ABSTRACT
The development of atherosclerotic plaques in both the coronary and carotid vasculature begins with local endothelial cell dysfunction, which increases its adhesiveness and permeability to leukocytes and platelets, and induction of a procoagulant state. 6 This permits the entry of lipoproteins into the vessel wall, oxidation of lipoproteins, and decreased nitric oxide synthesis, and causes increased oxidative stress. 7 Vascular smooth muscle cells migrate into the developing lesion, leading to intimal thickening of the artery. 6 These responses are mediated by leukocytes, specifically macrophages and certain T lymphocytes. 6,8
Intraplaque angiogenesis and hemorrhage are also thought to play important roles in destabilization. Immature leaky and fragile vessels promote inflammatory cell infiltration and extravasation of erythrocytes – rich in cholesterol and phospholipids – into the plaque center, leading to necrotic core expansion and plaque progression. Ceroid accumulation, red cell membrane lysis, and erythrophagocytosis cause lipid accumulation and
further recruitment of inflammatory cells. 9 Red blood cell membrane lysis produces free cholesterol and phospholipids and contributes heavily to necrotic core expansion. In humans with sudden coronary death, the degree of glycophorin A staining (red cell specific stain) correlated with the level of plaque instability. 10
Progressing plaques will develop a thinning fibrous cap and an expanding necrotic core (the so called ‘advanced lesion’), at which point the vessel can no longer compensate for flow obstruction by dilatation, and flow is diminished and altered. 6 Oxidized phospholipids increase the expression of vascular endothelial growth factor (VEGF) in the vessel wall, as well as interleukin 8 (IL-8), cyclooxygenase 2 (COX-2), and ADAMTS-1, which lead
to further inflammation. 11 This process of plaque destabilization leaves the lesion vulnerable to rupture and ulceration, resulting in a substrate for thrombi to form ( Figure 14.1 ). In contrast to coronary artery disease where occlusive thrombosis is a major etiology of acute coronary syndromes, unstable plaques in the carotid circulation rarely cause symptoms through plaque rupture with occlusive thrombus formation. Rather, there is a tendency for carotid plaques to ulcerate, rupture, form mural thrombus, and embolize. These are likely mechanisms for the transient ischemic events and strokes that are comorbid with carotid disease. 12
Based upon this understanding of the pathophysiology of atherosclerotic carotid artery, several therapies have been shown to be effective
Figure 14.1 Carotid plaque rupture with small organizing surface thrombus at the rupture site (arrrow). Movat pentachrome-stained sections. (a) Low power cross-section demonstrating advanced carotid plaque with disrupted fibrous cap. (b) High power magnification (boxed area in a) demonstrating necrotic core (NC), disrupted fibrous cap with an organized surface thrombus (Thr). (c, d) Higher power magnification (boxed area in b) shows abundant macrophage (CD68) staining around the necrotic core and in the cap (c) and sparse smooth muscle cells (SM actin) (d). (See color plate section, page xxvi)
at preventing or stabilizing the progression of atherosclerotic carotid artery disease to stroke. These therapies intervene with the disease at any number of stages through its advancement, and we have classified them by the particular pathways they are meant to interrupt ( Figure 14.2 ).
