. Although full recovery
with magnetic resonance imaging evidence of multi-
with good short-term outcomes have been reported
organ abnormalities (including native T1 values of the
in small case series of fulminant COVID-19 myocar-
myocardium) and reduced exercise tolerance.94
ditis, persistent inflammation with resulting
Future initiatives, including the use of follow-up
myocardial damage with or without residual symp-
questionnaires assessing the physical and mental
toms is also possible in patients with supposed
health of recovered patients with COVID-19, will go a
“recovery” from acute COVID-19. Patients with
long way toward helping discover other long-term
COVID-19-associated new-onset myocardial dysfunc-
consequences of the disease, which may be elusive
tion and inflammation or scarring on CMR might be
to small single- and multicenter studies. It is from
at increased risk for heart failure or re-entrant ar-
these datasets that clinicians can obtain a holistic,
rhythmias. Myocarditis following COVID-19 vaccina-
integrated, multidisciplinary picture of COVID-19
tion remains rare, and to date, no conclusive proof of
sequelae, including from its associated myocarditis.
causality is available. Regular follow-up with clinical
Nevertheless, to study myocardial disease, it is
examination, arrhythmia monitoring, and serial im-
crucial to use standardized cardiac imaging, such as
aging studies is therefore warranted in patients with
CMR protocols with consistent-strength scanners,
significant acute myocardial damage related to
including gadolinium contrast–based enhancement
COVID-19.
and multiparametric myocardial mapping (eg, native
T1 and T2). However, the reliance on CMR-based di- FUNDING SUPPORT AND AUTHOR DISCLOSURES
agnostics for the stratification of myocardial
involvement is also a limitation; for instance, dis- Dr Nazarian has received grants from the National Institutes of
Health, ImriCor, Biosense Webster, and ADAS; and is a consultant to
tinguishing endotheliitis, microvascular obstruction,
CardioSolv and ImroCor. All other authors have reported that they
type 1 or 2 MI, inflammatory-pattern injury, and new have no relationships relevant to the contents of this paper to
or old myocardial injury can be challenging, and the disclose.

specificity of these techniques has not been validated

for SARS-CoV-2-related myocardial injury, let alone in ADDRESS FOR CORRESPONDENCE: Dr C. Anwar A.
other groups of patients. The sensitivity of CMR- Chahal, WellSpan Center for Inherited Cardiovascular
based detection of myocardial injury also remains a Diseases, WellSpan Health, 140 North Pointe Boule-
concern; abnormal LGE was detected in only half of vard, Lancaster, Pennsylvania 17601, USA. E-mail:
troponin-positive patients with SARS-CoV-2 drachahal@doctors.org.uk.
JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. -, NO. -, 2021 Siripanthong et al 13
- 2021:-–- Long-Term Consequences of COVID-19 Cardiac Injury

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KEY WORDS athlete, cardiovascular
Medium-term effects of SARS-CoV-2 infection on coronavirus disease 2019: a case series of 3 pa-
magnetic resonance imaging, COVID-19,
multiple vital organs, exercise capacity, cogni- tients infected with SARS-CoV-2. HeartRhythm
inflammation, myocardial injury, myocarditis,
tion, quality of life and mental health, post- Case Rep. 2020;6:652–656.
sudden cardiac death, troponin
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