key: cord-0943207-hopoykg9
authors: Lima, João A. C.; Bluemke, David A.
title: Myocardial Scar in COVID-19: Innocent Marker versus Harbinger of Clinical Disease
date: 2021-08-10
journal: Radiology
DOI: 10.1148/radiol.2021211710
sha: e9abcea5db21239e7d94820db87f319ab6aef5e0
doc_id: 943207
cord_uid: hopoykg9

nan

I n p r e s s SARS-CoV-2 infection and its accompanying immune response are characterized by intense inflammation in the acute phase of infection. The cardiopulmonary system is involved either directly and indirectly via a systemic inflammatory response (i.e., cytokine release and prothrombotic state) (1) . Up to 60% of patients hospitalized due to COVID-19 have been reported to have evidence of myocardial injury (2) . Following hospital discharge, investigators estimate that approximately 10% of patients report palpitations and 5% have ongoing chest pain months later (3) . Prolonged symptoms due to COVID-19 (frequently referred to as "longhaul COVID") portend the potential for chronic cardiac sequelae, as of yet, unknown duration and severity. These concerns have led to detailed investigation employing powerful phenotyping tools such as cardiac MRI.

In this issue of Radiology, Kravchenko et al (4) studied 41 participants with chronic symptoms including fatigue and exertional dyspnea 3 months after COVID-19 infection. Patients were compared to 42 volunteer study participants matched by sex and age who had no history of previous exposure to SARS-CoV-2. Importantly, none of the study patients had been hospitalized for COVID-19. Patients had no evidence of acute myocardial inflammation on T2 mapping or interstitial fibrosis on MRI. However, three of 41 patients (7%) had unequivocal late gadolinium enhancement (LGE) on MRI and two of them had sub-epicardial LGE compatible with sub-acute or chronic replacement fibrosis. The third patient had a focal mid-myocardial LGE abnormality commonly seen in a patient with right ventricular overload due to pulmonary hypertension, pulmonary disease, or in asymptomatic individuals. As incidental findings on cardiac MRI, the authors also report that 1 patient had a pericardial effusion, another presented signs of right ventricular overload, and 4 patients had pulmonary findings including persistent opacities (one patient) and pleural effusions (two patients).

The findings of Kravchenko et al are important for several reasons. First, these results underscore early reports of convalescing COVID-19 patients that also showed replacement myocardial fibrosis. Second, the patients evaluated by Kravchenko et al were not hospitalized nor were they individuals who required evaluation before returning to sports activities. Instead, these patients enrolled in the study because of chronic symptoms and physical limitations many weeks after recovery from acute infection. Interestingly, active myocardial inflammation was not present on the 3-month post-COVID-19 cardiac MRI. Previous studies in previously hospitalized and non-hospitalized post-COVID-19 patients with and without persisting symptoms have reported active cardiac inflammation (demonstrated by T2 weighted imaging or T2 mapping). Finally, despite sub-epicardial myocardial scar, chronic interstitial fibrosis was not found, also in contrast to other studies. The work by Kravchenko et al highlights the dissociation between diffuse interstitial and focal replacement fibrosis as sequelae from SARS-CoV-2-induced myocarditis.

Sub-epicardial myocardial scars are the hallmark of myocardial damage commonly seen in conditions classified as non-ischemic cardiomyopathies. Sub-epicardial LGE is also common in patients with acute viral myocarditis not caused by SARS-CoV2. The same MRI pattern may I n p r e s s persist into the sub-acute and chronic phases of the disease, representing a harbinger of potential progression to myocardial dysfunction or arrhythmia. In patients with acute or subacute myocarditis, as well as in those with other conditions such as autoimmune rheumatic processes, Duchenne cardiomyopathy and Fabry disease, the precise pathogenetic pathways leading to sub-epicardial inflammation and/or scar remain unknown.

In contrast to nonischemic injury, myocardial damage due to coronary artery disease is more common in the sub-endocardial (inner) layer of the myocardium. Sub-endocardial injury results from severely reduced myocardial perfusion or unusually elevated levels of wall stress. The subendocardial layer of the myocardium is perfused by perforating transmural arterioles that supply blood from epicardial coronary arteries to these innermost myocardial layers. The myocardial blood supply traverses the ventricular wall in perpendicular orientation and is compressed during myocardial contraction. Such structural-functional characteristics place subendocardial myocytes at greater risk of damage in conditions associated with ischemia and overload.

In certain nonischemic cardiomyopathies, sub-epicardial myocytes may be exposed to greater risk than those in other myocardial layers in conditions associated with pericardial inflammation. These conditions include infectious pathogens, auto-immune diseases, and invasive processes originating in the lungs or other organs in contiguity or close proximity to the heart. Viral pericardial involvement has been well documented in isolated pericarditis, but also in association with viral myocarditis and systemic disease. Similarly, autoimmune rheumatic diseases, particularly lupus erythematosus and scleroderma, are well known to preferentially involve the pericardium and sub-epicardium in many patients, supporting the idea of subepicardial inflammation, necrosis, and replacement fibrosis in association with pericardial inflammatory involvement. However, a multitude of other cardiomyopathic processes are also associated with sub-epicardial and mid-myocardial scar formation without prominent pericardial involvement. In addition, the concept of contiguity between the pericardium and sub-epicardium does not entirely explain why such diseases may demonstrate involvement of the entire thickness of the myocardium, rather than preferential sub-epicardial myocardial damage. In this regard, further investigation into the pathogenesis of non-ischemic myocardial MRI LGE patterns is needed.

What is the clinical importance of SARS-CoV-2-associated myocardial scar? How common are myocardial scars in considering the entire population of individuals who have had COVID-19? Will the extent of cardiac scarring become a broader public health problem, given that sooner or later an ever-growing number of individuals across the world are being exposed to SARS-CoV2? In the best case, COVID-19-associated myocardial scar is a mere marker of having had acute COVID-19 infection. Unfortunately, early reports suggest that at least in some individuals, myocardial scar from COVID-19 is associated with lower myocardial function.

In middle and older age adults in the United States, approximately 4% of individuals have MRIdetectable nonischemic myocardial scar without direct clinical consequence. However, MRI-I n p r e s s detected scar tends to be associated with risk factors for cardiovascular disease, myocardial interstitial fibrosis, and left ventricular hypertrophy. Among patients with myocarditis accompanied by chest pain and troponin elevation, myocardial scars may be associated with ventricular arrhythmias and sudden cardiac arrest, even in the setting of normal or near normal left ventricular function. The work by Kravchenko et al suggests that myocardial scar may be uncommon (or even rare) among patients who did not have moderate to severe acute COVID-19 infection. However, the true prevalence of persistent myocardial injury among individuals who had COVID-19 with or without prolonged long-haul COVID-19 symptoms remains unknown at the present time.

The work by Kravchenko et al invites further epidemiologic investigation regarding the prevalence of myocardial involvement in individuals who have been infected by SARS-CoV-2. Ideally, we need to examine individuals who have had different degrees of systemic, pulmonary, or upper respiratory involvement, as well as different levels and types of comorbidities and cardiovascular risk factor profiles. Their work suggests the need for detailed cardiovascular phenotyping of patients with long-COVID-19 symptoms in relationship to inflammation, healing or adverse patterns of hypertrophy, fibrosis, and myocardial injury. In this regard, an ongoing initiative to carefully demarcate the cardiopulmonary and cerebral consequences of COVID-19 by the National Heart Lung and Blood Institute, together with other related units composing the National Institutes of Health, is extremely important.

Association of Cardiac Injury with Mortality in Hospitalized Patients with COVID-19 in Wuhan, China

Characterization of Myocardial Injury in Patients With COVID-19

6-month consequences of COVID-19 in patients discharged from hospital: a cohort study

Cardiac MRI in patients with prolonged cardiorespiratory symptoms after mild to moderate COVID-19 infection

p r e s s Dr Joao A. C. Lima is professor of medicine at Johns Hopkins University and has studied cardiac remodeling, hypertrophy and fibrosis for over 30 years using MRI, CT and ultrasound in clinical and population studies. He is fully funded by the National Heart, Lung and Blood Institute as a SOL, MESA, CARDIA and MACSWIHS investigator. Dr. Lima has also dedicated significant effort in mentorship of young investigators pursuing research in medicine, radiology, epidemiology and biomedical engineering. His group at Hopkins also functions as the core imaging laboratory in current studies exploring cell therapy and small molecules to treat heart failure.