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.


OBJECTIVE
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<or=0.02). As a result, the TF/TFPI (mol/mol) ratio was higher in D+ than in D- or S+ patients (p<or=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.
Zawadzki
Christophe
C
Institut National de la Recherche Médicale (INSERM)-ERI-9, Université de Lille 2, EA-2693, IFR 114, France.
Susen
Sophie
S
Richard
Florence
F
Haulon
Stéphan
S
Corseaux
Delphine
D
Jeanpierre
Emmanuelle
E
Vincentelli
André
A
Lucas
Christian
C
Torpier
Gérard
G
Martin
Annie
A
Van Belle
Eric
E
Staels
Bart
B
Jude
Brigitte
B
D000368:Aged; D016632:Apolipoprotein A-I / Q000032:analysis; D001055:Apolipoproteins B / Q000032:analysis; D002340:Carotid Artery Diseases / Q000503:physiopathology*; D016022:Case-Control Studies; D015331:Cohort Studies; D050171:Dyslipidemias / Q000188:drug therapy / Q000503:physiopathology*; D004691:Endarterectomy; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D008074:Lipoproteins / Q000378:metabolism*; D008297:Male; D013925:Thromboplastin / Q000187:drug effects / Q000378:metabolism*; D013927:Thrombosis / Q000503:physiopathology*
D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin