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

Disclosures

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

In This Article

What is the Evidence for SARS-CoV-2 as a Cause of Myocarditis?

Coronaviruses are a family of enveloped, positive-sense, single-stranded, and highly diverse RNA viruses. To date, there have been 3 documented, highly pathogenic, and lethal human coronaviruses: SARS-CoV, Middle East Respiratory Syndrome–CoV, and SARS-CoV-2. SARS-CoV-2 shares approximately 79.5% genomic homology with SARS-CoV, but only about 50% with Middle East Respiratory Syndrome–CoV, indicating that SARS-CoV-2 is closer to SARS-CoV.[22] SARS-CoV was highly lethal, but its presence was mitigated effectively by intense public health measures. Although many similarities exist between SARS-CoV and SARS-CoV-2, important differences also exist in transmissibility and disease pathogenesis. Nonetheless, lessons learned from the effects of SARS-CoV may have some degree of relevance to our current understanding of how SARS-CoV-2 might affect the heart. Autopsy data from 20 patients who died during the SARS outbreak in 2003 identified viral RNA in the hearts of 7 of these patients.[23] Immunohistochemical staining of postmortem myocardial tissue using macrophage-specific marker (CD68) revealed a significant amount of macrophage infiltration, which was increased in patients who had evidence of SARS-CoV (by PCR) in their hearts with only minor elevation in those without SARS-CoV. By contrast, immunohistochemical staining for T-cell specific (CD3) cell surface markers showed that myocardial lymphocytic infiltration was minimal with no differences in lymphocyte counts between those with and without SARS-CoV in their hearts. Although virus entry occurs predominantly via the angiotensin-converting enzyme receptor 2 for both SARS-CoV and SARS-CoV-2, organ tropism may be different given the differing clinical presentations and infectiousness of the 2 pathogens.

To date, 9 cases have been reported where EMB was performed in COVID-19–positive subjects.[24–27] The diagnostic criteria for myocarditis were met in only 2 of these cases. In all studies, there was no direct evidence of SARS-CoV-2 within cardiomyocytes. For the most part, direct proof that SARS-CoV-2 infects myocytes leading to virus-induced necrosis and cell death with troponin release is lacking. In 1 of the cases that met the authors' diagnostic criteria for myocarditis, a 43-year-old woman had an inverted Takotsubo pattern in the setting of COVID-19 infection.[24] The final diagnosis was virus-negative immune-mediated myocarditis, because the PCRs of EMB samples were negative for the SARS-CoV-2 genome. In another case, a 48-year-old man with newly diagnosed heart failure in the setting of COVID-19 infection underwent EMB.[26] Histological assessment met the Dallas criteria with necrosis of myocytes and pronounced myocardial inflammation with macrophages and lymphocytes, and PCR of the EMB sample was positive for the viral genome (albeit at a very low level). A summary of the results of prior studies published to date on EMB samples in the setting of COVID-19 infection is shown in Table 1.

Another method to demonstrate the effect of COVID-19 on the heart is through autopsy studies. Although many studies have focused on the pulmonary findings of COVID-19, few studies have been conducted specifically examining the effects of COVID-19 on the heart. In the largest series of autopsies conducted in a New York hospital in subjects dying of COVID-19 infection, hearts from 25 cases were evaluated.[28] Most hearts showed evidence of pre-existing atherosclerotic or hypertensive heart disease, with 60% of cases showing nonspecific patchy, mild interstitial chronic inflammation within the myocardium without associated myocyte necrosis. More recently, and as mentioned in the previous text, Lindner et al.[6] quantified viral load in 39 consecutive autopsy cases from Germany and demonstrated that SARS-CoV-2 could be documented in 24 of 39 (61.5%); yet, none of these cases were found to meet the criteria for myocarditis. Recently Basso et al.[29] reported a multicenter autopsy case series examining 21 hearts from COVID-19 cases. They found myocarditis in 3 cases (3 of 21; 14.2%), defined as the presence of an inflammatory infiltrate associated with myocyte injury not due to other causes and observed in multiple foci.[29] All 3 cases had CD3-positive lymphocytes (2 had CD4, 1 had CD8 predominance) as well as macrophages. The high rate of myocarditis reported in this paper may in part be due to selection bias, as cases were referred from 4 separate institutions. A recently published literature review of 277 autopsied hearts across 22 publications found that myocarditis was present in 20 hearts (7.2%), with closer examination by the authors revealing that most cases were likely not functionally significant, and in their opinion, the true prevalence was much lower (<2%).[30] A list of the findings of published papers that included pathological analysis of hearts from COVID-19–positive subjects using specific and well-adopted criteria for the diagnosis of myocarditis are listed in Table 1. Of the collective 201 hearts (or EMB samples) examined in published series, in 9 cases (4.5%), investigators found some evidence of myocarditis of unclear extent and nature. In most of these cases, analysis for the virus in the heart was not performed and evidence for direct infection of cardiac myocytes has not been shown.

An import caveat to the analysis of these studies (as well as to the clinical diagnosis of SARS-CoV-2) is the possibility of false-negative results, which in the case of tissue samples, might be caused by either sampling errors or by degradation of viral RNA during the process of fixation prior to analysis.[31] Indeed, a recent case report documented the occurrence of 2 subjects with clinically suspected myocarditis whose nasopharyngeal swab tests for COVID-19 were negative but the virus was recovered by PCR from EMB specimens.[27] It is important to recognize the reliability of SARS-CoV-2 RNA tests when examining diagnostic pathology reports.

In addition to the possibility of false-negative PCR results during tissue sampling, it is also likely that given the low overall expression of ACE2 receptor in myocardial cells, tropism of SARS CoV-2 for the heart is not likely.[32] Takotsubo syndrome is another potential cause of myocardial injury in the setting of electrocardiographic abnormalities and troponin-positive results with normal coronaries and should also be considered. In such cases, patients are known to have regional wall motion abnormalities, injury to myocytes, and infiltration of lymphocytes and macrophages in autopsy specimens. However, to be sure of the diagnosis, this requires exclusion of myocarditis. Troponin levels and CMR signs of edema can be found in both entities and each can mimic the other.

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