CVD is the leading cause of mortality in T1D; however, only ∼50% of this risk is explained by traditional risk factors. Recent studies show that subjects with T1D in the DCCT developed cardiac autoimmunity, defined by the presence of ≥2 Ab. We tested the hypothesis that some of the unexplained CVD risk in T1D is mediated by Ab-linked cytokine pathways. We measured Ab in serum from 892 post-DCCT EDIC subjects (mean age 49 and T1D duration 28 years), with no CVD events at baseline (Figure). Cumulative incidence of a first CVD event in subjects with 0, 1, and >2 Ab was 2.0%, 8.9%, and 43%, respectively, over 4-year median follow-up. In Cox regression models, ≥2 Ab predicted CVD events with minimal attenuation by known risk factors. Using a 42-plex array to measure baseline serum cytokines in subjects with ≥2 Ab and matched controls without Ab, the ≥2 Ab group showed 3.4-fold odds (95% CI, 1.6-6.1; P < 0.0001)of having a 1 tertile increase in a proinflammatory component comprising IFN-γ, TNF-α, G-CSF, MDC, IL1-RA, IL-8, and EGF. Risk of CVD events was also independently associated with IFN-γ, TNF-α, and G-CSF levels (HR, 5.4; 95% CI, 1.5-18.9; P = 0.009).

In conclusion, in this cohort with longstanding T1D, cardiac Ab identified subjects at high risk for CVD events, potentially through Ab-linked cytokine pathways. These findings raise the possibility to immunologically predict and prevent CVD in T1D.


G.R. Sousa: None. M. Niewczas: None. M.A. Lipes: None.


National Institutes of Health (DK1036909)

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at