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.