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PCSK9 and coronary atherosclerosis progression beyond LDL-cholesterol in coronary artery disease patients

Rosetta Ragusa1, Silvia Rocchiccioli1, Serena Del Turco1

  • 1CNR, Institute of Clinical Physiology, Pisa, Italy.

European Journal of Clinical Investigation
|June 4, 2025
PubMed

Insights

Plasma PCSK9 levels correlate with coronary artery disease (CAD) plaque progression, specifically the necrotic core. This suggests PCSK9 may promote adverse plaque phenotypes via inflammatory pathways beyond LDL-C.

Area of Science:

  • Cardiovascular Research
  • Atherosclerosis Biology
  • Molecular Medicine

Background:

  • Coronary artery disease (CAD) remains a leading cause of mortality worldwide.
  • Understanding the molecular mechanisms driving atherosclerosis progression is crucial for developing new therapies.
  • Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of LDL cholesterol metabolism.

Purpose of the Study:

  • To investigate the association between plasma PCSK9 levels and coronary plaque progression in patients with CAD.
  • To explore the molecular pathways potentially linking PCSK9 to atherogenesis.

Main Methods:

  • 159 patients with stable CAD underwent coronary computed tomography angiography (CTA) at baseline and after a mean follow-up of 6.5 years.
  • Plaque progression was quantified by annual changes in plaque volumes (Total, Fibrous, Fibro-fatty, Necrotic-Core, Dense-Calcium).
  • RNA-sequencing of whole blood and in vitro endothelial cell (EC) studies were performed to analyze PCSK9-related pathways.

Main Results:

  • Higher plasma PCSK9 levels were significantly associated with an increased annual progression of Necrotic-Core plaque volume (p=0.022), independent of traditional risk factors and lipid-lowering therapies.
  • RNA-sequencing revealed that PCSK9 expression is linked to genes involved in the innate immune response.
  • In vitro studies showed that PCSK9 treatment significantly upregulated inflammatory markers (ICAM-1, VCAM-1, MCP1, IL6) in endothelial cells.

Conclusions:

  • Plasma PCSK9 is an independent predictor of coronary plaque progression, particularly the vulnerable necrotic core component, in patients with CAD.
  • PCSK9 may contribute to the development of prognostically adverse plaque phenotypes through inflammatory mechanisms, independent of its role in LDL-C regulation.
  • These findings highlight PCSK9 as a potential therapeutic target for stabilizing atherosclerotic plaques.
Abstract

Keywords:
PCSK9coronary artery diseasecoronary atherosclerosis progressioninflammation

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