Abbreviations

ACS: Acute coronary syndrome; AHA: American Heart Association; CMR: Cardiac magnetic resonance; CT: Computerized tomography; MHC: Major histocompatibility complex; SCMR: Society for Cardiovascular Magnetic Resonance; TNF: Tumor necrosis factor; WHO: World Health Organization.

Introduction

The ongoing pandemic of Coronavirus Disease 2019 (COVID-19) was first described in Wuhan, China, and has rapidly spread across the globe [1–3]. In March 2020, it was declared a public health emergency by the World Health Organization (WHO) [1–3]. With the rapidly increasing number of confirmed cases every day, knowledge and the clinical presentation of COVID-19 infection have changed markedly. In addition to the common clinical presentation of respiratory involvement ranging from mild respiratory symptoms to respiratory failure caused by COVID-19, the cardiovascular manifestations prompted by this viral disease has raised significant concern as a part of multiorgan involvement [3–6].

COVID-19 infection with associated cardiac manifestations has been reported with a wide spectrum of cardiovascular complications, including acute coronary syndrome (ACS), myocardial injury, arrhythmias, acute-onset heart failure, myocarditis, and cardiac arrest [6–8]. Myocardial injury is considered relatively common in COVID-19 patients. Further, myocarditis was considered as a cause of death in few COVID-19 patients. However, the prevalence of myocarditis in COVID-19 cases is not clear, limited evidence exists that myocarditis can be the cause of myocardial injury, and our knowledge on COVID-19 is still limited. We, therefore, reviewed current literature on the present pandemic to provide insights into the current understanding of the pathophysiology, clinical manifestations, and possible management of myocarditis related to COVID-19.

Incidence of COVID-19-Related Myocarditis

Among the long-term impacts of COVID-19, cardiac dysfunction is relatively not among the most common symptoms. However, cardiovascular manifestations, along with cardiac injury induced by COVID-19, has been reported in a considerable number of confirmed cases [6,9]. Several studies showed that cardiovascular manifestations (mostly acute myocardial injury) have been observed in less than 10% of confirmed COVID-19 cases [10–12]. More recently, Shi et al. reported that as much as 20% of COVID-19 patients in their study experienced cardiac injury [6].

Due to the limited number of case reports and retrospective studies, the exact incidence of myocarditis due to COVID-19 infection is unclear. Moreover, myocarditis could be associated with several factors including lack of proper diagnostic criteria and modalities.

Myocardial injury can be defined as a persistently elevated serum troponin level, where myocardial ischemia is clinically evident. Driggin et al. reported 7% of COVID-19-related deaths were attributed to myocardial damage with associated circulatory failure without a definitive diagnosis of myocarditis [13]. Another study of critically ill COVID-19 patients demonstrated that 33% (n = 7) of patients developed cardiomyopathy [14]. Other reports have described autopsy findings of inflammatory mononuclear infiltrate in myocardial tissue without the presence of SARS-CoV-2,whichCOVID-19, in the myocardium in the setting of acute death due to fulminant myocarditis with high viral load and even without respiratory symptoms [4,9,15–18].

Risk Factors of Developing COVID-19-Related Myocarditis

Cardiac involvement including myocarditis can be subclinical or can present with overt manifestations even without respiratory symptoms [5,17]. Several studies have identified various risk factors for developing cardiovascular involvement of COVID-19 along with myocarditis [3,4,11,18,19]. The most described risk factors include older age, hypertension, diabetes, chronic heart failure, and pre-existing coronary artery diseases [3,4,11,18,19]. Patients with more serious comorbidities are also at greater risk of mortality [3,18].

Disproportionate mortality rates have been seen among certain ethnic groups which may be due to different pre-existing health-related factors. For example, the African American population, who also had an increased number of cardiac risk factors, have shown higher death rates due to COVID-19 compared to other ethnicities in many American states [20].

Pathophysiology of COVID-19 Associated Myocarditis

Myocarditis is an inflammatory disease of the heart muscles without any ischemia. Viral infection is the most commonly recognized cause [21,22]. T lymphocyte-mediated cytotoxicity, alongside direct cell injury, contributes to viral myocarditis and the cytokine storm syndrome has a detrimental effect on it [21]. Several animal models have provided evidence of pathological phases that begin with viral-mediated myocyte lysis. This viral-mediated injury leads to activation of the innate immune response with the release of proinflammatory cytokines [23]. Proteins released through cell lysis might display epitopes similar to the viral antigens and be presented via the major histocompatibility complex (MHC). Myosin heavy chain, a major structural protein of the heart muscle, is an example of this molecular mimicry. Adaptive immune response is mediated by activating antibodies and T cells. T-helper cells and cytotoxic T cells orchestrate their responses by triggering inflammatory cascade and cytolysis [Th1 interferon (IFN)-c, Th2 – e.g., IL-4, Th17 – IL-17, and Th22 – IL-22]. Later, macrophages migrate to the site of cardiac injury [23,24]. There may be either recovery or low levels of chronic inflammation with concomitant development of left ventricular dysfunction in the late stage [24].

Pathophysiology of acute myocarditis of SARS-CoV-2 is still elusive. Different mechanisms have been proposed which is similar to the mechanism of viral myocarditis. Several studies reported that patients contracted SARS-CoV-2 infection have high levels of interleukin-1 (IL-1) beta, IL-6, interferon (IFN) gamma, IFN-inducible protein-10 (IP-10) and monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF), leading to cytokine storm through activation of T-helper-1 cell [25,26]. Zheng et al. proposed a different mechanism where this viral myocarditis could have a possible relation with angiotensin-converting enzyme 2 (ACE2)[27]. SARS-CoV-2 binds to ACE2 via its S-spike protein, using it as an entry point to the cell [28].

Although there is limited evidence that COVID-19 directly invades myocardium, the viral RNAs similar to SARS-CoV-2 (Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV) have been identified in the cardiac tissues of infected animals [25,29]. Recently, Dolhnikoff et al. detected SARS-CoV-2 RNA on a post-mortem nasopharyngeal swab and in cardiac and pulmonary tissues of a child by real-time RT-PCR [29].

It is not still certain whether the response to COVID 19 infection is related to inflammation, autoimmunity, or a blend of both since we have little proof that is specific for the COVID-19 pathophysiological mechanism.

Clinical Scenario/ Symptoms

Established myocarditis is a moderately uncommon sequela of COVID-19 infection that can cause clinical jeopardy due to presence of overlapping symptoms with primary COVID- 19 infection. Myocarditis seems to be more prevalent in male patients than in female patients, with a male/female ratio of 1.5:1. Patients with myocarditis exhibit a range of symptoms, ranging from fatigue, chest pain, and palpitations to sudden cardiac arrest [22,30]. The clinical scenario of COVID-19-related myocarditis varies in the literature. While some studies reported patients with mild chest discomfort and palpitations, other studies recorded fatigue, dyspnea, chest pain, and chest tightness are among the common presentations, which make it challenging to distinguish it from other causes in most patients [16,31–33].

However, some critical COVID-19 cases may experience fulminant myocarditis, suggesting that COVID-19 is also related to this condition. Fulminant myocarditis in those patients displayed as ventricular dysfunction and heart failure within 2-3 weeks of the viral infection. Early signs of fulminant myocarditis include low pulse pressure with a febrile presentation, sinus tachycardia, and livedo reticularis, which highly resemble early signs of sepsis [22].

Table 1: Clinical Presentation of COVID-19 Associated Myocarditis

Diagnosis of COVID-19-Related Myocarditis

A combination of clinical findings, biomarkers and imaging is essential for the diagnosis of myocarditis in COVID-19 patients. The myocardial injury appears to be a very likely late presentation when COVID-19 patients develop severe respiratory infection with hypoxia or Acute Respiratory Distress Syndrome (ARDS) [13]. Mild chest discomfort and palpitations might be the only clinical manifestations of COVID-19 myocarditis, making it challenging to characterize the condition in most patients. ACS is one of the major differential diagnoses of COVID-19-related myocarditis. Myocarditis is considered in the differentials when a cardiac injury is evident despite the absence of ACS. Significant serum troponin elevation indicates cardiac involvement in cases of severe COVID-19 [34]. However, myocarditis cannot be excluded with low troponin value, especially for atypical forms of myocarditis such as giant cell myocarditis or chronic myocarditis [35].

The echocardiogram (ECG) usually is commonly deployed in the diagnosis of myocarditis. Patients with myocarditis usually present echocardiogram abnormalities, such as ST elevation, PR depression. Other abnormalities seen in patients with myocarditis include new-onset bundle branch block, QT prolongation, pseudoinfarct pattern, premature ventricular complexes, and bradyarrhythmia with atrioventricular nodal block [31,36]. ECG is, however, neither specific nor sensitive for myocarditis. Nonetheless, It is mandatory to perform ECG in all hospitalized patients with COVID-19 infection as it may help in identifying the presence and severity of myocardial injury.

Blood tests reveal that serum lactate and other inflammatory markers in the blood are often elevated when CVID-19 patients have myocarditis. Also, NT-proBNP levels are often increased in the COVID-19-related myocarditis cases and could increase secondary to myocardial stress [37].

Echocardiography, especially transthoracic echocardiography (TTE), is an important first-line non-invasive test for the diagnosis of myocarditis. It can help preclude different causes of heart failure such as myocardial infarction and valvular heart disease [38]. Global left ventricular hypokinesis, regional wall motion abnormalities, and dilated and/or hypertrophic ventricles are the mentioned findings of TTE in literature [39].

Cardiac magnetic resonance (CMR) imaging is a valuable approach in the diagnosis of myocarditis. Lake Louise criteria for CMR offer high diagnostic accuracy and reliability for diagnosing myocarditis, with a specificity of 91% and a sensitivity of 67% [40–42]. In several studies, researchers have fulfilled the Lake Louise criteria for the diagnosis of COVID-19 associated myocarditis with the use of CMR imaging [15,32,33,43]. Yet, CMR is precluded for unstable patients by many authors. In such critical cases, ECG-gated computerized tomography (CT) with contrast is a suitable option.

Finally, Endomyocardial biopsy (EMB) has been recognized as the gold standard diagnostic test for myocarditis. EMB findings include nonischemic necrosis and mononuclear cell infiltrates of myocytes, but not always possible in a clinical setting [22]. We did not find any evidence of direct viral particles into cardiac tissue except in a study where SARS-CoV-2 RNA was detected on post-mortem myocardium by RT-PCR [29].

Table 2: The connection between myocardial injury and COVID-19 as discussed in ten relevant studies.

Management of COVID-19-related Myocarditis

Evidence and cumulative clinical data from large trials have suggested low-dose dexamethasone in the management of severe COVID-19 cases on supplemental oxygen or ventilatory support although dexamethasone is not recommended for mild to moderate COVID-19 (patients not on oxygen) [44]. In the US, the FDA has approved emergency use authorization for Remdesevir for hospitalized children and severely ill COVID-19 patients. Data from randomized trials have shown Remdesevir to have clinical benefit critically ill patients, while it offers a modest benefit for non-severe patients [44].

The outcome and prognosis of myocarditis depend on many factors. While 50% of acute cases resolve in 2-4weeks, 25% may develop persistent cardiac dysfunction and 12-25% may either die or progress to end-stage dilated cardiomyopathy and eventually need heart transplantation [22]. Despite current variability in practice, supportive therapy is still the mainstay management of myocarditis since no clear evidence supports immunosuppressants offer a clinical benefit in COVID-19 patients with myocarditis [22]. Interestingly, a number of case reports have shown successful management of COVID-19 related fulminant myocarditis using mainly systemic steroids, immune-modulators, and other supportive measures [31,47]. Although for viral myocarditis, antiviral therapies have been previously used but RCTs of these therapies have shown no clinical benefit and are thus not used as therapeutic agents anymore [48].

According to the American Heart Association (AHA) and European Society of Hypertension (ESC) suspected patients of COVID-19 associated myocarditis should be treated according to existing guideline protocol for heart failure and arrhythmia as they are common sequelae [22,42]. Both guidelines, AHA and ESC, recommend using inotropes and/or vasopressors and mechanical ventilation for patients with acute myocarditis complicated by cardiogenic shock. Extracorporeal membrane oxygenation (ECMO), ventricular assist device (VAD), or an intra-aortic balloon pump are most common interventions for long term management of prolonged cardiogenic shock resulting from myocarditis. Whereas Arrhythmia may require temporary cardiac pacing or antiarrhythmic drugs, no benefit of using intravenous immunoglobulin is reported in the literature [45,46].

Conclusion

Although myocarditis is a rare cause of myocardial injury related to COVID-19, it may remain underdiagnosed because of its varied clinical manifestations in critically ill COVID-19 patients. Owing to the fatal outcome it imposes, we recommend that critically ill patients with COVID-19 should be screened for myocarditis. A multidisciplinary approach should be endorsed when treating severely ill COVID-19 patients. Simple bedside tests such as serial ECG and cardiac biomarkers should be established in early evaluation since they can raise suspicion for myocarditis. Finally, we recommend that further research be conducted to more readily distinguish and comprehend the association of myocarditis and COVID-19 as well as the proper management of such patients.

References

1. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in china, 2019. The New England Journal of Medicine 382 (2020): 727-33.
2. World Health Organization. WHO website. Available from: https://www.who.int/.
3. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese center for disease control and prevention. JAMA 323 (2020): 1239-42.
4. Zumla A, Niederman MS. Editorial: The explosive epidemic outbreak of novel coronavirus disease 2019 (COVID-19) and the persistent threat of respiratory tract infectious diseases to global health security. Current Opinion in Pulmonary Medicine 26 (2020): 193-6.
5. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet Respiratory Medicine 8 (2020): 420-2.
6. Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiology 5 (2020): 802-10.
7. Han H, Xie L, Liu R, et al. Analysis of heart injury laboratory parameters in 273 COVID-19 patients in one hospital in Wuhan, China. Journal of Medical Virology 92 (2020): 819-23.
8. Deng Q, Hu B, Zhang Y, et al. Suspected myocardial injury in patients with COVID-19: Evidence from front-line clinical observation in Wuhan, China. International Journal of Cardiology 311 (2020): 116-21.
9. Ruan Q, Yang K, Wang W, et al. Correction to: Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, china. Intensive Care Medicine 46 (2020): 1294-7.
10. Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiology 5 (2020): 811-8.
11. Guan W-J, Ni Z-Y, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in china. The New England Journal of Medicine 382 (2020): 1708-20.
12. Mishra AK, Sahu KK, George AA, et al. A review of cardiac manifestations and predictors of outcome in patients with COVID - 19. Heart & Lung : The Journal of Critical Care (2020).
13. Driggin E, Madhavan MV, Bikdeli B, et al. Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic. Journal of the American College of Cardiology 75 (2020): 2352-71.
14. Arentz M, Yim E, Klaff L, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in washington state. JAMA 323 (2020): 1612-4.
15. Shaw ML. Mortality, risk factors of patients with cardiac injury and COVID-19. American Journal of Managed Care (March 25, 2020).
16. Fan BE, Chong VCL, Chan SSW, et al. Hematologic parameters in patients with COVID-19 infection. American Journal of Hematology 95 (2020): E131-E134.
17. Sala S, Peretto G, Gramegna M, et al. Acute myocarditis presenting as a reverse tako-tsubo syndrome in a patient with SARS-cov-2 respiratory infection. European Heart Journal 41 (2020): 1861-2.
18. Tavazzi G, Pellegrini C, Maurelli M, et al. Myocardial localization of coronavirus in COVID-19 cardiogenic shock. European Journal of Heart Failure 22 (2020): 911-5.
19. 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. International Journal of Infectious Diseases 94 (2020): 91-5.
20. Yancy CW. COVID-19 and African Americans. JAMA 323 (2020): 1891-2.
21. 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. European Heart Journal 34 (2013): 2636-2648.
22. Esfandiarei M, McManus BM. Molecular biology and pathogenesis of viral myocarditis. Annual Review of Pathology 3 (2008): 127-55.
23. Esfandiarei M, McManus BM. Molecular biology and pathogenesis of viral myocarditis. Annual Review of Pathology 3 (2008): 127-55.
24. Blyszczuk P. Myocarditis in humans and in experimental animal models. Frontiers in Cardiovascular Medicine 6 (2019): 64.
25. Gangaplara A, Massilamany C, Brown DM, et al. Coxsackievirus b3 infection leads to the generation of cardiac myosin heavy chain-α-reactive CD4 t cells in a/j mice. Clinical Immunology (Orlando, Fla.) 144 (2012): 237-49.
26. Chen C, Zhou Y, Wang DW. SARS-cov-2: A potential novel etiology of fulminant myocarditis. Herz 45 (2020): 230-2.
27. Chen G, Di Wu, Guo W, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. The Journal of Clinical Investigation 130 (2020): 2620-9.
28. Zheng Y-Y, Ma Y-T, Zhang J-Y, et al. COVID-19 and the cardiovascular system. Nature Reviews. Cardiology 17 (2020): 259-60.
29. Turner AJ, Hiscox JA, Hooper NM. ACE2: From vasopeptidase to SARS virus receptor. Trends in Pharmacological Sciences 25 (2004): 291-4.
30. Dolhnikoff M, Ferreira Ferranti J, Almeida Monteiro RA de, et al. SARS-cov-2 in cardiac tissue of a child with COVID-19-related multisystem inflammatory syndrome. The Lancet Child & Adolescent Health 4 (2020): 790-4.
31. Fairweather D, Cooper LT, Blauwet LA. Sex and gender differences in myocarditis and dilated cardiomyopathy. Current Problems in Cardiology 38 (2013): 7-46.
32. Inciardi RM, Lupi L, Zaccone G, et al. Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19). JAMA Cardiology 5 (2020): 819-24.
33. Kim I-C, Kim JY, Kim HA, et al. COVID-19-related myocarditis in a 21-year-old female patient. European Heart Journal 41 (2020): 1859.
34. Zeng J-H, Liu Y-X, Yuan J, et al. First case of COVID-19 complicated with fulminant myocarditis: A case report and insights. Infection (2020).
35. Akhmerov A, Marbán E. COVID-19 and the heart. Circulation Research 126 (2020): 1443-55.
36. Siripanthong B, Nazarian S, Muser D, et al. Recognizing COVID-19-related myocarditis: The possible pathophysiology and proposed guideline for diagnosis and management. Heart Rhythm 17 (2020): 1463-71.
37. He J, Wu B, Chen Y, et al. Characteristic electrocardiographic manifestations in patients with COVID-19. The Canadian Journal of Cardiology 36 (2020): 966.e1-966.e4.
38. Januzzi JL. Troponin and BNP use in COVID-19 - American college of cardiology. Available from: https://www.acc.org/latest-in-cardiology/articles/2020/03/18/15/25/troponin-and-bnp-use-in-covid19 [cited 2020 Sep 19].
39. Pirzada A, Mokhtar AT, Moeller AD. COVID-19 and myocarditis: What do we know so far? CJC Open 2 (2020): 278-85.
40. Bière L, Piriou N, Ernande L, et al. Imaging of myocarditis and inflammatory cardiomyopathies. Archives of Cardiovascular Diseases 112 (2019): 630-41.
41. Friedrich MG, Sechtem U, Schulz-Menger J, et al. Cardiovascular magnetic resonance in myocarditis: A JACC white paper. Journal of the American College of Cardiology 53 (2009): 1475-87.
42. Ezekowitz JA, O’Meara E, McDonald MA, et al. 2017 comprehensive update of the Canadian cardiovascular society guidelines for the management of heart failure. The Canadian Journal of Cardiology 33 (2017): 1342-433.
43. Han Y, Chen T, Bryant J, et al. Society for cardiovascular magnetic resonance (SCMR) guidance for the practice of cardiovascular magnetic resonance during the COVID-19 pandemic. Journal of Cardiovascular Magnetic Resonance : Official Journal of the Society for Cardiovascular Magnetic Resonance 22 (2020): 26.
44. Doyen D, Moceri P, Ducreux D, et al. Myocarditis in a patient with COVID-19: A cause of raised troponin and ECG changes. The Lancet 395 (2020): 1516.
45. Kim AY, Gandhi RT. Coronavirus disease 2019 (COVID-19): Management in hospitalized adults. Available from: https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-management-in-hospitalized-adults [cited 2020 Sep 19].
46. Hu H, Ma F, Wei X, et al. Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin. European Heart Journal (2020).
47. Tschöpe C, Cooper LT, Torre-Amione G, et al. Management of myocarditis-related cardiomyopathy in adults. Circulation Research 124 (2019): 1568-83.
48. Robinson JL, Hartling L, Crumley E, et al. A systematic review of intravenous gamma globulin for therapy of acute myocarditis. BMC Cardiovascular Disorders 5 (2005): 12.
49. Chen HS, Wang W, Wu SN, et al. Corticosteroids for viral myocarditis. The Cochrane Database of Systematic Reviews (2013): CD004471.
50. Kwenandar F, Japar KV, Damay V, et al. Coronavirus disease 2019 and cardiovascular system: A narrative review. International Journal of Cardiology. Heart & Vasculature 29 (2020): 100557.