Inflammation during the life cycle of the atherosclerotic plaque

Abstract

Inflammation orchestrates each stage of the life cycle of atherosclerotic plaques. Indeed, inflammatory mediators likely link many traditional and emerging risk factors with atherogenesis. Atheroma initiation involves endothelial activation with recruitment of leucocytes to the arterial intima, where they interact with lipoproteins or their derivatives that have accumulated in this layer. The prolonged and usually clinically silent progression of atherosclerosis involves periods of smouldering inflammation, punctuated by episodes of acute activation that may arise from inflammatory mediators released from sites of extravascular injury or infection or from subclinical disruptions of the plaque. Smooth muscle cells and infiltrating leucocytes can proliferate but also undergo various forms of cell death that typically lead to formation of a lipid-rich 'necrotic' core within the evolving intimal lesion. Extracellular matrix synthesized by smooth muscle cells can form a fibrous cap that overlies the lesion's core. Thus, during progression of atheroma, cells not only procreate but perish. Inflammatory mediators participate in both processes. The ultimate clinical complication of atherosclerotic plaques involves disruption that provokes thrombosis, either by fracture of the plaque's fibrous cap or superficial erosion. The consequent clots can cause acute ischaemic syndromes if they embarrass perfusion. Incorporation of the thrombi can promote plaque healing and progressive intimal thickening that can aggravate stenosis and further limit downstream blood flow. Inflammatory mediators regulate many aspects of both plaque disruption and healing process. Thus, inflammatory processes contribute to all phases of the life cycle of atherosclerotic plaques, and represent ripe targets for mitigating the disease.

Keywords: Atherosclerosis; Coronary artery disease; Endothelium; Leucocytes; Lipids; Macrophages.

Figure 1

A depiction of the life cycle of an atherosclerotic plaque. (A) Depicts a normal artery. (B) Portrays the initiation of a fatty streak with mononuclear phagocyte recruitment and foam cell formation. The fatty streak may be reversible. (C) A fibrofatty lesion forms when smooth muscle cells lay down extracellular matrix in the intima that enrobes the foam cells. Some smooth muscle cells also accumulate lipid and take on the appearance and markers of foam cells derived from leucocytes of the myeloid series. With further evolution of the plaque, foam cells and smooth muscle cells undergo death and extracellular lipid accumulates from the debris of dying or dead cells and accumulated lipoproteins, forming a lipid core forms in many plaques. A fibrous cap typically forms above the lipid core. Due to decreased synthesis and increased breakdown of extracellular matrix macromolecules such as collagen, this fibrous cap thins creating a thin-capped atheroma (D). Other plaques may evolve to accumulate more matrix and less lipid. For example, the typical substrate of a plaque that has undergone thrombosis due to superficial erosion lacks an organized lipid core, but contains abundant proteoglycan and glycosaminoglycans. This type of plaque does not have a thin fibrous cap and may harbour many smooth muscle cells (E). The thin-capped fibroatheroma can rupture and provoke thrombosis (F). The more fibrous atheromata can undergo erosion (G). The thrombus that complicates eroded plaques is generally an eccentrically located sessile mural thrombus that is more platelet-rich (white thrombus) that the fibrin and erythrocyte rich red thrombus typically provoked by plaque rupture. The ruptured plaque more often gives rise to an ST segment elevation myocardial infarction (STEMI) than a non-ST segment elevation myocardial infarction (NSTEMI) whereas superficial erosion more often gives rise to NSTEMI than STEMI. Regardless of the mechanism of plaque disruption, the resultant thrombi provoke a wound healing response due to elaboration of mediators such as PDGF and TGF-β that augment extracellular matrix synthesis and promote smooth muscle cell migration. Thrombin itself is a mitogen for smooth muscle cells. The incorporation of thrombus provides a provisional matrix replicating within the previously disrupted intima recapitulating the well-known stages of wound healing. The accumulation of extracellular matrix in the healing plaque can lead to increasing luminal stenosis. Such healed, layered plaques tend to have a thicker fibrous cap, less likely to rupture, but these stenotic lesions can give rise to chronic stable angina as depicted by the electrocardiogram characteristic of a positive stress test (H).

Figure 2

Contrasting mechanisms of plaque disruption due to fibrous cap rupture vs. superficial erosion. These two forms of plaque disruption involve distinct vascular cellular protagonists: Smooth muscle cells produce the interstitial collagens that lend strength to the plaque’s fibrous cap. Plaque regions depleted of smooth muscle cells have impaired ability to repair and maintain the collagenous extracellular matrix of the plaque’s protective fibrous cap. In contrast, endothelial cell death and desquamation proves pivotal in plaque disruption due to superficial erosion. The interstitial collagenases, matrix metalloproteinases (MMPs) -1, 8, and -13, attack the fibrillar collagen (types I and III) mostly produced by smooth muscle cells that protect the plaque from rupture. In contrast, the Type IV collagenases, MMPs -2 and -9, degrade the non-fibrillar Type IV collagen in the basement membrane underlying the endothelial cell monolayer thus dissolving the substrate on which endothelial cells attach to the intimal surface. Deprived of their extracellular matrix substrate, endothelial cells can undergo death by anoikis and slough more readily. Oxidative stress due to hypochlorous acid (HOCl) generated by myeloperoxidase or superoxide anion (${\mathrm{O}}_2^{-})$ produced by NADPH oxidase can damage the endothelial monolayer and promote desquamation. Pro-inflammatory cytokines including interleukin-1β, tumour necrosis factor, and CD40 ligand participate in plaque rupture by inducing the interstitial collagenases and tissue factor, the instigator of thrombosis in ruptured plaques. In superficial erosion, NETs contribute to thrombosis and can amplify and propagate endothelial damage through NET-associated interleukin-1α. The main cellular effectors of rupture vs. erosion differ as well, foam cells derived from monocytes or smooth muscle cells predominate in the pathophysiology of fibrous cap rupture. These cells can eventually die from apoptosis or oncosis. In superficial erosion, polymorphonuclear leucocytes appear prominent and can undergo NET formation. Activated platelets contribute to thrombus formation and growth in both forms of plaque disruption. However, thrombi produced by plaque rupture appear more fibrin rich, entrapping erythrocytes, forming ‘red’ thrombi. In contrast, plaques disrupted by erosion tend to generate platelet-rich ‘white’ thrombi. As noted in Figure 1, fibrous cap rupture causes ST segment elevation (STEMI) more commonly than non-ST segment myocardial infarction (NSTEMI) whereas eroded lesions more frequently associate with NSTEMI than STEMI.

Figure 3

Shows a healed plaque with different strata of an intima without a lipid-rich core but plates of calcium, areas of neovascularization, and a layer of extracellular matrix probably laid down after a plaque disruption (labelled Healing Intima, surrounded by a corona of microvessels), yielding a substantial narrowing of the coronary arterial lumen. Indicated are components of this healed plaque. There are also calcium plates at 5 and 7 O’clock in the intima. Richard N. Mitchell MD, PhD, Department of Pathology, Brigham and Women’s Hospital, generously provided this photograph..

Figure 4

This specimen of a human atherosclerotic aorta shows that ulcerated lesions harbouring a thrombus can coexist with raised fibrous lesions shown in pale yellow and atheromata that more resemble a fatty streak. This aorta also developed a small saccular aneurysm. These simple morphological observations show the idea that an individual’s plaques share the same stage in the life cycle is erroneous, as plaques of different characteristics can coexist in close proximity as demonstrated here. Richard N. Mitchell MD, PhD, Department of Pathology, Brigham and Women’s Hospital, generously provided by this photomicrograph.