Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque.

Area of Science:

• Cardiology
• Biochemistry
• Pharmacology

Background:

• Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is abundant in coronary lesion necrotic cores.
• Its enzymatic products may promote inflammation and cell death, increasing plaque vulnerability.
• Coronary artery disease (CAD) remains a leading cause of mortality worldwide.

Purpose of the Study:

• To evaluate the effect of darapladib, an Lp-PLA(2) inhibitor, on coronary atheroma characteristics.
• To assess changes in necrotic core size and plaque deformability in patients with CAD.
• To determine if Lp-PLA(2) inhibition impacts high-sensitivity C-reactive protein levels.

Main Methods:

• A 12-month randomized, double-blind, placebo-controlled trial involving 330 patients with CAD.
• Patients received either daily oral darapladib (160 mg) or placebo.
• Coronary atheroma characteristics were assessed using intravascular ultrasound palpography and radiofrequency analysis.

Main Results:

• Darapladib significantly inhibited Lp-PLA(2) activity by 59% (P<0.001).
• Necrotic core volume significantly increased in the placebo group but was halted with darapladib (P=0.012).
• No significant differences were observed in plaque deformability or high-sensitivity C-reactive protein between groups.

Conclusions:

• Lp-PLA(2) inhibition with darapladib effectively prevented necrotic core expansion in vulnerable coronary plaques.
• Necrotic core expansion, a marker of plaque vulnerability, was observed to continue in placebo-treated patients.
• Lp-PLA(2) inhibition represents a potential novel therapeutic strategy for stabilizing atherosclerotic plaques.