Cerebrovascular Disease: The Unstable Carotid Plaque

Introduction

Carotid artery disease is highly prevalent, with approximately 12.5% of men and 6.9% of women over the age of 70 years in the United States having asymptomatic carotid disease. The association between atherosclerotic disease of the carotid artery and ischemic stroke is well-documented. Carotid disease accounts for approximately 8%–37% of all strokes ^, (see Ch. 88 , Cerebrovascular Disease: Epidemiology and Natural History). Early randomized controlled trials of surgical treatment of carotid atherosclerotic disease vs. medical treatment (NASCET, ACAS, ECST, and ACST) established the superiority of surgical endarterectomy in stroke prevention among asymptomatic patients with high-grade stenosis and symptomatic patients with moderate stenosis, assuming patients have a reasonable life expectancy and are appropriate surgical candidates.

The vast majority of strokes from carotid artery plaques are from focal ischemic brain injury. While hemodynamic compromise due to restriction of flow in patients with high-grade carotid stenoses can contribute to ischemic stroke, rich intracranial collateral flows from the contralateral carotid artery and vertebral arteries provide robust protection of the brain from ischemic injury. Strokes due to carotid stenosis-related hypoperfusion tend to occur in the watershed areas of arterial distribution and in the presence of inadequate cross-collateralization. A vast majority of strokes attributable to carotid disease are caused by carotid plaque disruption and distal embolization, which is supported by detection of embolic signals in the middle cerebral artery of patients with carotid stenosis. Therefore, carotid plaque disruption with embolic cerebral infarction, rather than hemodynamic compromise from luminal narrowing, is the primary contributor in the pathogenesis of stroke in patients with carotid atherosclerotic stenosis.

Stable Versus Unstable Plaque

The risk of embolization from carotid plaques varies greatly. Some have reported a 0.5% per year stroke risk in patients with high-grade stenosis, while others have shown a risk of more than 10% per year in patients with severe carotid stenosis. Although there were different definitions of “high-grade” stenosis in early clinical trials, most clinicians have now agreed that 70%–99% stenosis, based on NASCET criteria, is considered high-grade. The variations in stroke risk are largely related to heterogeneity of carotid plaques. Recent advances in basic and clinical vascular sciences have shown that not all carotid plaques behave in the same manner. So-called “unstable” or “vulnerable” plaques appear to be more likely to cause cerebrovascular accident (CVA) or transient ischemic attack (TIA), even at mild or moderate levels of stenosis. In fact, silent, micro-infarcts have been observed in patients with apparently unstable carotid artery plaques. ^, Some authors refer to these plaques as “high-risk” and stable plaques as “quiescent.” It is important to view atherosclerotic carotid plaques as dynamic lesions that may progress or regress over time.

Plaque stability can be analyzed broadly using several different lenses, including surface characteristics, plaque content and morphology, plaque mobility, and plaque hemodynamics. In terms of surface features, plaque ulceration has been widely studied and consistently shown to correlate with vulnerable plaque and microembolic activity. ^, Studies have shown that ulcerated plaques often have an element of overlying thrombosis and that there tends to be increased platelet aggregation and activity on the surface of ulcerated plaques. ^, Typical atherosclerotic plaques are composed of two main components: a soft, lipid-rich portion and a hard, sclerotic portion formed mainly of connective tissue elements. The calcified, connective tissue component has been proposed to stabilize the plaque; thus, plaques with an increased calcific component may be less prone to rupture. ^{, ,} In contrast, the inner atheromatous component of the lesion is weak and thrombogenic, with increased macrophage activity and cellular debris. This in turn leads to necrosis and intraplaque hemorrhage (IPH). High lipid content and necrotic core that appear echolucent or hypoechoic on ultrasound are two of the most widely accepted features of unstable plaque. ^, IPH characterized on magnetic resonance imaging (MRI) is also associated with increased necrotic core volume and decreased luminal diameter. Both overall plaque size and necrotic core size have been related to increased risk of plaque rupture. ^, Plaque mobility has also been shown to increase the risk of microembolization and subsequent cerebral infarction. ^, One study showed that 9.3% of ICA plaques were mobile on ultrasound; those patients with mobile plaque were more likely to demonstrate progressive ischemic symptoms.

In terms of plaque hemodynamics, extensive research has identified the relationship between shear stresses on the carotid wall and plaque development (see “Biomechanics” section below). The “upstream” region distal to the plaque has been shown to be particularly susceptible to shear stresses, with resultant changes in stability. Longitudinal plaque asymmetry is linked to vulnerability and increased risk of rupture. The implications for understanding plaque stability in this context are clear: relative differences in shear stress on the arterial wall have been linked to increased apoptosis and subsequent thinning and disruption of the overlying fibrous cap. Plaque neovascularization (via angiogenesis) occurs in response to increasing hypoxia within a plaque’s core and has also been associated with instability. ^{, , ,} At least one group has shown a disproportionate increase in neovascularization in soft, lipid-rich plaques when compared to hard, more heavily calcified plaques.

Interestingly, the relationship between the degree of stenosis and plaque vulnerability is still unclear. Multiple studies, including ACAS and ACST, have failed to demonstrate a relationship between degree of stenosis and development of cerebrovascular symptoms. ^, However, it is thought that a higher degree of stenosis is associated with larger plaque size. Both increased overall plaque size and necrotic core size increase risk of plaque rupture. ^, The lack of clear association between plaque vulnerability and degree of stenosis is significant because treatment paradigms for those with unstable plaques may ultimately differ from those for patients with stable plaques ( Table 89.1 ).

Histomorphology

Histologically, all atherosclerotic lesions, regardless of the vessel in which they develop, begin as a fatty streak – an accumulation of lipids and inflammatory cells within a vulnerable region of intima. Fatty streaks develop early in life, and progress to atheroma. The American Heart Association (AHA) has developed a classification system for describing atherosclerotic lesions. Type I lesions consist essentially of microscopic lipid deposition within the intima and are found almost exclusively in infants and young children. The fatty streak corresponds to a type II lesion, and a type III lesion is defined by the development of extracellular lipid droplets and subsequent intimal thickening. Lesions of types I–III precede true atheroma and have no embolic potential. Type IV lesions demonstrate a large lipid core and increased numbers of foam cells; classically, they develop within the fourth decade of life. Type V lesions have an additional fibrous tissue component, and are broken down into types Va, Vb, and Vc, depending on the presence of a lipid core and/or a calcified cap. Type VI lesions are so called “complicated” lesions: they are type IV or V lesions that also demonstrate either surface disruption, hematoma or hemorrhage, or thrombosis. Lesions of type IV–VI have the potential to embolize.

There is general agreement between morphological features and plaque vulnerability, despite certain inconsistencies ( Fig. 89.1 ). A large histological study of 526 carotid plaque specimens from symptomatic patients demonstrated features of AHA grade VI (cap rupture, intraplaque hemorrhage, and inflammation) in the majority of the plaques. Interestingly, there were no significant histological differences in patients who had stroke vs. TIA vs. amarosis fugax. A smaller analysis confirmed that unstable plaques had the thinnest fibrous caps and the largest lipid cores. However, another study did not find significant difference in cross-sectional size, necrotic core size, or presence of IPH among those patients with clinical neurologic symptoms, compared to those without symptoms.

Biomechanics

The carotid bifurcation is important for understanding plaque stability because of unique hemodynamic stresses that occur in this region. Turbulent flow at the area of the carotid bifurcation results in changes in sheer stress and accumulation of atherosclerotic material. ^, Arterial bifurcations and branch points, such as the CCA bifurcation, are especially susceptible to mechanical stresses as cross-sectional area changes. ^, Biophysicists have hypothesized that atherosclerotic lesions develop at least in part because bioactive substances (macrophages, low density lipoproteins [LDLs], and other molecules involved in plaque progression) tend to re-circulate within turbulent flow areas, resulting in prolonged absorption times over endothelial surfaces. ^, Sheer stress has been shown to affect cellular inflammatory responses by altering ribonucleic acid (RNA) expression to upregulate inflammatory protein pathways, with resultant endothelial cell apoptosis. ^, The arterial wall initially compensates for increased mechanical stress by expanding, but at a certain point it can no longer accommodate an enlarging plaque, and luminal narrowing occurs. Carotid atheroma tends to deposit in areas of low sheer stress. Over time, however, stress distributions around the arterial wall change, and several fluid dynamic studies and experimental animal model studies have actually shown a correlation between elevated shear stress and plaque rupture. ^, The takeoff angle of the ICA has also been shown to be a prognostic indicator for plaque formation. In a landmark paper that used high-resolution ultrasound to measure several anatomic features of carotid arteries in 1300 healthy subjects, Sitzer and colleagues identified acute angle of ICA origin (>60 degrees) as a risk factor for development of extracranial carotid disease. A separate study using computed tomographic angiography corroborated this finding, showing that increasing ICA take-off angle (in relation to the vertical axis of the CCA) predicted increased ICA stenosis (OR, 1.05 per degree increment; 95% CI, 1.04–1.07). Several authors have also shown that tortuosity is a proxy for increased vessel wall exposure to disturbed flow. ^,

Mechanical forces at the area of the atheroma also appear to play a role in plaque stability. Although low sheer stress is involved in initial plaque formation, ^, elevated shear stress in portions of the CCA and ICA has been linked to increased risk of plaque rupture and subsequent ischemic infarct. ^, Long-term increases in sheer stress lead to eccentric plaque growth and ultimately contribute to transformation of a plaque to an unstable phenotype. When arterial wall stress exceeds the strength of the fibrous cap, which is lower in thinner or ulcerated caps, plaque rupture occurs. A study has shown that plaque wall stress appears to be higher in symptomatic patients than in asymptomatic patients, and another study using US or MRI showed that sheer strain and axial stress correlated with plaque vulnerability.