Dyslipidemia shifts the tissue factor/tissue factor pathway inhibitor balance toward increased thrombogenicity in atherosclerotic plaques: Evidence for a corrective effect of statins

Background Tissue factor (TF) is a key mediator of atherosclerotic plaque thrombogenicity and may be regulated by plaque TF pathway inhibitor (TFPI). High atherogenic lipoproteins are a well-known arterial risk factor, but their effects on the TF/TFPI balance in atherosclerotic plaques, as well as those of widely used lipid-lowering agents such as statins, are incompletely understood. Objectives We analyzed the TF/TFPI balance in carotid plaques from 86 patients, according to the presence of dyslipidemia and statin therapy. Results: In patients with untreated dyslipidemia (ApoB/ApoA1 ratio >0.7) (D+) (n = 44), TF antigen (TF) tended to be higher than in those without dyslipidemia (D−) (n = 16). In patients with statins (S+) (n = 26), TF was lower than in D+ (p = 0.02) and similar to that of D− patients. TFPI antigen was higher in D− than in D+ and S+ patients (p ≤ 0.02). As a result, the TF/TFPI (mol/mol) ratio was higher in D+ than in D− or S+ patients (p ≤ 0.005). TF activity correlated to TF/TFPI ratio (p < 0.0001), and was higher in the D+ than in the D− and in the S+ patients (p = 0.02). Among analyzed clinical risk factors and biological parameters, including CRP, dyslipidemia was the only independent predictor for low plaque TFPI and high TF/TFPI ratio. Histochemistry showed that TF and TFPI were mainly expressed in macrophage-rich regions surrounding the lipid-rich core in the three groups. Conclusions These results indicate that dyslipidemia is associated with a shift of the TF/TFPI balance and of TF activity toward higher plaque thrombotic potential. Statins correct this equilibrium mainly by decreasing plaque TF together with blood atherogenic lipoproteins.