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Objective— The classical complement pathway has been assigned both protective and pathological effects in cardiovascular disease (CVD), but human data are lacking. We determined the associations of the pattern recognition factor C1q and the regulator C1-INH (C1-inhibitor) with incident CVD, carotid intima–media thickness, endothelial dysfunction, and low-grade inflammation. Approach and Results— Baseline concentrations of C1q and C1-INH were measured in the CODAM study (Cohort on Diabetes and Atherosclerosis Maastricht; n=574; 61% men; age, 60±7 years). The 7-year incidence of CVD in participants free of CVD at baseline was evaluated using logistic regression analyses (n=342; 73 cases). The lowest incidence of CVD was observed in the middle tertile of C1q (Tlow compared with Tmiddle : odds ratio, 2.38 [95% confidence interval, 1.14–4.95]; Thigh compared with Tmiddle : odds ratio, 1.96 [95% confidence interval, 0.94–4.07]). C1-INH was not associated with CVD. During the 7-year follow-up period, C1q and C1-INH were not, or inconsistently, associated with carotid intima–media thickness or with biomarker scores reflecting endothelial dysfunction and low-grade inflammation.Conclusions— Our results suggest a nonlinear association between C1q and incident CVD. This supports the concept that early steps in classical pathway activation may have both protective and pathological effects on human CVD.

Classical Pathway of Complement Activation: Longitudinal Associations of C1q and C1-INH With Cardiovascular Outcomes