Coronavirus disease 2019 (COVID-19), an unprecedented public health crisis, has been established as a cause of significant cardiovascular (CV) complications including myocarditis, acute coronary syndrome, thromboembolism, and arrhythmias.¹ Cardiac injury is a major determinant of COVID-19 related deaths, and even patients who experience minimal COVID-19 symptoms on initial presentation have evidence of persistent cardiac abnormalities and dysfunction several months after recovery.

Synopsis

A new study by clinical researchers in Germany helps to understand the subacute effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing COVID-19 disease, on the heart. The primary findings, published in JAMA Cardiology by Puntmann et al.² revealed that cardiac inflammation detected on cardiovascular magnetic resonance (CMR) is common in the convalescent phase of COVID infection, even in patients who were minimally symptomatic during the acute phase of the infection. In the paper, survivors of COVID infection underwent cardiac MRI (CMR) with gadolinium contrast a median of 71 days after acute infection. Many patients reported symptoms at the time of the CMR exam including atypical chest pain, palpitations and shortness of breath. The authors observed that myocardial inflammation and other cardiac abnormalities were present on CMR in the majority of patients (78%) in the cohort of recovered COVID patients which included those who recovered at home (approximately 2/3) or were hospitalized (approximately 1/3). Furthermore, they found that high sensitivity troponin was elevated in the majority of patients recovered from COVID-19 (>70%) although only a minority experienced significant troponin elevation. Furthermore, several patients with significant troponin elevations were found to have biopsy-confirmed myocarditis.

In terms of cardiac structural abnormalities, patients who recently recovered from COVID-19 compared to controls tended to have mildly reduced left ventricular (LV) ejection fraction, increased LV mass and higher LV volumes. Of the CMR parameters studied, the authors reported that native T1 (indicating diffuse myocardial edema and/or fibrosis) was elevated in 71% of patients, and 60% had elevated T2, a more specific marker for high water content and myocardial edema/inflammation when compared to healthy controls without COVID-19. About one third of patients had late gadolinium enhancement (LGE), indicating scar, and 22% had pericardial involvement. Notably, the degree of T1 and T2 abnormalities on CMR was not associated with the clinical severity of disease on acute presentation, suggesting that even patients who were mildly symptomatic were at risk for residual myocardial inflammation. The CMR measures that best categorized the ability to reflect COVID-19-related myocardial pathology were native T1 (myocardial fibrosis and/or edema) and native T2, even more than traditional CMR measures of cardiac function. Furthermore, T1 values were significantly associated with myocardial injury as measured by high sensitivity troponin. Another recent CMR study in COVID-19 patients similarly reported that over half of recovered patients had evidence of active inflammation (by T1 and T2 mapping) and LGE in 31%.³ Taken together, these studies show that a significant number of recovered COVID-19 patients have persistent cardiac inflammation and/or fibrosis on follow up by CMR, and many have persistent cardiac injury even after presenting with mild symptoms. Fortunately, biopsy-confirmed myocarditis in the setting of COVID-19 is uncommon, however it is important to diagnose early and monitor patients closely for the developed of heart failure, life-threatening arrhythmias, and circulatory collapse.^4,5

Role of LGE in Inflammatory Cardiomyopathies

CMR plays an important role in the diagnosis and risk stratification of inflammatory cardiomyopathy (CM) particularly for predicting arrhythmias, heart failure, and adverse CV outcomes.⁶ LGE has been related to adverse outcomes in patients with inflammatory CMs and myocarditis,^7-9 although this has not yet been shown in the setting of COVID-19 infection. In the paper by Puntmann et al., evidence of ongoing inflammation was suggested by the high frequency of lingering myocardial injury, with histological confirmation of cardiac lymphocytic infiltration in a subset of patients with severely increased troponin and extent of CMR inflammation. Many of the patients had LGE in a non-ischemic pattern, which predicts poor outcomes in patients with myocarditis. Although the long-term CV effects of the CMR findings is not yet determined in this population, several of the CMR findings observed including abnormalities in T1, T2 and LGE were previously related to adverse outcomes in other types of inflammatory cardiomyopathies.^6,7,10 Higher native T1 as reported in this and other COVID-19 CMR papers represent myocardial fibrosis and/or edema, whereas increased native T2 values are considered a more specific indication of higher water content and thus edema. Therefore, patients with both high native T1 and T2 measures are experiencing ongoing imaging evidence of active inflammation. Notably, other non-invasive imaging studies have reported early reduced LV dysfunction by strain imaging localized to the base of the heart,^11,12 an area surrounded by epicardial adipose tissue, where ACE2 (angiotensin-converting enzyme 2, receptor for SARS-CoV-2) is highly expressed and which is enriched in pro-inflammatory cytokines that may mediate downstream LV dysfunction via pro-inflammatory effects. Thus far, published reports of CMR imaging findings support ongoing cardiac inflammation after COVID-19 infection in a subset of patients.

Knowledge Gaps and Future Directions

Although the long term clinical significance of the CMR abnormalities in COVID-19 is yet unknown, it is possible that CMR evidence of persistent cardiac inflammation will carry prognostic value in COVID-19 patients as evidenced by the strong prognostic value of tissue characterization (T1, T2 mapping) in both ischemic and non-ischemic CMs.¹³ Moreover, the combination of CMR with cardiac enzyme assessment may be of value. Cardiac enzymes (troponin) are often persistently elevated, indicating ongoing myocardial inflammation and injury in recovery, and were previously related to adverse short term outcomes, even if they were only minimally elevated.¹⁴ Some of the important knowledge gaps in COVID-19 include determining the significance of subclinical inflammation on CMR, its relationship to long term outcomes, and if preventative measures for heart failure or increased monitoring for arrhythmias is warranted in patients recovering from COVID-19 with these abnormalities. Future prospective research should include long-term clinical outcomes of COVID-19 survivors with a focus on determining additive value of non-invasive imaging findings on prognosis and clinical decision making. Special attention to control groups is essential in order to better understand cardiac imaging features related to this novel infection.

References

1. Nishiga M, Wang DW, Han Y, Lewis DB, Wu JC. COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives. Nat Rev Cardiol 2020;17:543-58.
2. Puntmann VO, Carerj ML, Wieters I, et al. Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19). JAMA Cardiol 2020;Jul 27:[Epub ahead of print].
3. Huang L, Zhao P, Tang D, et al. Cardiac involvement in patients recovered from COVID-2019 identified using magnetic resonance imaging. JACC Cardiovasc Imaging 2020;May 12:[Epub ahead of print].
4. Ammirati E, Cipriani M, Moro C, et al. Clinical presentation and outcome in a contemporary cohort of patients with acute myocarditis: Multicenter Lombardy Registry. Circulation 2018;138:1088-99.
5. Caforio ALP, Pankuweit S, Arbustini E, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013;34:2636-48,2648a-2648d.
6. Ferreira VM, Schulz-Menger J, Holmvang G, et al. Cardiovascular magnetic resonance in nonischemic myocardial inflammation: expert recommendations. J Am Coll Cardiol 2018;72:3158-76.
7. Grani C, Eichhorn C, Biere L, et al. Prognostic value of cardiac magnetic resonance tissue characterization in risk stratifying patients with suspected myocarditis. J Am Coll Cardiol 2017;70:1964-76.
8. Lurz P, Luecke C, Eitel I, et al. Comprehensive cardiac magnetic resonance imaging in patients with suspected myocarditis: The MyoRacer-Trial. J Am Coll Cardiol 2016;67:1800-11.
9. Messroghli DR, Moon JC, Ferreira VM, et al. Clinical recommendations for cardiovascular magnetic resonance mapping of T1, T2, T2* and extracellular volume: a consensus statement by the Society for Cardiovascular Magnetic Resonance (SCMR) endorsed by the European Association for Cardiovascular Imaging (EACVI). J Cardiovasc Magn Reson 2017;19:75.
10. Aquaro GD, Perfetti M, Camastra G, et al. Cardiac MR with late gadolinium enhancement in acute myocarditis with preserved systolic function: ITAMY Study. J Am Coll Cardiol 2017;70:1977-87.
11. Goerlich E, Gilotra NA, Minhas AS, Bavaro N, Hays AG, Cingolani OH. Prominent longitudinal strain reduction of basal left ventricular segments in patients with COVID-19. J Card Fail 2020;Sep 26:[Epub ahead of print].
12. Stobe S, Richter S, Seige M, Stehr S, Laufs U, Hagendorff A. Echocardiographic characteristics of patients with SARS-CoV-2 infection. Clin Res Cardiol 2020;Aug 14:[Epub ahead of print].
13. Karamitsos TD, Arvanitaki A, Karvounis H, Neubauer S, Ferreira VM. Myocardial tissue characterization and fibrosis by imaging. JACC Cardiovasc Imaging 2020;13:1221-34.
14. Lala A, Johnson KW, Januzzi JL, et al. Prevalence and impact of myocardial injury in patients hospitalized with COVID-19 infection. J Am Coll Cardiol 2020;76:533-46.

Clinical Topics: Acute Coronary Syndromes, COVID-19 Hub, Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Heart Failure, COVID-19, Coronavirus, severe acute respiratory syndrome coronavirus 2, Pandemics, Myocarditis, Gadolinium, Peptidyl-Dipeptidase A, Troponin, Prognosis, Stroke Volume, Cicatrix, Acute Coronary Syndrome, Cytokines, Control Groups

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