Atorvastatin Reduces Collagen-Induced Platelet Function in Aspirin-Treated Patients with Acute Myocardial Infarction: Mechanisms Involved.

Abstract 3126

Poster Board III-63

Treatment with statin at the onset of acute myocardial infarction (AMI) has demonstrated a clinical benefit. The effects of statins on platelet TXA₂ synthesis or platelet function could be involved in the clinical benefit, but has not been previously evaluated in patients with AMI. Collagen-induced (1μg/mL)-platelet aggregation, activation (¹⁴C-5HT release, TXA₂ synthesis) and platelet recruitment (proaggregatory activity of activated platelets cell-free releasate) (1, 2) were evaluated in 184 patients with AMI within 48h of the onset of the acute event. Patients were divided into 2 groups: treated with aspirin (ASA) alone (n=139) and treated with both ASA and atorvastatin (AT; n=45). Insufficient inhibition of TXA₂ (<95% vs. ASA-free normal subjects) was detected in 25% of patients treated with ASA vs. 9% in the group treated with ASA+AT (p<0.05), and persistent TXA₂ synthesis was reduced by 87.5% in patients treated with ASA+AT vs. ASA alone. Reduction of TXA₂ by AT was associated with significant inhibitions of collagen-induced: aggregation (30%), ¹⁴C-5HT release (39%) and recruitment (33%). To evaluate the biochemical mechanisms involved in the AT effect on TXA₂ synthesis, experiments in vitro with washed platelets from normal subjects were performed. Incubation of AT alone (1-20μM) or AT plus a suboptimal ASA concentration (1μM) resulted in a significant inhibition of collagen-induced (1μg/mL) TXA₂ synthesis and aggregation, confirming the results in the patients. In contrast, AT did not influence arachidonic acid-induced aggregation, suggesting an effect of the statin on the cytosolic phospholipase A₂ (cPLA₂) activity rather than on cyclooxygenase-1. cPLA₂ activity is known to be regulated by its phosphorylation by MAPK (p38 or erk 1/2) and the increase in cytosolic Ca²⁺. In kinetic studies we found that AT reduced collagen-induced cPLA2 and erk 1/2 phosphorylation, but did not modify p38 phosphorylation. In addition, AT almost blocked collagen-induced increase in cytosolic Ca²⁺. In conclusion, AT associated with ASA significantly reduced collagen-induced persistent TXA₂ synthesis and platelet reactivity early at the onset of AMI, reducing aspirin resistance in these patients. This effect is mediated by the AT control of cPLA2 activity via both erk1/2-mediated cPLA₂ phosphorylation and blockade of collagen-induced elevation of cytosolic calcium. 1. Santos MT et.al. J Clin Invest 1991;87:571-80; 2. Vallés J et.al. Blood 2002;99:3978-84.FIS07/0463/MMA2006/RD06/0026