Relationships Between Plasma Cytokine Balance and Cardiac Magnetic Resonance Imaging in Long-Term Post-Covid Follow-Up: a Cross-Sectional Preliminary Study

Abstract Background COVID-19 infection can lead to a constellation of long-lasting post-infectious sequelae, including myocardial dysfunction, whose outcome is strongly affected by a fine-tuned balance between pro- and anti-inflammatory systemic immune responses. Plasma cytokines are key mediators of this immunological balance. In this preliminary study we evaluated the cross-sectional association between the circulating levels of the main pro- and anti-inflammatory cytokines and cardiac magnetic resonance (CMR) abnormalities. Methods 71 subjects (59% female, mean age 52±14) with previous diagnosis of COVID-19 infection were enrolled at our institution for MULTICOVID protocol, comprehensive of CMR and biomarkers assessment performed >3 months and <1 year following the first negative swab test. CMR protocols consisted of conventional sequences (cine, T2-weighted imaging, and late gadolinium enhancement [LGE]) and quantitative mapping sequences (T1, T2, and extracellular volume [ECV] mapping). Plasma levels of cytokines TNF-α, IL-1β, IL-1α, IFN-α2, IL-6, IL-8, IL-13, IL-10, IL-17A, IL-18, IP-10, MIG and MCP-1 were quantified by Multiplex Immunoassays on the Luminex technology platform. Soluble cardiologic and biochemical biomarkers were measured by routine laboratory analysis. Results After a median of 9 (IQR 6–11) months following negative swab, CMR was normal in 48 subjects, while in 23 (32%) it revealed tissue characterization abnormalities (myocardial late enhancement and/or edema). By multivariate regression analysis (adjusted for age, sex, vaccination, severity degrees of the initial COVID disease, presence of comorbidities, smoke, time interval between COVID diagnosis and CMR assessment) the cytokine ratio TNF-α/(IL-10+IL-13) was independently associated (OR=2.89, 95% CI 1.19–7.04, p=0.02) with CMR abnormalities. Interestingly, the cumulative pro-/anti-inflammatory cytokine ratio (IL-1β+TNF-α+IFN-α2+IL-6+IL-17A+IL-8)/(IL-10+IL-13) showed a positive (OR=1.70, 95% CI: 1.04–2.75) and significant (p=0.03) association with CMR imaging aspects. Also, the ratio IFN-α2/(IL-10+IL-13), although without achieving a complete statistical significance (p=0.09), was associated positively with CMR findings. Conclusions The preliminary results of this cross-sectional study suggest that the systemic inflammatory environment, long-lasting unbalanced towards a prevalent cytokine-driven pro-inflammatory condition following COVID infection, could affect the development of CMR-detectable myocardial edema and fibrosis in long-term post-COVID subjects. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Tuscany Region