Pathophysiology and Cardiac Autopsy in COVID-19 related Myocarditis
Francesca Gattaa*, Ciaran Dolanb
aCastle Hill Hospital, Hull University Teaching Hospitals NHS Trust, UK
bHull Royal Infirmary, Hull University Teaching Hospitals NHS Trust, UK
*Corresponding Author: Francesca Gatta, Castle Hill Hospital, Hull University Teaching Hospitals NHS Trust
Received: 17 July 2020; Accepted: 26 July 2020; Published: 03 August 2020
Francesca Gatta, Ciaran Dolan. Pathophysiology and Cardiac Autopsy in COVID-19 related Myocarditis. Cardiology and Cardiovascular Medicine 4 (2020): 376-385.View / Download Pdf Share at Facebook
On the 11th of March 2020, the coronavirus disease-2019 (COVID-19) was declared a global Pandemic by the World Health Organization. This infectious disease is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS?CoV?2) which emerged in Wuhan, China, in December 2019, and rapidly spread across the world. Respiratory involvement ranging from a mild flu-like illness to potentially lethal acute respiratory distress syndrome is the predominant clinical manifestation. However, major cardiovascular complications have also been reported, with myocarditis contributing to mortality in up to a third of cases with severe COVID-19. In the presence of normal coronary arteries, acute myocarditis in SARS-CoV-2 cases may present with varying clinical severity, including myopericarditis, fulminant myocarditis, and cardiogenic shock. The pathophysiology of myocardial injury caused by SARS-CoV2 is not fully understood. The extent to which direct viral cytopathic effects contribute to the pathophysiology, compared with indirect systemic toxicity, remains unclear. The autopsy-proven myocardial localisation of the virus has rarely been reported.
Myocarditis; Acute myocardial injury; COVID-19; SARS-CoV-2
On the 11th of March 2020, the coronavirus disease-2019 (COVID-19) was declared a global Pandemic by the World Health Organization. This infectious disease is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS?CoV?2) which emerged in Wuhan, China, in December 2019, and rapidly spread across the world. As of June 2020, the World Health Organization reports 7 553 182 cases, with 423 349 deaths worldwide.
Respiratory involvement ranging from a mild flu-like illness to potentially lethal acute respiratory distress syndrome is the predominant clinical manifestation of SARS-CoV-2 . However, major cardiovascular complications have been reported  . Analysis of current literature revealed that 5-25% of COVID-19 related hospital admissions was a result of acute myocardial injury of multifactorial pathophysiology  . Myocardial injury significantly contributed to patient morbidity and mortality. In particular, myocarditis was a contributing factor to mortality in up to one third of cases with severe COVID- 19 . In the presence of normal coronary arteries, acute myocarditis in SARS-CoV-2 can present with varying clinical severity, including myopericarditis, fulminant myocarditis, and cardiogenic shock. The pathophysiology of myocardial injury caused by SARS-CoV2 is not yet fully understood and the extent to which direct viral cytopathic effects contribute to this, compared with indirect systemic toxicity, remains unclear .
The authors conducted a comprehensive literature review and searched for papers using the following key words: “myocarditis”, “acute myocardial injury”, “COVID-19”, and “SARS-CoV-2”. A total of 44 articles were selected. Retrospective studies, prospective studies, systematic reviews and meta-analyses, narrative reviews, clinical guidelines and case reports was included in this analysis. Pre-printed articles were also included. No language restrictions were applied.
Epidemiology and Clinical Manifestations
Acute myocardial injury, defined by high sensitivity?cardiac Troponin (hs-cTn) above the 99th percentile of upper reference limit, was found in 5-25% of COVID-19 cases admitted to hospital  .
Shi and colleagues analysed a single?centre cohort of 416 patients hospitalized due to COVID?19, and 19.7% of the sample size reported acute myocardial injury. Patients with cardiac injury reported a greater rate of mechanical ventilation (22.0% vs 4.2%; p<0.001), and mortality (51.2% vs 4.5%; p<0.001) .
A correlation between cardiac biomarkers and intensive care unit (ICU) admissions was published by Wang in a clinical cohort of 138 patients (hs?cTn level 11.0pg/mL vs 5.1pg/mL; p=0.004) .
Guo has classified 187 patients presenting with SARS?CoV?2 according to their levels of cTn (reported to be high in 27.8% of these cases) and demonstrated that higher levels of cTn were correlated with greater complications and higher mortality (59.6% vs 8.9%) .
In Ruan’s analysis of 68 deaths in a cohort of 150 patients positive for SARS-CoV-2, 7% were attributed to myocarditis with hemodynamic collapse, whilst in 33% of cases, myocarditis could have been a significant contributing factor to mortality .
The true incidence of myocarditis in COVID-19 cases remains unknown. Case reports worldwide have provided evidence of SARS-CoV-2 related myocarditis. Despite this, the pathophysiology of how SARS-CoV-2 causes myocardial damage still remains unclear.
Myocarditis is inflammation of the myocardium which can affect the contractility and the electrical signalling of the heart. This can lead to impaired systolic function and arrhythmias.
The diagnosis of myocarditis is often challenging. The cardinal diagnostic tools include clinical examination, electrocardiogram (ECG), echocardiography, cardiac magnetic resonance imaging (MRI) and endomyocardial biopsy. Clinical diagnosis can be obtained via the 2013 European Society of Cardiology's position statement that includes a clinical symptom such as chest pain, as well as a diagnostic criterion, for example high levels TnT or TnI . The classical echocardiographic signs of myocarditis include increased wall thickness, chamber dilatation, pericardial effusion and, of course, ventricular systolic dysfunction . The revised Lake Louise consensus criteria for the diagnosis of myocarditis with the cardiac MRI include (A) oedema, (B) irreversible cell injury, and (C) hyperaemia or capillary leak . Endomyocardial biopsy is recommended by both the American Heart Association (AHA) and the European Society of Cardiology (ESC), and typical histological findings are inflammatory infiltrates and viral RNA/DNA [9,12]. Nevertheless, early diagnosis of cardiac involvement in COVID-19 can be misguided in patients with chronic cardiac conditions by symptoms like fatigue (51%, 95% CI: 34?68%), dyspnoea (30%, 95% CI: 21?40%), and cough (67%, 95% CI: 59?76%), as these can also be manifestations of decompensated heart failure .
Patients with acute myocarditis related to SARS-CoV-2 can present with varying clinical severity (Table 1 [14-27]) including myopericarditis, fulminant myocarditis, and cardiogenic shock, in the presence of normal coronary arteries. Clinical symptoms vary from nonspecific flu-like symptoms to anginal chest pain. Similarly, a variety of ECG changes have been reported; bradyarrhythmias with high degree atrio-ventricular block and tachyarrhythmias (such as ventricular tachycardia), including ST elevation and T wave inversion. Conversely, almost all case reports document raised inflammatory markers, cTn and NT pro-BNP. Furthermore, left ventricle ejection fraction (LVEF) appears to be reduced, up to a severe degree, in the majority of patients. Cardiac MRI, when performed, shows a varying degree of myocardial oedema and ventricular hypokinesis. Finally, prior to discharge, echocardiography and/or cardiac MRI can demonstrate a full recovery of the LVEF.
Cases of pericardial effusion requiring emergency pericardiocentesis have also been reported [23,24].
Rapid deterioration into cardiogenic shock or acute respiratory distress syndrome (ARDS) makes the use of intra-aortic balloon pump (IABP) and veno-arterial extracorporeal membrane oxigenation (VA-ECMO) common among COVID-19 patients with a suspicion of myocarditis [15,23,24,26].
Beri’s article focused on the sudden cardiac death of a COVID-19 patient. The history of chest pain, dyspnoea and ventricular tachycardia (VT) on ECG pointed towards myocarditis .
Analysis of the paediatric population is beyond the aim of this review, however cases of suspected myocarditis in COVID-19 paediatric patients have been reported worldwide. A multicentre study analysed a case series of febrile paediatric patients admitted to ICU for cardiogenic shock, left ventricular dysfunction and severe inflammatory state, potentially associated with SARS-CoV-2. LVEF <30% was reported in one third and 28% required ECMO. The high levels of inflammation markers were suggestive of cytokine storm and macrophage activation, indicating indirect myocardial damage . A further multicentre analysis described a case series of acute myocarditis and major systemic inflammation following SARS-CoV-2 infection in 20 critically ill children. LVEF was 35% (25–55) and cTn 269 ng/mL (31–4607) .
Table 1: Case reports on COVID-19 related myocarditis
cTn: cardiac Troponin. NT pro-BNP: N-terminal pro B-type natriuretic peptide. LVEF: left ventricle ejection fraction. AV: atrio-ventricular. cMRI: cardiac magnetic resonance imaging. AF: atrial fibrillation. VR: ventricular rate. LV: left ventricle
The acute myocardial injury caused by SARAS-CoV-2 appears to have a multifactorial pathophysiology which is not yet fully characterized. Several explanatory theories have been postulated. Case reports of myocarditis in COVID19 provide evidence for cardiac inflammation but do not reveal the mechanism, thus it remains unclear how much of the cardiac injury is attributable to direct viral infection (cytopathic damage) versus indirect systemic toxicity [7,31].
Prior acute myocarditis experience with alternative viruses suggests that direct cellular injury is related to a combination of cardiotropic viral entry into myocytes and the subsequent innate immune response that can lead to focal or diffuse myocardial necrosis [32,33]. Within a few days of this direct cellular injury, oedema and necrosis can lead to contractile dysfunction and clinical symptoms [32,33].
Chronic cardiovascular diseases may become unstable in the setting of a viral infection as a consequence of the imbalance between the infection?induced increase in metabolic demand and reduced cardiac reserve [5,34].
A key role in the pathophysiology of myocarditis is played by the prompt and severe downregulation of myocardial ACE-2 (angiotensin-converting enzyme 2) pathways. Beyond its function in cardiovascular homeostasis, ACE-2 is also a functional receptor widely expressed in the lungs, as well as other organs, including the heart, and constitutes a portal of entry for SARS-CoV-2 . The binding of SARS-CoV-2 to ACE-2, particularly in the epicardial adipose tissue , results in alteration of the neurohumoral signalling pathways, thereby resulting in direct myocardial injury . Importantly, brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) transcripts are co-upregulated in ACE2-postive cardiomyocytes (CMs). BNP, ANP, and ACE2 may form a feedback loop associated with the RAAS (renin-angiotensin-aldosterone-system)/Ang II signalling pathway. One of the most interesting findings is that ACE-2 appears not to be equally expressed in all of the ventricular and atrial CMs, but only expressed in approximately 5% normal ventricular or atrial CMs. Conversely, ACE-2 expression is increased to 30% in the ventricular CMs of failing hearts, indicating that heart failure patients are more prone to develop myocardial injury if SARS-CoV-2 positive .
Other proposed mechanisms of myocardial injury include a cytokine storm triggered by an imbalanced response by type 1 and 2 T?helper cells [4,38], and strong interferon?mediated immunopathological events , resulting in indirect injury. IL(interleukin)-6, IL-2, IL-7, TNF (tumor necrosis factor)-α, IFN (interferon)-γ IP (inducible protein)-10, MCP (monocyte chemoattractant protein)-1, MIP (macrophage inflammatory protein)-1α, G-CSF (granulocyte-colony stimulating factor), CRP (C-reactive protein), procalcitonin, and ferritin activate immune cell differentiation and the trafficking of leukocytes to sites of infection [7,40].
Finally, respiratory dysfunction and hypoxemia caused by COVID?19 can lead to myocardial cell damage .
Thus far, the data demonstrating the presence of SARS-CoV-2 within myocardial tissue is inconsistent .
For the first time, Tavazzi and colleagues were able to demonstrate the presence of viral particles in the heart of a COVID-19 patient in cardiogenic shock. The pathologic study showed low-grade interstitial and endocardial inflammation, as well as large (>20μm), vacuolated, CD68-positive macrophages. The ultrastructural study demonstrated single or small groups of viral particles with the morphology (dense round viral envelope and electron-dense spike-like structures on their surface) and size (variable between 70 and 120 nm) of coronaviruses, in cytopathic, structurally damaged interstitial cells with loss of the cytoplasmic membrane integrity. Cardiac myocytes showed non-specific features consisting of focal myofibrillar lysis, and lipid droplets .
In New Orleans, examination of the heart in 9 deceased COVID-19 cases was carried out. Cardiomegaly and right ventricular dilatation were the main gross abnormalities. Histologically, there was scattered individual cell myocyte necrosis, and rare small interstitial collections of lymphocytes were noted. There was no obvious viral cytopathic effect by light microscopy. These findings might represent an early stage of viral myocarditis .
Similarly, the autopsy performed in a SARS-CoV-2 positive patient in Houston showed multifocal lymphocytic infiltrates in the epicardium with enlarged hyperchromatic nuclei, suggestive of an acute injury .
Cardiac autopsy from a deceased SARS-CoV-2 patient showed a few interstitial mononuclear inflammatory infiltrates, but no other substantial damage in the heart tissue. However, during hospitalization, the patient did not show any clinical signs of myocardial involvement as their symptoms were mainly respiratory .
Interestingly, Craven reported a case of eosinophilic myocarditis in a SARS-CoV-2 positive 17-year-old patient. Microscopically, diffuse inflammatory infiltrates composed of lymphocytes, and macrophages, with prominent eosinophils were detected. This inflammation was primarily in the interstitium, and was associated with multiple foci of myocyte necrosis in both ventricles .
Since the outspread of severe acute respiratory syndrome coronavirus 2 (SARS?CoV?2), remarkable e?orts have been made to increase the understanding of the pathophysiology of myocardial injury in COVID-19 patients. Whether this is a result of a direct cytopathic effect of the virus on the myocardium (SARSCoV-2 viral myocarditis), or an indirect result of the complications of the disease remains unclear.
It would be highly desirable that the future studies on COVID-19 specifically described the incidence, outcomes and cardiac autopsy results of patients with a diagnosis of myocarditis.
This review consists of some limitations, which merit consideration. Firstly, the significant heterogeneity in study design, patient selection and outcomes. Secondly, di?erent criteria for the diagnosis of myocarditis may be used, and this may a?ect incidence between studies. Finally, due to the current pandemic, a consistent amount of literature is published in a preprint form, prior to full peer review.
Authors declare no conflict of interest.
- Bansal M. Cardiovascular disease and COVID-19. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14 (2020): 247-250.
- Alderighi C, Rasoini R, Ambrosio G, et al. Nuove acquisizioni sulla gravità del danno cardiaco acuto in corso di COVID-19. G Ital Cardiol 21 (2020): 328-331.
- Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol (2020).
- Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395 (2020): 497-506.
- Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. Jama 323 (2020): 1061-1069.
- Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 46 (2020): 846-848.
- Akhmerov A, Marbán E. COVID-19 and the Heart. Circ Res 126 (2020): 1443-1455.
- Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol (2020).
- 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 34 (2013): 2636-2648.
- Siripanthong B, Nazarian S, Muser D, et al. Recognizing COVID-19-related myocarditis: The possible patophysiology and proposed guidelines for diagnosis and management. Heart rhythm (2020): S1547-5271.
- Friedrich MG, Sechtem U, Schulz-Menger J, et al. Cardiovascular magnetic resonance in myocarditis: a JACC White Paper. J Am Coll Cardiol 53 (2009): 1475-1487.
- Kociol RD, Cooper LT, Fang JC, et al. Recognition and initial management of fulminant myocarditis: a scientific statement from the American Heart Association. Circulation 141 (2020): e69-e92
- Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta?analysis,» Int J Infect Dis 94 (2020): 91-95.
- Asif T, Ali Z. Transient ST segment elevation in two patient with COVID-19 and a normal transthoracic echocardiogram,» Eur J Case Rep Iintern Med 7 (2020): 001672
- Zeng J, Liu Y, Yuan J, et al. First case of COVID 19 complicated with fulminant myocarditis: a case report and insights. Infection (2020): 1-5.
- Cizgici AY, Agus HZ, Yildiz M. COVID-19 myopericarditis: it should be kept in mind in today's conditions. Am J Emerg Med (2020): S0735-6757.
- Kir D, Mohan C, Sancassani R. HEART BRAKE-An unusual cardiac manifestation of Coronavirus disease 2019 (COVID-19). JACC Case Rep (2020).
- Coyle J, Igbinomwanhia E, Sanchez-Nadales A, et al. A Recovered Case of COVID-19 Myocarditis and ARDS Treated with Corticosteroids, Tocilizumab, and Experimental AT-001. JACC Case Rep (2020).
- Doyen D, Moceri P, Ducreux D, et al. Myocarditis in a patient with COVID-19: a cause of raised troponin and ECG changes. Lancet 395 (2020): 1516
- Paul J, Charles P, Richaud C, et al. Myocarditis revealing COVID-19 infection in a young patient. Eur Heart J Cardiovasc Imaging (2020).
- Hu H, Ma F, Wei X, et al. Coronavirus fulminant myocarditis treated with glucocorticoid and human immunoglobulin. European Heart Journal (2020).
- Inciardi RM, Lupi L, Zaccone G, et al. Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19). JAMA Cardiol (2020).
- Irabien-Ortiz A, Carreras-Mora J, Sionis A, et al. Miocarditis fulminante por COVID-19. Rev Esp Cardiol (2020).
- Khalid N, Chen Y, Case BC, et al. COVID-19 (SARS-CoV-2) and the heart - An ominous association. Cardiovasc Revasc Med (2020): S1553-8389.
- Kim I, Kim JY, Kim HA, et al. COVID-19-related myocarditis in a 21-year-old female patient. Eur Heart J 41 (2020): 1859.
- Tavazzi G, Pellegrini C, MAurelli M, et al. Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Eur J Heart Fail 22 (2020): 911-915.
- Warcho? I, D?bska?Koz?owska A, Karcz?Socha I, et al. Terra incognita: clinically suspected myocarditis in a patient with severe acute respiratory syndrome coronavirus 2 infection. Pol Arc Intern Med 130 (2020): 446-448.
- Beri A, Kotak K. Cardiac injury, arrhythmia and sudden death in a COVID-19 patient. HeartRhythm Case Report (2020).
- Belhadjer Z, Meot M, Bajolle F, et al. Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic. Circulation (2020).
- Grimaud M, Starck J, Levy M, et al. Acute myocarditis and multisystem inflammatory emerging disease following SARS-CoV-2 infection in critically ill children. Ann Intensive Care 10 (2020): 69.
- Yao XH, Li TY, He ZC, et al. A pathological report of three COVID-19 cases by minimally invasive autopsies. Zhonghua Bing Li Xue Za Zhi 49 (2020): 411-417.
- Cooper LT Jr. Myocarditis. N Engl J Med 360 (2009): 1526–1538.
- Hendren NS, Drazner MH, Bozkurt B, et al. Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome. Circulation 141 (2020): 1903-1914.
- Kochi AN, Tagliari AP, Forleo GB, et al. Cardiac and arrhythmic complications in patients with COVID-19. J Cardiovasc Electrophysiol 31 (2020): 1003-1008.
- Zhao L. Obesity accompanying COVID-19: the role of epicardial fat. Obesity (Silver Spring) (2020).
- Oudit GY, Kassiri Z, Jiang C, et al. SARS?coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SAR. Eur J Clin Invest 39 (2009): 618-625.
- Xu D, Ma M, Xu Y, et al. Single-cell Transcriptome Analysis Indicates New Potential Regulation Mechanism of ACE2 and NPs signaling among heart failure patients infected with SARS-CoV-2. medRxiv (2020).
- Wong CK, Lam CWK, Wu AKL, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol 136 (2004): 95-103.
- Cameron MJ, Bermejo-Martin JF, Danesh A, et al. Human immunopathogenesis of severe acute respiratory syndrome (SARS). Virus Res 133 (2008): 13-19.
- Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 395 (2020): 1033-1034.
- Fox SE, Akmatbekov A, Harbert JL, et al. Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans. Lancet Resp Med (2020): S2213-S2600.
- Buja LM, Wolf DA, Zhao B, et al. The emerging spectrum of cardiopulmonary pathology of the coroavirus disease 2019 (COVID-19): Report of 3 autopsies from Houston, Texas, and review of autopsy findings from other Unites States cities. Cardiovasc Pathol 48 (2020): 107233.
- Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 8 (2020): 420-422.
- Craver R, Huber S, Sandomirsky M, et al. Fatal Eosinophilic Myocarditis in a Healthy 17-Year-Old Male with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2c). Fetal Pediatr Pathol 39 (2020): 263-268.