Cytokine storms and AF
SARS-CoV-2 triggers immune responses with a cytokine storm syndrome.20The majority of severe cases had elevated levels of infection-related biomarkers and inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), IL-6, interleukin 1β (IL-1β), interleukin-2 (IL-2), IL-7, IL-10, granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, interferon-γ induced protein, monocyte chemoattractant protein 1, fibroblast growth factor, vascular endothelial growth factor, and macrophage inflammatory protein 1-α.5,14,20Cytokine storm might trigger a violent immune system response, and cause ARDS and hypoxemia, which indirectly damage myocardial cells.5,14,20,21Additionally, some cytokines have direct effects on cardiomyocytes. The aforementioned factorsmight induce atrial electrical and structural remodeling, and lead to AF occurrence.
Although the electrophysiological effects of cytokines remain incompletely understood, distinctive cytokines have been shown to induce AF in bench work and translational researches.22,23TNF-α increases AF vulnerability and exerts direct effects on atrial structural and electrical remodeling.24,25 TNF-α induced triggered activity in pulmonary vein cardiomyocytes, which was attributed to increased activity of sodium/calcium exchanger (NCX) and impaired sarcoplasmic reticulum (SR) ATPase.24Abnormal Ca2+ leak from SR could also be induced by TNF-α.26TNF-α and IL-1β both impair cardiac contractility,25,26,27and contribute to arrhythmogenesis through mechano-electrical feedback. IL-6 reduces cardiac connexins and promotes electrical remodeling during acute inflammatory status.28Different cytokines, including TNF-α, IL-1β, fibroblast growth factor, and vascular endothelial growth factor all increase cardiac fibrosis and underlie arrhythmogeneity.29,30The activation of inflammasome NLRP3-related signals was hypothesized after SARS-CoV-2 infection.31Increased activity of NLRP3 inflammasome was similarly observed in AF patients, which might be associated with macrophage recruitment, fibrosis, and myocardial dysfunction in the heart.32,33Several therapeutic trials have been launched according to these inflammatory hypotheses. Hydroxychloroquine (HCLQ), a potential therapeutic candidate for COVID-19 could reduce activity of NLRP3 inflammasome in inflammatory cells.34The immune-suppressive agent, tocilizumab (an IL-6 inhibitor), was approved for phase 3 trial in severely ill COVID-19 patients in order to reduce the complication of COVID-19 by the US Food and Drug Administration.