• coagulation;
  • coronary heart disease;
  • factor XII;
  • plasma kallikrein–kinin system;
  • risk factors

Summary. Background: The plasma kallikrein–kinin system (PKKS) has been implicated in cardiovascular disease, but activation of the PKKS has not been directly probed in individuals at risk of coronary heart disease (CHD) or stroke. Objective: To determine the involvement of the PKKS, including factor XI, in cardiovascular disease occurring in a nested case–control study from the Second Northwick Park Heart Study (NPHS-II). Methods and results: After a median follow-up of 10.7 years, 287 cases of CHD and stroke had been recorded and 542 age-matched controls were selected. When FXIIa–C1 esterase inhibitor (C1-inhibitor) concentrations were divided into tertiles (lowest tertile as reference), the odds ratios (ORs) at 95% CIs for CHD were 0.52 (0.34–0.80) in the middle tertile and 0.73 (0.49–1.09) in the highest tertile (P = 0.01 for the overall difference; P = 0.01 for CHD and stroke combined). For kallikrein–C1-inhibitor complexes, the ORs for stroke were 0.29 (0.12–0.72) and 0.67 (0.30–1.52) in the middle and high tertiles, respectively (P = 0.02). FXIIa–C1-inhibitor and kallikrein–C1-inhibitor complexes were negatively related to smoking and fibrinogen (P < 0.005). FXIa–inhibitor complexes correlated strongly with FXIIa–inhibitor complexes. Conclusions: Lower levels of inhibitory complexes of the PKKS enzymes and particularly of FXIIa contribute to the risk of CHD and stroke in middle-aged men. This observation supports the involvement of the PKKS in atherothrombosis.