COVID-19 vs. Classical Myocarditis Associated Myocardial Injury Evaluated by Cardiac Magnetic Resonance and Endomyocardial Biopsy

Background: Despite the ongoing global pandemic, the impact of COVID-19 on cardiac structure and function is still not completely understood. Myocarditis is a rare but potentially serious complication of other viral infections with variable recovery, and is, in some cases, associated with long-term cardiac remodeling and functional impairment.

Aim: To assess myocardial injury in patients who recently recovered from an acute SARS-CoV-2 infection with advanced cardiac magnetic resonance imaging (CMR) and endomyocardial biopsy (EMB).

Methods: In total, 32 patients with persistent cardiac symptoms after a COVID-19 infection, 22 patients with acute classic myocarditis not related to COVID-19, and 16 healthy volunteers were included in this study and underwent a comprehensive baseline CMR scan. Of these, 10 patients post COVID-19 and 13 with non-COVID-19 myocarditis underwent a follow-up scan. In 10 of the post-COVID-19 and 15 of the non-COVID-19 patients with myocarditis endomyocardial biopsy (EMB) with histological, immunohistological, and molecular analysis was performed.

Results: In total, 10 (31%) patients with COVID-19 showed evidence of myocardial injury, eight (25%) presented with myocardial oedema, eight (25%) exhibited global or regional systolic left ventricular (LV) dysfunction, and nine (28%) exhibited impaired right ventricular (RV) function. However, only three (9%) of COVID-19 patients fulfilled updated CMR–Lake Louise criteria (LLC) for acute myocarditis. Regarding EMB, none of the COVID-19 patients but 87% of the non-COVID-19 patients with myocarditis presented histological findings in keeping with acute or chronic inflammation. COVID-19 patients with severe disease on the WHO scale presented with reduced biventricular longitudinal function, increased RV mass, and longer native T1 times compared with those with only mild or moderate disease.

Conclusions: In our cohort, CMR and EMB findings revealed that SARS-CoV-2 infection was associated with relatively mild but variable cardiac involvement. More symptomatic COVID-19 patients and those with higher clinical care demands were more likely to exhibit chronic inflammation and impaired cardiac function compared to patients with milder forms of the disease.

Background
The systemic (immune) response to a SARS-CoV-2 infection varies widely, ranging from asymptomatic or mildly symptomatic respiratory infection to a systemic life-threatening condition with multiple organ failure. A three-phase model of pathogenesis of COVID-19 has been proposed (1) where a significant minority of patients progress to a critical hyperinflammation phase characterized by a systemic host response with elevated IL-2, IL-6, IL-7, TNF-α, C-reactive protein, and D-dimer levels. Several studies (2–4) demonstrated cardiac pathologic modifications reflected by elevated troponin and N-terminal pro B-type natriuretic peptide in 10–28% of COVID-19 patients, requiring hospitalization. In a large multicentre study (5), myocardial injury was diagnosed in 62% of cases presenting with troponin elevation and was associated with higher percentage of abnormal echocardiographic findings and higher mortality. Moreover, patients with cardiovascular comorbidities are more likely to develop severe forms of COVID-19 (2, 3).

Several pathogenic mechanisms may explain the specific cardiac findings post-COVID-19: triggered pan-endotheliitis (4) or macrophage activation (6) precipitating acute plaque rupture and coronary events (7), imbalanced activation of helper T cells leading to cytokine storm and direct myocardial injury (3), sepsis, or hypoxia-induced myocyte apoptosis (8).

A recent cardiac magnetic resonance (CMR) cross-sectional study (9) suggested that COVID-19 might be responsible for a sustained subacute or chronic inflammatory state of the myocardium comparable with cases of viral myocarditis and prone to cause long-term cardiac impairment by downstream activation of ventricular remodeling and fibrosis. However, the clinical relevance of these findings has been discussed controversially, given the lack of a matched comparison group (10). To date, studies comparing CMR findings including late gadolinium enhancement (LGE) and mapping with histology are limited, and longitudinal analyses are completely missing in this context (11).

In this study, we used an advanced CMR protocol to examine potential effects of COVID-19 on cardiac function and structural remodeling in consecutive patients with a recent SARS-CoV-2-infection using endomyocardial biopsy (EMB) data as the reference standard. In addition, we sought to compare these findings to healthy volunteers and a cohort of patients with “classic” myocarditis. Follow-up CMR assessment was performed in patients with COVID-19 and in those with “classic” myocarditis. To compare histological and/or immunohistological findings between patients with COVID-19 and patients with myocarditis, available EMB samples were evaluated according to the current diagnostic criteria for myocarditis (12).