Chapter A10: Atlas of Atherosclerosis

How aggressive lipid lowering alters coronary atheromata. This figure depicts how rigorous low-density lipoprotein (LDL) lowering affects human arterial plaques as shown by imaging modalities. The lumen changes little, the lipid core becomes smaller, and the proportion of the plaque composed of fibrous tissue increase. The amount of calcification actually increases with statin treatment, a point to keep in mind when considering coronary artery scores. (From P Libby: How does lipid lowering prevent coronary events? New insights from human imaging trials. Eur Heart J 36:472, 2015.)

Coronary artery cross-sections. Various mechanisms can cause coronary thrombosis that results from superficial erosion vs fibrous cap fissure. This diagram represents cross-sectional views of human coronary arteries. On the left, thrombosis provoked by erosion causes a “white” thrombus complicating a lesion rich in proteoglycan and glycosaminoglycan. Endothelial cell desquamation uncovers basement membrane collagen that can activate platelets. Polymorphonuclear leukocytes (PMN) then accumulate and cause a “second wave” of local injury, and amplification and propagation of clotting, in part due to formation of neutrophil extracellular traps (NETs). Erosion may contribute more frequently to non-ST-segment elevation myocardial infarction (NSTEMI) than to STEMI. The image on the right portrays thrombosis resulting from rupture of a thin-capped fibroatheroma. Such thrombi often have a “red” fibrin-rich character. Macrophage-derived tissue factor provokes clotting complicating plaque rupture. (From P Libby: Superficial erosion and the precision management of acute coronary syndromes: not one-size-fits-all. Eur Heart J: 38:801, 2017.)

A. “Two-Hit” concept of thrombosis caused by plaque erosion. This figure depicts a longitudinal section of a coronary artery that harbors an extracellular matrix-rich atheroma. The dark brown represents deposits of extracellular matrix macromolecules abundant in eroded plaques including hyaluronic acid. Instigators of damage to the endothelium include pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and other activators of TLR2, and innate immune receptor that we have implicated in superficial erosion. Various inflammatory stimuli can impair endothelial cell viability. Proteolytic enzymes including the matrix metalloproteinases can digest basement membrane components to which endothelial cells adhere. Type IV collagenases (MMP-2 and MMP-9) can thus favor detachment of endothelial cell to the underlying basement membrane, rich in type IV collagen. When a patch of endothelial cells slough or die they can form tissue factor bearing microparticles that stimulate clotting. Recruitment of granulocytes provides a source of the proinflammatory and thrombogenic mediator MRP-8/14 and of reactive oxygen species such as hypochlorite produced by myeloperoxidase (MPO), as well as superoxide anion (O₂⁻). We hypothesize that neutrophil numbers increase secondarily, rather than cause initial intimal injury. Activated polymorphonuclear leukocytes can release strands of DNA and histones giving rise to neutrophil extracellular traps (NETs). NETs can extend thrombosis. Local activation of neutrophils and platelets augments the availability of cytokines including interleukin-6 and RANTES. Platelets also elaborate plasminogen activator inhibitor-1 (PAI-1) that blocks fibrinolysis. (With permission from T Quillard et al: TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion. Eur Heart J 36:1394, 2015.)

Risk factors and their modification can regulate atherosclerosis by altering inflammation. Risk modifiers alter atherosclerosis by regulating inflammation as determined by changes in biomarkers. The selected risk factors at the top elicit various pro-inflammatory cytokines including interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α). These mediators can accelerate atherogenesis by direct effects on the lesions, and also trigger the release of acute phase reactant from hepatocytes signaled by interleukin-6, that we have dubbed the “messenger cytokine.” Products of the acute phase response include fibrinogen and plasminogen activator inhibitor-1 (PAI-1) that regulate thrombosis and clot stability and also biomarkers of inflammation such as C-reactive protein (CRP) or serum amyloid A (SAA) that although not causal risk factors can serve as clinically useful gauges of inflammatory status. Factors that may lower risk of atherosclerotic events such as dietary factors or physical activity may mitigate inflammation as monitored by CRP. (From P Libby, F Crea: Clinical implications of inflammation for cardiovascular primary prevention. Eur Heart J 31:777, 2010.)

Rheumatic diseases accelerate atherosclerotic risk. Rheumatologic disorders elevate systemic inflammation and can thus potentiate atherothrombosis. (From JC Mason, P Libby: Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions. Eur Heart J 36:482, 2015.)

Rheumatologic conditions can potentiate the pathogenesis of atherosclerosis. Patients with inflammatory rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosis, and various vasculitides can have a higher burden of traditional risk factors for atherosclerosis than well individuals. Abbreviations: Ab, antibody; ANCA, antineutrophil cytoplasmic antibody; dsDNA, double-stranded DNA; CCP, cyclic citrullinated peptide; EC, endothelial cells; IFN, interferon; FcγR, Fc gamma receptor; HOCL, hypochloride; MPO, myeloperoxidase; ROS, reactive oxygen species; T reg, regulatory T lymphocytes. (From JC Mason, P Libby: Cardiovascular disease in patients with chronic inflammation: mechanisms underlying premature cardiovascular events in rheumatologic conditions. Eur Heart J 36:482, 2015.)