Pathophysiology of COVID-19-related Cardiac Injury
Acute myocarditis is a potentially life-threatening disease, which is most commonly caused by a viral infection. Among the viruses, the most cited are enteroviruses (especially coxsackievirus), adenovirus and parvovirus B19 and, rarely, coronavirus.
Recently, coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), was declared by the WHO to be a pandemic. There has been an upsurge in patients presenting with COVID-induced myocarditis globally.
Although the pathophysiology of acute myocarditis of SARS-CoV-2 is not fully understood, several mechanisms have been proposed. Some studies have suggested cytokine release syndrome is the core pathophysiology of SARS-CoV-2 fulminant myocarditis. Chen et al. reported that patients who are infected with SARS-CoV-2 had 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), which probably led to massive activation of T-helper-1 cell response.1 Higher granulocyte colony-stimulating factor, IP-10, MCP-1, macrophage inflammatory protein-1A and tumour necrosis factor alpha have also been reported, suggesting that the cytokine storm might affect disease severity.1
Another mechanism, proposed by Zheng et al., was that it might be related to angiotensin-converting enzyme 2 (ACE2); this is widely expressed not only in the lungs but also in the cardiovascular system, so ACE2-related signalling pathways might also have a role in heart injury.2 ACE2 is a membrane-bound aminopeptidase that has been identified as a functional receptor for coronaviruses. SARS-CoV-2 infection is triggered by the spike protein of the virus binding to ACE2, which is highly expressed in the heart and lungs resulting in ARDS and fulminant myocarditis. This hypothesis has generated a lot of anxiety among patients on ACE-inhibitors or angiotensin-receptor blockers.
Moreover, in a less-adopted hypothesis, several authors have speculated that SARS-CoV-2-induced severe acute respiratory distress syndrome (ARDS) results in intractable hypoxaemia leading to myocardial cell damage.2
Management of COVID-19 Myocarditis
The prevalence of COVID-19-induced myocarditis varies between reports, and is involved in up to 7% of COVID-related deaths.3
Screening for myocardial injury in patients admitted to the hospital with COVID-19 is advisable, given that the diagnosis will change the management, especially regarding fluid administration. Siripanthong et al. recommended a baseline ECG, and assessing troponin and B-type natriuretic peptide levels on hospital admissions.
If myocarditis is suspected, an echocardiogram should be done because it is more accessible than other imaging modalities; moreover, point-of-care ultrasound is often readily available. Although cardiac magnetic resonance would provide more information than an echocardiogram, its use is limited because of prolonged acquisition time, the need for breath-holding and, given that COVID-19 is highly contagious, the requirement for deep cleaning after use.4
If myocarditis is still suspected and cardiac magnetic resonance cannot be performed, ECG-gated CT with contrast would be a reasonable option. Since many COVID-19 patients will undergo a chest CT at some point, adding the cardiac component to the CT is a feasible technique to use to obtain valuable information. If none of these modalities provide the information needed, an endomyocardial biopsy would be warranted.
The current European Society of Cardiology (ESC) position statement recommends treating patients with acute myocarditis complicated by cardiogenic shock with inotropes and/or vasopressors and mechanical ventilation.5 Additionally, in patients requiring longer-term support, extracorporeal membrane oxygenation (ECMO) and ventricular assist devices should be used.
Generally, glucocorticoid and immunoglobulin therapy are discouraged in acute myocarditis. In a systematic review, Chen et al. reported that corticosteroids did not reduce mortality.6 Moreover, a systematic review of IV immunoglobulins as acute myocarditis therapy showed insufficient evidence to support their routine use.7 Partly because of these data, the ESC recommends that immunosuppression should be started only after ruling out an active infection.5
Interestingly, three case reports have noted successful management of COVID-19 fulminant myocarditis using mainly immune-modulators and supportive measures. Zeng et al. reported the successful treatment of a patient with COVID-19 presenting with fulminant myocarditis, ARDS and multiple organ dysfunction syndrome using ventilatory support, high-flow oxygen, lopinavir-ritonavir antiviral therapy, interferon alpha-1b, methylprednisolone, immunoglobulin and ECMO with gradual improvement of left ventricular ejection fraction (LVEF).8 Hu et al. described successful management of fulminant myocarditis using methylprednisolone, immunoglobulin, inotropes and diuretics with gradual improvement of LVEF and cardiac biomarkers over several weeks.9 Inciardi et al. described a case of peri-myocarditis as the sole manifestation of COVID-19, without interstitial pneumonia, with gradual improvement of symptoms and LVEF using hydroxychloroquine, lopinavir/ritonavir, methylprednisolone, inotropic support and diuresis.10
In general, the use of corticosteroids and IV immunoglobulins are not supported by the guidelines for the management of acute myocarditis. However, in the very few patients who have been diagnosed with COVID myocarditis, management with immunomodulators showed positive results. This suggests that the core pathophysiologic process of COVID-19-related cardiac injury is linked to a cytokine storm.