Secondary Logo

Journal Logo

Viewpoint

COVID-19 and myocardial injury: is there a role for interleukin-1 inhibition?

Imazio, Massimo; Andreis, Alessandro; De Ferrari, Gaetano Maria

Author Information
Journal of Cardiovascular Medicine: July 2020 - Volume 21 - Issue 7 - p 465-466
doi: 10.2459/JCM.0000000000000998
  • Free

Coronavirus pneumonia 2019 (COVID-19) pandemic was declared on 11 March 2020 by the WHO, with more than 400 000 people infected and more than 18 000 died as of 26 March.

Myocardial injury is common in COVID-19 patients, particularly in the ICU.1 Shi et al.2 recently reported myocardial injury in 20% patients with COVID-19 associated with a death rate of 51 vs. 4.5% (P < 0.001). Although the mechanism of myocardial injury is unknown, it may be caused by cardiac adrenergic hyperstimulation during cytokine storm syndrome. Arrhythmia was a cause of ICU admission in 44% patients with COVID-19 infection.1

Macrophage activation syndrome (MAS) is a frequently undiagnosed severe and fulminant form of cytokine storm syndrome, mostly observed during viral sepsis and caused by overwhelming release of pro-inflammatory cytokines. Indeed, increased plasmatic concentrations of cytokines resembling MAS phenotype were found in ICU patients with COVID-19, along with higher levels of troponin I; NT-proBNP stands for N-terminal pro-Brain Natriuretic Peptide and C-reactive protein.2,3 In MAS, T-cells and antigen-presenting cells are hyperactivated through Toll-like receptors with repeated stimulation causing a massive autocrine loop of interleukin (IL)-1 and a subsequent, uncontrolled release of pro-inflammatory cytokines, including IL-6, IL-18, interferon (IFN)-γ, tumour necrosis factor alpha (TNFα) and ferritin, further precipitating clinical conditions, leading to endothelial dysfunction, multiple organ dysfunction and death (Fig. 1).4

Fig. 1
Fig. 1:
Cytokine storm with sympathetic nervous system activation, myocardial lesion and endothelial damage leading to multiple organ failure. ANS, autonomic nervous system.

IL-1 blockade gave encouraging results in similar clinical settings. Indeed, a posthoc analysis of a phase III randomized trial on the IL-1 receptor antagonist anakinra in septic patients showed improved 28-day survival (35 vs. 65%, P < 0.001) in patients with MAS phenotype. Furthermore, IL-1 blockade with anakinra in septic patients is currently being assessed in PROVIDE (Personalized RandOmized trial of Validation and restoration of Immune Dysfunction in sEvere infections and sepsis; ClinicalTrials.gov NCT03332225).4 CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study) showed that IL-1 inhibition in patients with a previous myocardial infarction and increased C-reactive protein effectively reduced recurrent cardiovascular events.5 In the setting of COVID-19 infection, the additive effect of overwhelming IL-1 production associated with cardiovascular comorbidities, MAS and incessant adrenergic stimulation may synergize in a deadly vicious circle. In specific settings, such as pericarditis, nonselective inhibition of IL-1, either alfa and beta is superior to the selective inhibition of IL-1 beta because of the blocking of IL-1 alfa that can be secreted by mesothelial cells.6

Considering the potential key role of IL-1 in COVID-19 infection, its inhibition may be proposed as a potential therapeutic option. Randomized trials are needed to clarify the potential usefulness of IL-1 blocking agents.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

References

1. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA 2020; 323:1061–1069.
2. 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; doi: 10.1001/jamacardio.2020.0950. [Epub ahead of print].
3. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395:497–506.
4. Karakike E, Giamarellos-Bourboulis EJ. Macrophage activation-like syndrome: a distinct entity leading to early death in sepsis. Front Immunol 2019; 10:55.
5. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377:1119–1131.
6. Brucato A, Imazio M, Gattorno M, et al. Effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence: the AIRTRIP randomized clinical trial. JAMA 2016; 316:1906–1912.
© 2020 Italian Federation of Cardiology - I.F.C. All rights reserved.