If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Address for Correspondence:D. Ian Paterson, Division of Cardiology, University of Ottawa Heart Institute 40 Ruskin Street - Ottawa, Ontario, Canada K1Y 4W740 Ruskin Street - Ottawa, Ontario, Canada K1Y 4W7
Following the first confirmed case in 2019, coronavirus disease (COVID)-19 rapidly spread worldwide and overwhelmed the medical community. In the intervening time, we have learned about COVID-19’s clinical manifestations and have developed effective therapies and preventative vaccines. Severe COVID-19 infection is associated with many cardiovascular disorders in the acute phase and patients with recovered illness can also manifest long-term sequelae, including long-COVID syndrome. Furthermore, severe acute respiratory syndrome– related coronavirus-2 messenger RNA (mRNA) vaccination can trigger rare cases of myopericarditis.
We have gained significant knowledge of the acute and long-term cardiovascular complications of COVID-19 and mRNA vaccine associated myocarditis through clinical and investigative studies using cardiac imaging. In this review, we will describe how cardiovascular imaging can be used to understand the cardiovascular complications and cardiac injury associated with acute COVID-19 infection, we will review the imaging findings in patients with recovered illness and we will discuss the role and limitations of cardiac imaging in COVID-19 mRNA vaccine associated myocarditis.
Severe acute respiratory syndrome– related coronavirus-2 (SARS-CoV-2) is a member of the coronavirus family, which are enveloped, positive-strand RNA viruses. Coronavirus disease (COVID)-19 arises from the binding of viral spike proteins to host angiotensin-converting enzyme-2 (ACE-2) receptors which are highly expressed in the lungs, heart and vasculature. Thus, cardiovascular disease arising from COVID-19 illness is a potentially important clinical concern. Indeed, myocardial injury during acute illness is associated with increased risk of death and other adverse outcomes
Raisi-Estabragh Z, Cooper J, Salih A, Raman B, Lee AM, Neubauer S, et al. Cardiovascular disease and mortality sequelae of COVID-19 in the UK Biobank. Heart Br Card Soc. 2022;heartjnl-2022-321492.
. A poor understanding of the mechanisms governing the cardiac complications in COVID-19 has resulted in a lack of consensus on effective management strategies.
The role of cardiac imaging has evolved during the pandemic. Echocardiography was initially used to characterize cardiac function in patients with severe, acute illness with or without myocardial injury. Its role subsequently expanded to include the evaluation of persistent or de novo cardiac symptoms in patients with recovered COVID-19. Cardiac magnetic resonance imaging (CMRI) has often been used clinically to complement echocardiography, particularly when a non-ischemic injury is suspected. This modality allows cardiac tissue characterization and facilitates the detection of myocardial scar and/or edema using contrast enhanced and non-contrast techniques. More recently, CMRI has also been used to diagnose mRNA vaccine related myocarditis given that it is the recommended imaging modality in community acquired cases
. Cardiac computed tomography and nuclear imaging have also been used to diagnose suspected myocardial ischemia, particularly when coronary angiography is not possible. Collectively, these imaging modalities have provided significant phenotyping of cardiac structure and function during COVID-19 illness. There is also emerging imaging data on important extra-cardiac effects including adverse changes to vascular function. In this review, we will discuss imaging findings during (i) acute COVID-19 illness, (ii) in the recovery phase, including those patients with long-COVID syndrome, as well as in (iii) mRNA vaccine associated myocarditis. Finally, we will suggest an approach to cardiac imaging utilization in COVID-19.
The Role of cardiovascular imaging in acute COVID-19
Cardiovascular complications and cardiac injury due to COVID-19
Early reports during the pandemic, described cardiac injury, typically troponin elevation, in up to 45% of infected individuals
Cardiac injury is associated with severe outcome and death in patients with Coronavirus disease 2019 (COVID-19) infection: A systematic review and meta-analysis of observational studies.
. COVID-19 related cardiac injury has been attributed to several cardiovascular pathologies including myocarditis, myocardial ischemia or infarction, heart failure, arrhythmias and arterial or venous thromboembolism. Proposed mechanisms of injury include direct viral invasion of cardiomyocytes or vascular endothelium, secondary myocardial injury from systemic inflammation and cytokine storm, hypoxemia related supply-demand mismatch and vascular injury with coagulopathy
. As it can be challenging to determine the exact etiology of cardiac injury, non-invasive cardiac imaging, is often used to complement clinical data and baseline cardiac testing (see case examples in Figure 1).
Figure 1Spectrum of Cardiac Injury in Acute COVID-19. Top row. Cardiogenic shock. 32-year-old, unvaccinated female who presented with fever, myalgias, chest pain and dyspnea, 2 days after testing positive for COVID-19. Her Troponin I was elevated at 1262ng/L (normal <30ng/L). Her ECG showed diffuse ST segment elevation with ST depression in aVR. She was hemodynamically unstable, in cardiogenic shock, with severe LV dysfunction on echocardiography (A, video 1). Endomyocardial biopsy did not show evidence of active myocarditis. Subsequent CMRI at 3 weeks demonstrated improved cardiac function (B, video 2), no edema on T1 mapping (C) and pericardial enhancement on late gadolinium enhancement imaging (D). Middle Row. Myocardial infarction. 74-year-old male presenting after a fall. He tested positive for COVID-19 and had an increased Troponin T at 581ng/L (normal <15ng/L), peaking at 1967ng/L. An echocardiogram and CMRI demonstrated moderate LV dysfunction with basal-to-apical inferior, inferolateral and inferoseptal wall motion abnormality (E, video 3 and F, video 4). CMRI suggested inferoseptal edema on T1 mapping (blue arrow) and confirmed a moderate subendocardial inferior and inferolateral infarct on LGE imaging (green arrows). There was no evidence of myocarditis. His invasive coronary angiogram revealed significant 3-vessel coronary artery disease and he was referred for coronary artery bypass grafting. Lower Panel. Takotsubo cardiomyopathy. 49-year-old female presenting with acute diarrhea illness and flash pulmonary edema after fluid resuscitation. Her Troponin T was elevated at 174ng/L (normal <15ng/L) and she tested positive for COVID-19. An echocardiogram found severe left ventricular dysfunction (I, video 5). CMRI found mid ventricular akinesis with relative apical and basal sparing (J, video 6). Myocardial edema was present in the apical and mid ventricular segments on T1 mapping (blue arrows), and no myocardial scar was detected on LGE imaging. (See also video files)
Detection of viruses in myocardial tissues by polymerase chain reaction. evidence of adenovirus as a common cause of myocarditis in children and adults.
, acute myocarditis is a recognized complication of COVID-19 infection. The 2022 ACC/AHA Task Force on Clinical Data Standards defines COVID-19-associated myocarditis as acute myocardial injury with clinical, imaging and pathology evidence supporting inflammation and myocarditis in a patient with probable or confirmed infection
Bozkurt B, Das SR, Addison D, Gupta A, Jneid H, Khan SS, et al. 2022 AHA/ACC Key Data Elements and Definitions for Cardiovascular and Noncardiovascular Complications of COVID-19: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards. Circ Cardiovasc Qual Outcomes. 2022;15:e000111.
. Since endomyocardial biopsy may not be widely available or feasible, imaging, primarily CMRI, plays an important role in diagnosing acute myocarditis. In a multicentre, retrospective analysis of over 50,000 patients hospitalized with COVID-19, the prevalence of myocarditis was 2.4-4.1 per 1000 according to imaging and/or pathologic criteria
. Of these cases, 39% experienced a fulminant presentation, and 6% died within 120 days of presentation. However, none of the deaths were due to cardiac causes.
Given its availability and portability, transthoracic echocardiography (TTE) is used as the initial imaging modality in patients with suspected COVID-19 myocarditis. Left or biventricular dysfunction, abnormal strain, ventricular hypertrophy, and pericardial effusion can all be seen on TTE in COVID-19 myocarditis, but these findings are non-specific. A systematic review of 38 patients hospitalized for COVID-19 myocarditis described substantial heterogeneity with respect to clinical presentation and imaging findings
. In their review, 27 out of 34 cases had non-specific abnormalities on TTE, including increased wall thickness or global or regional hypokinesia. In larger studies of COVID-19 myocarditis
, the median left ventricular ejection fraction (LVEF) during the acute illness was 41%, and subsequently improved to 60% during follow-up (median 88 days). Moreover, tricuspid annular plane systolic excursion (TAPSE) was reduced in 30% of participants, suggesting right ventricular involvement. The TAPSE also normalized in all participants at follow-up.
Cardiac magnetic resonance imaging is the preferred imaging modality for myocarditis as its myocardial tissue characterization through T1 and T2 imaging identifies disease with high diagnostic accuracy according to the modified Lake Louise Criteria (LLC)
, all 25 patients undergoing CMRI had at least one finding for myocarditis, including myocardial edema on T2 weighted imaging or non-ischemic scar on late gadolinium enhancement (LGE) imaging. CMRI also significantly improves the detection of COVID-19 myocarditis in an ambulatory setting. In a cohort of 1597 American collegiate athletes with COVID-19 infection, the prevalence of myocarditis using symptom-directed screening was 0.31%. However, routine assessment with CMRI yielded a 7.4-fold increase in the detection of myocarditis
Prevalence of Clinical and Subclinical Myocarditis in Competitive Athletes With Recent SARS-CoV-2 Infection: Results From the Big Ten COVID-19 Cardiac Registry.
. In this cohort, 31/37 patients fulfilled criteria for myocarditis on CMRI and an additional 6 had symptoms and/or minor CMRI features of the disease. Follow-up CMRI was performed in 27/37 at a mean of 9.4 weeks from COVID positivity. On follow-up imaging myocardial edema had resolved in all participants, however 59% of affected patients had persistent LGE. Of the 3 with reduced LVEF at baseline, only 1 had follow-up imaging, which demonstrated recovered cardiac function. When CMRI findings of COVID-19 myocarditis are directly compared to other non-COVID-19 viral myocarditis, myocardial edema is less evident and thus fewer patients fulfill diagnostic criteria
Differences in Cardiac Magnetic Resonance Imaging Markers Between Patients With COVID-19-associated Myocardial Injury and Patients With Clinically Suspected Myocarditis.
. A study by Fronza et al. compared CMRI findings in patients with COVID-19 myocarditis to other causes of myocarditis and mRNA vaccine associated myocarditis
. Overall, they found a similar pattern of myocardial injury on CMRI in all three groups, though patients with vaccine-associated myocarditis had a higher LVEF and less extensive scar on LGE imaging, even after controlling for age, sex, and time from symptom onset to MRI. The findings of these studies are summarized in Table 1.
Table 1Summary of two studies comparing cardiac magnetic resonance imaging findings of COVID-myocarditis, other causes of myocarditis and mRNA vaccine myocarditis.
Differences in Cardiac Magnetic Resonance Imaging Markers Between Patients With COVID-19-associated Myocardial Injury and Patients With Clinically Suspected Myocarditis.
Cardiac computed tomography (CT) is another imaging method that has been used to evaluate COVID-19 myocarditis. Non-contrast chest CT is widely used to characterize pulmonary disease in patients hospitalized for COVID-19. In patients with suspected myocardial injury or myocarditis, the addition of contrast can be used to identify areas of subepicardial delayed enhancement, a marker of myocarditis
. Additionally, contrast enhanced chest CT can also be used to screen for pulmonary embolism and/or coronary artery disease. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is a nuclear imaging modality that can also identify myocardial inflammation and can be used to evaluate myocarditis. Segmental FDG uptake with matching perfusion defects are typical for myocarditis. At present, data on the utility of cardiac CT and FDG-PET for COVID-19 myocarditis and myocardial injury is limited to a small number of case reports
. However, in patients with cardiac implantable electronic devices, cardiac CT and FDG-PET may be considered for the diagnosis COVID-19 myocarditis.
The long-term prognosis of COVID-19 myocarditis has not been well described however imaging outcomes have been favourable. On follow-up imaging, most patients have normal or recovered cardiac function, even in fulminant cases
. The American College of Cardiology published a position statement, based on expert consensus, regarding the follow-up of COVID-19 myocarditis and return to play recommendations for competitive and masters-level athletes
Gluckman TJ, Bhave NM, Allen LA, Chung EH, Spatz ES, Ammirati E, et al. 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults: Myocarditis and Other Myocardial Involvement, Post-Acute Sequelae of SARS-CoV-2 Infection, and Return to Play: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2022;79:1717–1756.
. They recommend exercise abstinence for 3-6 months following COVID-19 myocarditis. There are no guideline recommendations regarding follow-up imaging for patients with COVID-19 myocarditis, but for patients with non-COVID-19 myocarditis, experts suggest repeat CMRI imaging 3 months after diagnosis to identify persistent high-risk LGE extent or patterns and residual inflammation
Myocardial injury in acute COVID-19: Insights from Echocardiography
Transthoracic echocardiography offers many advantages for cardiac assessment, including accessibility, portability and ease of reassessment if a patient’s condition evolves. Given its versatility, echocardiography is a valuable diagnostic tool in patients with suspected cardiovascular complications associated with COVID-19, such as myocardial ischemia, myocarditis, pulmonary embolism, pericardial effusion or heart failure. In addition to diagnostic utility, echocardiography also offers prognostic information since numerous echo measures have been associated with worse outcomes.
Several echocardiographic studies have described cardiac abnormalities in patients with acute COVID-19 infection. Szekely et al. performed echocardiography in 100 hospitalized patients with COVID-19 in the spring of 2020. They reported right ventricular (RV) dysfunction in 40%, left ventricular (LV) dysfunction in 10% and diastolic dysfunction in 16%
. In a small cohort study, LV dysfunction (LVEF <50%) was associated with increased in hospital mortality (odds ratio 8.2) and severe LV dysfunction, defined as LVEF <30%, was associated with the greatest risk of death in COVID-19 illness
. Additionally, subclinical LV dysfunction can be assessed on TTE by measuring global longitudinal strain (GLS). A meta-analysis of 38 studies reporting echocardiographic data in acute COVID-19 found that abnormal GLS was more frequent than overt LV dysfunction (34% vs. 25%)
Left ventricular systolic function evaluated by strain echocardiography and relationship with mortality in patients with severe sepsis or septic shock: a systematic review and meta-analysis.
. Similarly, in hospitalized patients with COVID-19, abnormal GLS is associated with a higher risk of in-hospital death including in those with preserved LVEF
Since the lungs are the main target of SARS-CoV-2 and acute respiratory distress syndrome is a known complication of COVID-19, the RV is thought to be particularly susceptible to dysfunction during acute infection. The Szekely et al. study found that in patients with worsening clinical status, changes in echocardiographic parameters included shortening of the pulmonic flow acceleration time, increased RV end-diastolic area and increased RV end-systolic area
. Moreover, 60% of deteriorating patients had RV dysfunction. In addition to suggesting worsening airspace disease, new RV dysfunction can be a sign of pulmonary embolism, a recognised complication of COVID-19 illness. In this study, almost half of the patients with new RV dysfunction had deep venous thromboses. Moreover, a systematic review and meta-analysis by Ghidini et al. concluded that in those with more severe COVID-19 illness, RV dilation is more frequently observed than LV or RV functional decline
. Right ventricular function is also an important prognostic marker as impaired TAPSE, RV S’, RV fractional area change and RV strain are not only frequent in patients with COVID-19 but also predict all-cause mortality
. In summary, right ventricle assessment on echocardiography appears to provide a surrogate measure of COVID-19 disease severity in hospitalized patients and predicts overall outcome.
Point-of-care-ultrasound (POCUS) are used as an adjunct to clinical assessment. One study examined 102 patients admitted with COVID-19 using POCUS. Patients with abnormal LV or RV structure or function and/or significant valvular disease had an increased risk of death, mechanical ventilation, shock or acute decompensated heart failure (odds ratio of 6.19)
. Thus, with appropriate interpretation, POCUS may be used to identify high risk individuals with COVID-19. Further clinical applications are amenable to future study.
Cardiac Injury in acute COVID-19: Insights from Cardiac MRI
There is little data on CMRI in myocardial injury in hospitalized patients with acute COVID-19. One study compared CMRI findings of 25 young adults with acute COVID-19 and at least one marker of cardiac involvement (abnormal electrocardiogram, elevated troponin or cardiac symptoms) to 25 healthy age- and sex-matched controls
. They separated patients with COVID-19 into those with elevated troponin (N=8) and normal troponin (N=17). The average delay from COVID-19 symptoms to CMRI was 3-8 days. Median GLS and LVEF was abnormal or reduced in the COVID-19 groups compared to controls (-12.3%, -13.1% and -15.7% respectively; 52% and 55% vs. 65% respectively). There was also evidence for myocardial edema on T1 and T2 mapping in both troponin-positive and -negative cases relative to controls. However, only 1 patient with COVID-19 had myocardial necrosis on LGE imaging. This CMRI study suggest that COVID-19 illness is often characterized by mild myocardial edema and inflammation without necrosis. The long-term implications of these findings are not known however it would seem reasonable to include CMRI in the imaging evaluation of acute COVID-19 illness in select cases (Figure 2).
Coronary microvascular and endothelial dysfunction in COVID-19 associated cardiac injury
There is emerging evidence that coronary microvascular dysfunction (CMVD) plays a key role in the pathophysiology of cardiac injury in COVID-19. CMVD can be evaluated by different imaging techniques including echocardiography, CMRI and PET. An echocardiography study reported reduced coronary flow velocity reserve, a measure of CMVD, among patients with severe COVID-19 infection compared to those with moderate illness and controls
Caliskan M, Baycan OF, Celik FB, Guvenc TS, Atici A, Cag Y, et al. Coronary microvascular dysfunction is common in patients hospitalized with COVID-19 infection. Microcirc N Y N 1994. 2022;29:e12757.
. Interestingly, those with COVID-19 had a similar impairment in global MPR compared to patients with hypertrophic cardiomyopathy, a condition where CMVD is frequently observed. There were no obvious clinical sequelae from these imaging findings.
In addition to CMVD, endothelial dysfunction is also described in COVID-19 illness. Vascular alterations during the acute phase of COVID-19 have been studied non-invasively using flow-mediated dilation (FMD), a vascular function technique which examines brachial artery dilation in response to ischemia, and pulse wave velocity (PWV), a measure of aortic stiffness. A systematic review by Mavraganis et al. identified endothelial dysfunction during the acute phase of COVID-19 as evidenced by lower FMD values compared to controls without COVID-19 infection
. Moreover, FMD was lower in those with severe respiratory manifestations compared to those with less impaired respiratory profiles. Reduced FMD was also associated with higher mortality and risk of admission to the intensive care unit
Thrombotic complications during COVID-19 infection
Patients with COVID-19 are at increased risk of thrombosis. A study of hospitalized patients reported an incidence of thrombotic events of 16%: 6.2% venous and 11.1% arterial (stroke, myocardial infarction or other systemic embolization)
. A larger observational study demonstrated that COVID-19 infection is an independent risk factor for acute myocardial infarction and ischemic stroke in the first 4 weeks following infection
. Early in the global pandemic, a consensus statement from the Society for Cardiovascular Angiography and Interventions (SCAI), the American College of Cardiology (ACC), and the American College of Emergency Physicians (ACEP) suggested patients presenting with ST segment elevation myocardial infarction (STEMI) or higher risk non-ST-elevation myocardial infarction (NSTEMI) should undergo invasive coronary angiography. They also recommended medical treatment for low risk NSTEMI and subsequently pursuing outpatient risk stratification
. To our knowledge, there have been no large studies evaluating non-invasive ischemia testing with nuclear imaging or stress echocardiography early after COVID-19 infection. In the context of unexplained myocardial injury during COVID-19 infection, coronary CT could also be used to rule out acute coronary syndrome in low to intermediate risk patients, due to its excellent negative predictive value
. Additionally, two studies have retrospectively examined premorbid coronary artery calcification on CT in patients hospitalized with COVID-19. Both studies observed worse outcomes in those with higher coronary artery calcium scores
Coronary calcium scoring assessed on native screening chest CT imaging as predictor for outcome in COVID-19: An analysis of a hospitalized German cohort.
. Given that many patients have CT chest imaging during COVID-19 infection, identifying coronary calcium may be useful in risk stratification and may represent an opportunity for secondary prevention once the patient is recovered.
Cardiac Imaging in Acute COVID-19: Knowledge Gaps
As our knowledge of the cardiovascular effects of COVID-19 evolves, the need for further research and understanding grows. Firstly, most reports on the cardiovascular effects of COVID-19 were during in the early waves of the global pandemic. Thus, further research is needed to understand whether the extent and severity of cardiac involvement is different with Delta, Omicron and other SARS-CoV-2 variants. Secondly, while it is reassuring that adverse events among those infected with COVID-19 are rare, further study is needed to understand healing and recovery and the role of cardiac imaging for follow-up and guiding clinical decisions. Finally, using imaging to broaden our understanding of the pathophysiology of acute COVID-19’s cardiovascular effects may inform on the risk and management of cardiac issues arising in long-COVID syndrome.
Cardiovascular Disease in Patients with Recovered COVID-19
Given the direct and indirect effects of COVID-19 on the heart and vascular function during the acute illness, several studies have characterized cardiovascular health in recovered patients. Furthermore, approximately 15% of Canadians are affected by long-COVID, a poorly understood syndrome defined by symptoms lasting more than 12 weeks from the initial illness
. Patients with long-COVID are often affected by fatigue, cough and/or shortness of breath however chest pain and palpitations are also frequently reported. Thus, cardiovascular health care professionals may become involved in the care of these patients. Imaging is often used to characterize latent effects in patients with recovered COVID-19, either to re-evaluate cardiovascular abnormalities discovered during acute illness or to investigate new or worsening symptoms related during convalescence. It has also recently been confirmed that survivors of COVID-19 are at substantial risk for incident cardiovascular disease, even in non-hospitalized cases
. Thus, there is an urgent need to better understand the long-term effects of COVID-19 on cardiovascular health.
Cardiovascular Imaging in Patients with Recovered COVID-19
Surveillance imaging studies of patients with recovered COVID-19 have revealed mild functional and/or structural abnormalities of unknown clinical significance. Echocardiographic studies have found abnormalities in GLS but no significant change in biventricular size or ejection fraction relative to healthy controls
. CMRI-based studies have also not detected any significant changes in cardiac structure or function. A case control study of 1285 volunteers from the UK Biobank did not find any significant change in biventricular size and function on CMRI in those with prior mild COVID-19 illness
Bai W, Raman B, Petersen SE, Neubauer S, Raisi-Estabragh Z, Aung N, et al. Longitudinal Changes of Cardiac and Aortic Imaging Phenotypes Following COVID-19 in the UK Biobank Cohort [Internet]. medRxiv; 2021 [cited 2022 Nov 4]. p. 2021.11.04.21265918. Available from: https://www.medrxiv.org/content/10.1101/2021.11.04.21265918v1
. However, several CMRI studies utilizing tissue characterization imaging have demonstrated subclinical myocardial edema with or without fibrosis in patients with recovered illness. A cohort study of 100 patients with recovered COVID-19 (median 71 days from illness) had a high prevalence of abnormal CMRI findings including increased myocardial T1 in 73%, increased myocardial T2 in 60% and myocardial scar in 32%
. These findings were significantly more prevalent than in healthy and risk-factor matched controls. These findings were heavily scrutinized by the scientific community and led to a review and reanalysis of the data however the primary findings were confirmed
Explanation for the Corrections for the Study of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019.
. A subsequent study of CMRI in 148 patients with prior severe COVID-19 illness (median 68 days from illness) found myocardial scar in 54% of cases including non-ischemic in 26%, ischemic in 22% and mixed etiology in 6%
. While 17% of non-athletes and 0.9% of athletes met CMRI criteria for myocarditis, minor myocardial abnormalities were observed in many cases. In non-athletes, the prevalence of myocardial scar on LGE imaging, abnormal myocardial T1 and abnormal myocardial T2 were 27.5%, 39.5% and 38.1%, respectively. In athletes, the prevalence of these abnormalities was lower: 10.8%, 5.7% and 1.9%, respectively. In general, CMRI studies have suggested subclinical myocardial edema, necrosis and/or fibrosis arising from COVID-19 illness.
Vascular function has also been studied during the recovery phase of COVID-19. Patients with prior COVID-19 infection had significantly lower flow-mediated dilation (FMD) values than controls without COVID-19
. As both FMD and PWV are useful in detecting patients who are at risk for cardiovascular events and those with higher mortality risk, assessment of endothelial function has been recommended in patients with convalescent COVID-19 for early detection of long-term CV complications by the European Society of Cardiology
Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science.
. Coronary microvascular dysfunction during the acute phase of COVID-19 infection could account for persistent symptoms described by some patients during the recovery phase of their illness. A PET based study by Ahmed et al. evaluated myocardial flow reserve (MFR) in patients with persistent cardiac symptoms following COVID-19 infection (median 190 days) compared to age- and sex-matched patient controls
Ahmed Ahmed Ibrahim, Saad Jean Michel, Han Yushui, Alahdab Fares, Malahfji Maan, Nabi Faisal, et al. Coronary Microvascular Health in Patients With Prior COVID-19 Infection. JACC Cardiovasc Imaging [Internet]. [cited 2022 Oct 9];0. Available from: https://doi.org/10.1016/j.jcmg.2022.07.006
. They found that 44% of patients with prior COVID-19 infection had global reductions in MFR compared to only 26% of controls. As such, in addition to acute cardiac injury, CMVD may be an important pathophysiologic link between acute COVID-19 and long COVID-19 syndrome.
Cardiac Imaging in Long-COVID
Long-COVID is a poorly understood syndrome complicating COVID-19 infection in approximately 15% of cases in Canada
. Common complaints include fatigue, exercise intolerance and brain fog however many also report cardiac symptoms including chest pain and palpitations. The pathophysiological basis for this syndrome is not well understood but imaging studies have tried to provide insight into this disorder. A recent prospective study of 346 individuals with prior COVID-19 underwent baseline and follow-up CMRI at a median of 109 days and 329 days respectively
. At baseline assessment, 73% reported cardiac symptoms, including dyspnea in 62%, palpitations in 28% and chest pain in 27%, and at follow-up symptoms persisted in 57%. Myocardial T2, a CMRI measure of edema, was higher at follow-up in the subgroup with persistent symptoms, and myocardial T1 at baseline, another potential measure of edema, was a significant predictor of persistent symptoms on multivariate analysis. Thus, these findings suggest a link between subclinical myocardial inflammation on CMRI and cardiac symptoms in recovered patients. However, a small case-control study of 20 patients with long-COVID syndrome and no prior cardiovascular disease found no abnormalities of cardiac structure, function, myocardial tissue, blood flow or cardiac energetics on CMR spectroscopy
. Given the multisystem nature of long-COVID syndrome, some imaging-based studies have included extra-cardiac characterization. An MRI-based, observational study of 58 patients with prior admission for COVID-19 found elevated myocardial T1 in 26% of cases
Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge.
. However, lung, kidney and brain abnormalities on MRI were also common and seen in 60%, 29% and 11% of cases respectively. We are also undertaking a multi-centre, prospective study of 215 patients with prior COVID-19 in Alberta characterising MRI abnormalities in multiple organ systems (NCT04525404). Relative to healthy controls without prior COVID-19, preliminary observations suggest pulmonary abnormalities consistent with persistent inflammation (Figure 3) and increased visceral adiposity in the liver (Figure 4) and skeletal muscle (Figure 5). The pulmonary and skeletal muscle abnormalities may suggest a mechanism for reduced exercise tolerance in COVID-19 survivors. Visceral adiposity has been associated with risk of adverse clinical outcomes in acute COVID-19
Raisi-Estabragh Z, Cooper J, Salih A, Raman B, Lee AM, Neubauer S, et al. Cardiovascular disease and mortality sequelae of COVID-19 in the UK Biobank. Heart Br Card Soc. 2022;heartjnl-2022-321492.
. These extra-cardiac findings following COVID-19 infection appear to support non-pharmacologic treatment options that include cardiac rehab and nutritional counselling as important interventions for long-COVID
Figure 3Lung water density images in a healthy individual (69 yrs, male) and a COVID-19 survivor (82 yrs, male) illustrate patchy regions of elevated water content 3 months post illness. Images are in units of relative lung water density (rLWD, %). The lower panels use a compressed range of values and a different colormap to highlight the regional variations within the lung parenchyma. One coronal slice from a three-dimensional acquisition is shown. Image acquisition and post-processing approach were previously described
Figure 4Proton density fat fraction (PDFF) liver images from a healthy individual (58 yrs, male) and a COVID-19 survivor (52 yrs, male). A significantly higher fat content was observed in the COVID-19 survivor versus the healthy individual, 21.0% vs. 1.0%. Images were acquired using the PROFIT1 method
Figure 5Fat and water separated muscle image (mid-thigh) illustrate the relatively low skeletal muscle quality (higher intermuscular fat content, %) in a COVID-19 survivor (50 yrs, female) as compared to a healthy individual (48 yrs, female). Images were acquired using the PROFIT1 method
Cardiac Imaging in Recovered Patients: Knowledge Gaps
MRI is an attractive imaging modality for patients with recovered COVID-19 given the possibility of multi-system effects with the potential to impact cardiovascular health. This imaging modality provides detailed information on tissue characterization and function and has an excellent safety profile. However, more work is needed in patients with recovered COVID-19 to confirm a link between cardiac symptoms and myocardial abnormalities on CMRI. Additionally, larger imaging studies of cardiac and extra-cardiac structures would likely contribute to our understanding of the increased risk for latent cardiovascular disease. Finally, the utility of serial imaging studies should be evaluated as a clinical strategy to assess the impact of therapies in high-risk patients with recovered COVID-19.
mRNA Vaccine Associated Myocarditis
mRNA Vaccine Myocarditis in Context
While mRNA vaccine associated myocarditis is a relatively new condition, a number of other vaccines have also resulted in myocarditis including the smallpox vaccine and live viral vaccines
. Similarly, mRNA vaccination for protection against severe COVID-19 infection appears to outweigh the risk of mRNA vaccine associated myocarditis but has become an important discussion point between patients and health care providers
. In younger males, the group with the highest incidence of cardiac complications after mRNA vaccine, the risk of myocarditis or pericarditis was 2-6 fold higher after COVID-19 infection than after vaccination
. Research is ongoing to better understand the underlying mechanisms and tailoring recommendations for those at highest risk of vaccine myocarditis (Figure 6)
Population studies have relied primarily on International Classification of Diagnosis (ICD) codes for identifying cases of mRNA vaccine associated myocarditis
. They identified 107 cases of incident vaccine associated myocarditis. However, they note that they did not have access to clinical measures such as cardiac imaging, troponin levels, nor endomyocardial biopsy. Therefore, they could not assess how many patients fulfilled any accepted criteria for myocarditis diagnosis.
Case definitions of vaccine associated myocarditis world-wide use either the Centers for Disease Control and Prevention (CDC) or Brighton Collaboration criteria
. These include various grades of certainty, with the highest levels of certainty assigning greatest weight to pathology, abnormal CMRI findings, and abnormal troponin
. Reasons for this may include reporting error, non-adherence to recommended imaging protocols, rapid resolution of myocardial inflammation, or small volume myocardial necrosis that is below the spatial resolution of CMRI
. Under-diagnosis of vaccine associated myocarditis is also a potential concern in regions with limited availability of CMRI. This is relevant in remote regions of Canada as well as many developing countries. Consequently, reporting bias may affect estimates of the prevalence of vaccine associated myocarditis depending on access to CMRI.
Table 2Summary of Brighton Criteria for Vaccine Myocarditis
Similar to Probable, but none specified. It is assumed testing is driven by symptoms.
Autopsy or endomyocardial biopsy showing myocardial inflammation OR Elevated Troponin AND Abnormal Cardiac Imaging (CMR or Echo) AND No alternative Diagnosis for symptoms
Level 2 - Probable
Cardiac symptoms (One), Non-specific symptoms (Two), or Infants/Children specific symptoms (Two)
Abnormal Cardiac Imaging (CMR or Echo) OR Abnormal Troponin or CK-MB OR Abnormal ECG (1 feature from specific list) AND No alternative Diagnosis for symptoms
Level 3 – Possible (High sensitivity, Lower specificity)
Cardiac symptoms (One), Non-specific symptoms (Two), or Infants/Children specific symptoms (Two)
Abnormal marker of inflammation (CRP/hs-CRP, ESR, D-Dimer) OR Abnormal ECG (1 feature from specific list) AND No alternative Diagnosis for symptoms
Figure 7CMR findings in a patient with mRNA vaccine associated myocarditis. 22-year-old male presented to hospital 2 days after his second COVID-19 mRNA vaccine with chest pain. Troponin T was elevated at 105ng/L (normal <15ng/L). CMRI demonstrated normal LV function (A, video 7). T1 mapping suggested myocardial edema in the inferoseptum and inferior segments (B, blue arrows) with corresponding non-ischemic scar on late gadolinium enhancement imaging (C, green arrows).
. This point must be emphasized, especially in patients with clinical presentations suggestive of alternate diagnoses. It is important to note that CMRI cannot definitively identity the etiology of myocarditis
. While endomyocardial biopsy has a low diagnostic yield, especially for patchy disease, it is still considered the gold-standard for detecting myocarditis
. However, vaccine myocarditis usually diagnosed based on CMRI findings and elevated cardiac biomarkers such as troponin, with very few patients undergoing biopsy
. For example, Truong et al. reported on 140 episodes of suspected mRNA vaccine associated myocarditis (49 confirmed and 91 probable), but no patients in this large study underwent endomyocardial biopsy
Clinically Suspected Myocarditis Temporally Related to COVID-19 Vaccination in Adolescents and Young Adults: Suspected Myocarditis After COVID-19 Vaccination.
. They found presence of mild lymphocytic infiltration in the myocardium without the necrosis of adjacent myocytes. Immunostaining for tenascin‐C and human leukocyte antigen ‐DR antigens supported immune activation. Further, there was the absence of viral genomes further supporting an immune‐mediated myocarditis.
While it is advantageous to spare young patients the invasive procedure, the downside of primarily relying on imaging is that important alternative etiologies of myocarditis can be missed. For example, Paddock et al. reported on two adolescents whose death was initially attributed to vaccine associated myocarditis
. These examples serve as cautionary tales for clinicians to carefully balance the need for further clinical data with the risk of invasive procedures.
Echocardiography and Computed Tomography in Vaccine Associated Myocarditis
The echocardiographic assessment of LVEF is a widely used for the Brighton criteria diagnosis of myocarditis (Table 2 and Table 3). However, it has been found to have low sensitivity to diagnose early or localized forms of mild myocarditis
. One systematic review of 238 patients with mRNA vaccine associated myocarditis found that 69.2% of patients had normal LVEF, 21.6% had mildly reduced LVEF, 1.7% had moderately reduced LVEF, and 1.4% had severely reduced LVEF
. On follow-up, 35 of the patients with reduced LVEF had recovery to normal, although repeat cardiac imaging was unavailable in many cases. Pericardial effusion was present in 18.6% and most were small. Importantly, this same study found that CMRI abnormalities consistent with myocarditis were discovered in 81.4% of patients with completely normal LVEF
. Abnormal echo findings included pericardial effusion in 5.1%, focal or global hypokinesis in 12.1% and/or reduction in ventricular ejection fraction in 21.9%.
Table 3Comparison of Cardiac Imaging used in the Brighton Criteria for Vaccine Myocarditis
New focal or diffuse left OR right ventricular function abnormalities
F095
Wall motion abnormalities
F095
Global systolic OR diastolic function abnormality
F095
Ventricular dilation
F095
Wall thickness change
F095
Widely available
F095
Safe, minimal contraindications
F095
Reasonable cost
F095
Portable exam in severely ill patients
F095
Failure to identify mild or moderate myocarditis
F095
Low sensitivity and specificity of echo abnormalities
Cardiac Magnetic Resonance
At least one of the findings:
F095
Edema on T2-weighted imaging
F095
Typically involving at least one non-ischemic pattern of late gadolinium enhancement
F095
High sensitivity and specificity for viral myocarditis
F095
Safe, minimal contraindications
F095
Multiparametric follow-up testing
F095
Cannot determine etiology of myocarditis
F095
Not easily accessible in all regions
F095
Higher cost
F095
Possible need for anesthesia in children
Adapted from: Sexson Tejtel SK, Munoz FM, Al-Ammouri I, et al. Myocarditis and pericarditis: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2022;40:1499–511
One case series of contrast enhanced CT in four patients with suspected mRNA vaccine myocarditis reported patchy mid-wall and sub-epicardial delayed iodine enhancement in the lateral wall
Viskin D, Topilsky Y, Aviram G, Mann T, Sadon S, Hadad Y, et al. Myocarditis Associated With COVID-19 Vaccination: Echocardiography, Cardiac Tomography, and Magnetic Resonance Imaging Findings. Circ Cardiovasc Imaging [Internet]. 2021 [cited 2022 Oct 14];14. Available from: https://www.ahajournals.org/doi/10.1161/CIRCIMAGING.121.013236
. Three systematic reviews have assessed the CMRI findings in mRNA vaccine associated myocarditis. Samimisedeh et al. identified 102 studies and 468 patients undergoing CMRI for suspected mRNA vaccine associated myocarditis
. LGE patterns were subepicardial and/or midwall in the majority of cases and were primarily localized to the basal or mid inferolateral segments of the left ventricle (61.4%). In their pooled analysis, 79% of patients with vaccine associated myocarditis met either old or revised CMRI criteria for myocarditis
. They report an abnormal CMRI in 67.8% of cases including pericardial, epicardial or subepicardial enhancement in 44% and myocardial edema in 35.3% . A third systematic review by Ilonze et al. identified 106 studies and 238 patients with vaccine associated myocarditis
. CMRI was abnormal in 175/178 patients and LGE was noted in 96% and edema on T1 or T2 imaging in 68.5%.
Cardiac Magnetic Resonance Follow-up of mRNA Vaccine Associated Myocarditis
Four studies have reported CMRI follow-up in patients with mRNA vaccine associated myocarditis. A case series of adolescents with vaccine myocarditis described CMRI findings at 3 months in 10 cases
Mustafa Alhussein M, Rabbani M, Sarak B, Dykstra S, Labib D, Flewitt J, et al. Natural History of Myocardial Injury After COVID-19 Vaccine–Associated Myocarditis. Can J Cardiol [Internet]. 2022 [cited 2022 Oct 15];0. Available from: https://www.onlinecjc.ca/article/S0828-282X(22)00500-1/fulltext
. They found that all patients had significant improvements in myocardial edema, LV function and LGE burden. However, they report that 90% of patients had persistent LGE
Mustafa Alhussein M, Rabbani M, Sarak B, Dykstra S, Labib D, Flewitt J, et al. Natural History of Myocardial Injury After COVID-19 Vaccine–Associated Myocarditis. Can J Cardiol [Internet]. 2022 [cited 2022 Oct 15];0. Available from: https://www.onlinecjc.ca/article/S0828-282X(22)00500-1/fulltext
Shiyovich A, Plakht Y, Witberg G, Aviv Y, Shafir G, Kornowski R, et al. Myocarditis Following COVID-19 Vaccination. JACC Cardiovasc Imaging [Internet]. [cited 2022 Oct 16];0. Available from: https://www.jacc.org/doi/10.1016/j.jcmg.2022.05.017
Shiyovich A, Plakht Y, Witberg G, Aviv Y, Shafir G, Kornowski R, et al. Myocarditis Following COVID-19 Vaccination. JACC Cardiovasc Imaging [Internet]. [cited 2022 Oct 16];0. Available from: https://www.jacc.org/doi/10.1016/j.jcmg.2022.05.017
. Therefore, all four studies demonstrate persistent LGE in some patients. In the acute setting, LGE can represent tissue necrosis and/or edema, but replacement fibrosis often occurs during convalescence. This suggests the potential need for long-term CMRI surveillance.
Cardiac Imaging and mRNA Vaccine Associated Myocarditis: Knowledge Gaps
There are many aspects of mRNA vaccine associated myocarditis where further research is needed. Firstly, studies are needed to improve our understanding of the pathophysiology of this condition. Several hypotheses have been proposed
. Mechanistic and clinical studies such as imaging studies combined with non-imaging metrics like serology and or pathology would be informative. Secondly, while the CMR LLC for myocarditis have been studied in viral myocarditis and other etiologies of myocarditis, there is a need to improve our diagnostic capabilities for vaccine associated myocarditis
. Developing imaging measures specific to this diagnosis and understanding the optimal timing post vaccination for imaging to characterize this condition is an important undertaking. Thirdly, there are few studies assessing which patients require follow-up imaging. The conventional practice is to repeat cardiac imaging only in those with significant abnormalities on baseline testing or during recurrence of symptoms. It will be important to study which parameters are most prognostic and what is the ideal frequency of follow-up imaging. Lastly, to our knowledge there is only one case report of FDG-PET in mRNA vaccine-associated myocarditis
. Further research is needed to understand if FDG-PET is a reasonable alternative for diagnosis and follow-up, especially in patients who may have a contraindication to CMRI.
Discussion and Future Directions
Since early 2020, research into COVID-19 has dominated the scientific community worldwide. Cardiovascular imaging, primarily echocardiography and CMRI, has played a significant role in characterizing the cardiovascular complications of COVID-19 during the acute and recovery phase of illness. Several echocardiography measures including LV strain and RV size and function have been identified as important prognostic measures in patients with myocardial injury and/or severe acute disease. Tissue characterization on CMRI can distinguish between ischemic and non-ischemic patterns of myocardial injury in acute disease and identify subclinical disease in patients with recovered illness, including those affected by long-COVID syndrome. Moreover, imaging may provide insight into important pathophysiologic links between acute and persistent disease arising from COVID-19 including residual myocardial abnormalities, endothelial and coronary microvascular dysfunction, and multi-organ abnormalities relevant to cardiovascular health. Cardiovascular imaging has also been paramount in the diagnosis of mRNA vaccine myocarditis and has helped confirm that this adverse event is rare.
Future work should evaluate optimal imaging pathways for the diagnosis and follow-up of COVID-19 and mRNA vaccine related cardiovascular complications. The role of cardiac CT angiography and nuclear imaging has not been well defined and their utility should also be evaluated in COVID-19 related myocardial injury or ischemia. Artificial intelligence is emerging as an important method to analyze cardiac imaging data and identify novel measures to aid in disease diagnosis and/or prognosis. This automated technique has recently been used to help identify echo parameters predicting all-cause mortality in a multicenter study of 870 patients admitted for COVID-19
Asch FM, Descamps T, Sarwar R, Karagodin I, Singulane CC, Xie M, et al. Human versus Artificial Intelligence–Based Echocardiographic Analysis as a Predictor of Outcomes: An Analysis from the World Alliance Societies of Echocardiography COVID Study. J Am Soc Echocardiogr [Internet]. 2022 [cited 2022 Nov 4]; Available from: https://www.sciencedirect.com/science/article/pii/S0894731722003510
. Similarly, multicenter studies of CMRI in patients with recovered COVID-19 are needed to confirm the high prevalence of subclinical myocardial disease. Artificial intelligence aided analysis of CMRI data would likely decrease post-processing time and reduce the potential for confirmation bias. Finally, as both SARS-CoV-2 and vaccination therapies continue to evolve, we will need to continue to refine our understanding of the potential for adverse cardiovascular effects. As such, cardiovascular imaging studies will continue to be a vital component of COVID-19 research.
Acknowledgements
Dr. Kafil receives support from the Myocarditis Foundation Fellowship program.
Funding Sources: Dr. Paterson’s MRI study of patients recovered COVID-19 (NCT04525404) is funded by the Canadian Institutes of Health Research.
Disclosures: All authors have no relevant disclosures.
Raisi-Estabragh Z, Cooper J, Salih A, Raman B, Lee AM, Neubauer S, et al. Cardiovascular disease and mortality sequelae of COVID-19 in the UK Biobank. Heart Br Card Soc. 2022;heartjnl-2022-321492.
Cardiac injury is associated with severe outcome and death in patients with Coronavirus disease 2019 (COVID-19) infection: A systematic review and meta-analysis of observational studies.
Detection of viruses in myocardial tissues by polymerase chain reaction. evidence of adenovirus as a common cause of myocarditis in children and adults.
Bozkurt B, Das SR, Addison D, Gupta A, Jneid H, Khan SS, et al. 2022 AHA/ACC Key Data Elements and Definitions for Cardiovascular and Noncardiovascular Complications of COVID-19: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards. Circ Cardiovasc Qual Outcomes. 2022;15:e000111.
Prevalence of Clinical and Subclinical Myocarditis in Competitive Athletes With Recent SARS-CoV-2 Infection: Results From the Big Ten COVID-19 Cardiac Registry.
Differences in Cardiac Magnetic Resonance Imaging Markers Between Patients With COVID-19-associated Myocardial Injury and Patients With Clinically Suspected Myocarditis.
Gluckman TJ, Bhave NM, Allen LA, Chung EH, Spatz ES, Ammirati E, et al. 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults: Myocarditis and Other Myocardial Involvement, Post-Acute Sequelae of SARS-CoV-2 Infection, and Return to Play: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2022;79:1717–1756.
Left ventricular systolic function evaluated by strain echocardiography and relationship with mortality in patients with severe sepsis or septic shock: a systematic review and meta-analysis.
Caliskan M, Baycan OF, Celik FB, Guvenc TS, Atici A, Cag Y, et al. Coronary microvascular dysfunction is common in patients hospitalized with COVID-19 infection. Microcirc N Y N 1994. 2022;29:e12757.
Coronary calcium scoring assessed on native screening chest CT imaging as predictor for outcome in COVID-19: An analysis of a hospitalized German cohort.
Bai W, Raman B, Petersen SE, Neubauer S, Raisi-Estabragh Z, Aung N, et al. Longitudinal Changes of Cardiac and Aortic Imaging Phenotypes Following COVID-19 in the UK Biobank Cohort [Internet]. medRxiv; 2021 [cited 2022 Nov 4]. p. 2021.11.04.21265918. Available from: https://www.medrxiv.org/content/10.1101/2021.11.04.21265918v1
Explanation for the Corrections for the Study of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019.
Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science.
Ahmed Ahmed Ibrahim, Saad Jean Michel, Han Yushui, Alahdab Fares, Malahfji Maan, Nabi Faisal, et al. Coronary Microvascular Health in Patients With Prior COVID-19 Infection. JACC Cardiovasc Imaging [Internet]. [cited 2022 Oct 9];0. Available from: https://doi.org/10.1016/j.jcmg.2022.07.006
Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge.
Clinically Suspected Myocarditis Temporally Related to COVID-19 Vaccination in Adolescents and Young Adults: Suspected Myocarditis After COVID-19 Vaccination.
Viskin D, Topilsky Y, Aviram G, Mann T, Sadon S, Hadad Y, et al. Myocarditis Associated With COVID-19 Vaccination: Echocardiography, Cardiac Tomography, and Magnetic Resonance Imaging Findings. Circ Cardiovasc Imaging [Internet]. 2021 [cited 2022 Oct 14];14. Available from: https://www.ahajournals.org/doi/10.1161/CIRCIMAGING.121.013236
Mustafa Alhussein M, Rabbani M, Sarak B, Dykstra S, Labib D, Flewitt J, et al. Natural History of Myocardial Injury After COVID-19 Vaccine–Associated Myocarditis. Can J Cardiol [Internet]. 2022 [cited 2022 Oct 15];0. Available from: https://www.onlinecjc.ca/article/S0828-282X(22)00500-1/fulltext
Shiyovich A, Plakht Y, Witberg G, Aviv Y, Shafir G, Kornowski R, et al. Myocarditis Following COVID-19 Vaccination. JACC Cardiovasc Imaging [Internet]. [cited 2022 Oct 16];0. Available from: https://www.jacc.org/doi/10.1016/j.jcmg.2022.05.017
Asch FM, Descamps T, Sarwar R, Karagodin I, Singulane CC, Xie M, et al. Human versus Artificial Intelligence–Based Echocardiographic Analysis as a Predictor of Outcomes: An Analysis from the World Alliance Societies of Echocardiography COVID Study. J Am Soc Echocardiogr [Internet]. 2022 [cited 2022 Nov 4]; Available from: https://www.sciencedirect.com/science/article/pii/S0894731722003510
00068-5&id=gr1.jpg){kind=link}
00068-5&id=gr2.jpg){kind=link}
00068-5&id=gr3.jpg){kind=link}
00068-5&id=gr4.jpg){kind=link}
00068-5&id=gr5.jpg){kind=link}
00068-5&id=gr6.jpg){kind=link}
00068-5&id=gr7.jpg){kind=link}