Pathological Evidence for SARS-CoV-2 as a Cause of Myocarditis

JACC Review Topic of the Week

Rika Kawakami, MD; Atsushi Sakamoto, MD; Kenji Kawai, MD; Andrea Gianatti, MD; Dario Pellegrini, MD; Ahmed Nasr, MD; Bob Kutys, PA; Liang Guo, PHD; Anne Cornelissen, MD; Masayuki Mori, MD; Yu Sato, MD; Irene Pescetelli, MD; Matteo Brivio, MD; Maria Romero, MD; Giulio Guagliumi, MD; Renu Virmani, MD; Aloke V. Finn, MD


J Am Coll Cardiol. 2021;77(3):314-325. 

In This Article

Clinical and Pathological Diagnosis of COVID-19-induced Myocardial Injury

Despite having endured the COVID-19 pandemic for over 6 months, many questions still remain about the best approaches for determining causes of cardiac injury in both hospitalized and nonhospitalized patients. In most cases, cardiac injury appears to result within the context of the overall respiratory infection rather than the first manifestation of disease. Coagulation abnormalities that may result as a part of the immune response to the disease have been shown to predispose these patients toward thrombotic processes, both in the venous and arterial circulation.[11] A single-center observational study on COVID-19 subjects with ST-segment elevation myocardial infarction (STEMI) documented higher troponin levels, multivessel thrombosis, and stent thrombosis when compared with COVID-19 patients without STEMI.[13] However, a substantial number of cases in subjects with STEMI had no evidence of coronary occlusion. In 1 case series from New York involving 18 patients with a confirmed diagnosis of COVID-19 and ST-segment elevation, 44% received a diagnosis of acute coronary thrombosis causing myocardial infarction, and 56% had evidence of noncoronary myocardial injury (defined as nonobstructive disease on coronary angiography).[14] It is precisely in cases such as these, or in situations where troponin levels are elevated but clinical suspicion of acute coronary syndrome is low, where diagnostic dilemmas may occur. Because the clinical presentation of myocarditis may vary and may include vague or nonspecific symptoms such as fatigue, dyspnea, palpitations, and chest discomfort, the diagnosis of myocarditis in this setting is not straightforward.

The World Health Organization defines myocarditis as an inflammatory disease of the myocardium diagnosed by established histological, immunological, immunohistochemical, and molecular criteria with endomyocardial biopsy (EMB) used to gain certainty on the diagnosis and to potentially identify etiology.[15] The current indication for EMB is "a strong reason to believe that the results will have a meaningful effect on subsequent therapeutic decisions" according to the American College of Cardiology guidelines.[16] These guidelines state that EMB should be performed in the setting of new-onset heart failure with hemodynamic compromise or new ventricular arrhythmias (Class I recommendation), but the timing and exact criteria for EMB in cases of myocarditis, especially in the setting of COVID-19 infection, remain uncertain.

Histological evidence from cardiac biopsies and autopsy hearts for myocarditis was initially diagnosed by the Dallas criteria (1985) and defined as histological evidence of inflammatory infiltrates within the myocardium associated with myocyte degeneration or necrosis (myocytolysis) of nonischemic origin.[17] In the absence of necrosis and the presence of lymphocytic infiltrate, myocarditis was defined as borderline. In addition to a sampling error in EMBs containing PCR-detectable viral pathogens, the Dallas criteria were absent in 50% of virus positive cases.[18] For these reasons, the use of Dallas criteria alone to diagnose myocarditis has been discouraged. More recently, immunohistochemical criteria have been added to address these shortcomings. By immunohistochemistry, myocarditis is defined according to the presence of an abnormal inflammatory infiltrate, defined as follows: ≥14 leukocytes/mm2 including up to 4 monocytes/mm2 with the presence of CD3-positive T-lymphocytes ≥7 cells/mm.[19] Cell counts must be accompanied by evidence of myocyte degeneration and necrosis of nonischemic origin.

The appearance of inflammatory infiltrates alone in the absence of myocyte necrosis can be seen in normal myocardium as has been reported by us and others in individuals dying a noninfectious death.[20,21] From our experience, it is the pattern of inflammatory infiltrate (concentrated collection of inflammatory cells [predominance of lymphocytes versus macrophages] around myocytes), extent, and presence of myocyte necrosis that defines myocarditis.[16] Molecular biology diagnosis is defined as histological evidence for myocarditis associated with positive viral PCR to confirm the diagnosis of infectious myocarditis. Virus-negative myocarditis is defined as histological myocarditis with negative viral PCR.

Practically speaking, EMB is not routinely used to diagnose myocarditis and patients may be given the diagnosis of COVID-19 myocarditis based upon circumstantial evidence such as abnormal echocardiography or magnetic resonance imaging examinations. In 1 series where cardiac involvement was evaluated (using CMR) in 15 patients who reported cardiac symptoms but were considered recovered from COVID-19, 58% had abnormal CMR findings consisting mostly of myocardial edema, fibrosis, and impaired right ventricular function.[3] In another series of 100 recovered patients, 78% had detectable cardiac involvement via CMR with 75% having detectable troponin levels.[4] These studies raise the possibility that months after infection, ongoing myocardial inflammation with resultant left ventricular dysfunction may occur. In the following text, we will discuss data regarding the findings of EMB in cases of suspected COVID-19–induced myocarditis or unexplained heart failure and the low overall diagnostic yield of such investigations. Our opinion on the role of EMB in cases of suspected COVID-19 myocarditis is given later in this review.