Plaque vulnerability Key role of macrophages Figure 14 Factors which play a key role in increasing plaque vulnerability. These include: lipid core formation; parietal vascular inflammation; thinning of the fibrous cap; thrombus formation.

Vulnerable plaque Key role of the macrophage in vascular wall inflammation Figure 15 Macrophages play a key role in the formation of a vulnerable plaque. This is achieved because they: liberate cytokines, which cause vascular wall inflammation; produce Tissue Factor (TF), which results in further cell recruitment; decrease fibrous cap resistance.

Fibrinogen is an independent risk factor for atherosclerosis Figure 16 Activated macrophages release pro-inflammatory cytokines (IL-6, IL-1, TNFa). Cytokines increase hepatic fibrinogen expression and hence plasma concentration. The risk of cardiovascular disease increases with increasing fibrinogen concentrations.

Vulnerable plaque Key role of the macrophage in the degradation of the fibrous cap Figure 17 Macrophages weaken the fibrous cap by releasing metalloproteases. This release results in: degradation of the fibrous cap around the lipid core; degradation of connective tissue within the lipid core.

Thrombus formation The macrophages release coagulation factors Figure 18 Activated macrophages increase TF production, which results in: further cell recruitment (monocytes and platelets); increased coagulability, which facilitates thrombosis; increased predisposition to plaque rupture.

Tissue factor: the initiator of coagulation and thrombogenesis in vivo Figure 19 Tissue Factor initiates the coagulation cascade, which culminates in thrombus formation. It is released from platelets and endothelium as well as activated macrophages.

Oxidized LDL and thrombogenesis Figure 20 Oxidized LDL activates macrophages and stimulates TF expression. It also stimulates increased production of plasminogen activator inhibitor type 1 (PAI-1), which inhibits fibrinolysis. The end result is a state of hypercoagulability around the plaque, which plays a major role in thrombus formation during plaque rupture.

Plaque disruption (plaque cracking, fissuring, rupture – thrombosis start point) Figure 21 Plaque rupture produces occlusive thrombosis. The occlusion may be partial (such as a wall thrombus, which is fibrin- and platelet-rich) and gives rise to unstable angina, or complete myocardial infarction (the thrombi of which are thrombin-rich). Partial occlusions are prone to embolization and, as such, can give rise to distal occlusions.