Pathologic Mechanisms of Atherosclerosis

The word carotid, derived from the Greek word karos, means deep sleep. Hippocrates, around 400 BC, was one of the first to describe the symptoms of stroke.³ Chiari is credited as being the first to propose that occlusive disease of the extracranial blood vessels could be responsible for neurological symptoms. In 1905, in a series of 400 autopsies, Chiari found seven patients who had thrombus superimposed on atherosclerosis near the carotid bifurcation. Four of these patients had suffered a cerebral embolism, and he presumed the source was the extracranial carotid artery.⁴ In 1927, Egas Moniz described the first successful cerebral angiogram.³ Initially, this technique was used predominantly to visualize the intracranial cerebral circulation; however, it represented an opportunity to visualize the carotid artery before direct visualization at surgery. Published in 1951, C. Miller Fisher’s article, Occlusion of the Internal Carotid Artery, is unquestionably the landmark publication describing the relationship between carotid artery disease and transient ischemic attacks (TIAs) and stroke. Fisher described the clinical history, available premortem studies, and available postmortem examinations of the carotid arteries in eight patients with stroke.⁵ Interestingly, the clinical descriptions of previous symptoms included several patients with transient monocular blindness ipsilateral to the diseased carotid artery. Fisher later reported the clinicopathologic results of 45 more patients with occlusion or near occlusion of the carotid arteries.⁶

The pathology of the atherosclerotic plaque is quite complex. Essentially, however, it represents a disease of the arterial intima that, in subsequent stages, progresses to luminal narrowing. Over the years, various theories regarding the genesis and growth of atherosclerotic lesions have been promoted, usually concentrating on endothelial injury, smooth muscle cell proliferation, lipid accumulation, and more recently, inflammatory cells.^7,8

Infectious agents such as Chlamydia pneumonia and cytomegalovirus have been associated with carotid atherosclerosis. Evidence of C. pneumonia organisms has been found in atherosclerotic plaques removed at the time of carotid endarterectomy by both reverse-transcriptase polymerase chain reaction and immunohistochemical techniques.^9,10 A population-based cohort study showed a graded relation between the odds of intimal-medial carotid artery thickening measured by carotid ultrasonography and the levels of cytomegalovirus antibody titers in sera.¹¹ Whether these agents cause carotid atherosclerosis, contribute to its progression, or simply represent a superimposed infection remains to be studied.

A combination of these elements causes the development of significant plaque. Atherosclerosis is likely initiated by injury to or dysfunction of the endothelium.

The reactive endothelium allows the inward migration of mononuclear cells and lymphocytes and stimulates medial smooth muscle cells to migrate and proliferate. Lipids are deposited or taken up by monocytes or macrophages through lipoproteins, most notably low-density lipoproteins (LDLs). Lipid-laden macrophages, or foam cells, continue to accumulate, as do various connective tissue elements and smooth muscle cells.

Inflammatory cells also likely play a role in the progression of atherosclerotic plaque. Oxidative stress and free radical production also play a role in the pathogenesis of atherosclerosis. As the various elements accumulate, the lesion grows, and the diameter of the vessel narrows. Eventually, a complicated lesion with a fibrous cap overlying a core of lipid and necrotic tissue is formed. Certainly, the atherosclerotic plaque is a complex environment of cells, connective tissue elements, lipids, cytokines, growth factors, and calcium. The plaque may fissure, ulcerate, or rupture, exposing thrombogenic nonendothelial cells and substances. The adherence of platelets and the formation of fibrin clot are precursors for further narrowing or occlusion of the artery and distal embolization.

Typically, the mechanism of ischemic stroke in atherosclerosis of the proximal internal carotid artery (ICA) is attributed to either “hemodynamically consequential” narrowing of the vessel lumen, proximal carotid artery–to–distal vessel embolus, or thrombosis of the proximal vessel leading to perhaps both hemodynamic compromise and potential artery-to-artery embolization. Blood flow in a larger artery like the ICA remains fairly constant until its internal diameter is reduced to about 70% of its normal diameter.¹² Further diminution in blood flow follows higher levels of stenosis. Some authors, however, argue that true cerebral hemodynamics cannot be assumed on the basis of the degree of carotid stenosis and that other factors, especially the adequacy of collateral circulation, play important roles.^13,14

Carotid atherosclerosis develops in regions of low wall shear stress. Symptomatic carotid artery plaque involves primarily the carotid artery bulb. Plaque morphology and, specifically, plaque ulceration may also play a role in the risk for stroke. Ulcerated, echolucent, and heterogenous plaque with a soft core may be unstable with a high risk for arterioarterial embolization.¹⁵ Cranial computed tomography (CT) of patients with carotid artery plaque shows a sixfold increase in the frequency of cerebral infarction in patients with echolucent carotid artery plaque compared with patients with echogenic carotid artery lesions.¹⁶ However, it is quite difficult to determine the exact risk associated with ulcerations given the various radiographic modalities used to image the carotid artery, the various definitions for the severity of ulcerations, and the various degrees of stenosis that accompany ulcerations.¹⁷ In an analysis of patients with severe carotid stenosis (70% to 99%) in the North American Symptomatic Carotid Endarterectomy Trial (NASCET), the presence of angiographically defined ulceration for medically treated patients was associated with an increased risk for stroke.¹⁸

Clinical Manifestations of Atherosclerosis

Recognition of the symptoms and signs of TIAs or strokes related to carotid artery atherosclerotic disease is important in evaluating patients (Table 349-1). About 10% to 15% of those who experience a stroke have a history of preceding TIAs. Among patients with a TIA who survive 5 years, a third will experience a stroke. Estimates indicate that the risk for stroke after a TIA is about 5% during the first month after the event and 12% during the first year.¹⁹ Patients with hemispheric TIAs have a greater risk for ipsilateral stroke than patients with retinal TIAs.²⁰ The ICA and its branches supply blood to the eye and the largest portions of the cerebral hemispheres. Therefore, it is almost impossible to describe one or a few sets of syndromes related to cerebral ischemia in its territory. The type and severity of symptoms depend on the location of the occlusion, the amount of brain or retinal tissue affected, and the availability of collateral circulation. The important clinical features of lesions of the carotid artery or its branches, including the ophthalmic artery, middle cerebral artery (MCA), anterior cerebral artery (ACA), anterior choroidal artery, and sometimes the posterior cerebral artery (PCA), are summarized.

TABLE 349-1 Symptoms of Carotid Artery Territory Transient Ischemic Attacks

The only feature that truly differentiates the ICA syndrome from the MCA syndrome is transient monocular blindness or amaurosis fugax. Patients describe the abrupt and painless onset of a visual disturbance in one eye, usually lasting 1 to 30 minutes. The classic description is one of a shade being pulled down over the eye, but it occurs only in a minority of patients. Blackout, graying, dimming of vision, or even a general constriction of the visual field in one eye can be described. Marginal perfusion causing diminished retinal blood flow or microemboli to the retinal circulation are the causes. Different types of microemboli may be seen on funduscopic evaluation of the retinal vessels, including bright plaques (Hollenhorst), so-called white plugs, or calcium. Hollenhorst plaques are composed of cholesterol crystals, whereas “white plugs” typically consist of platelets and fibrin.²¹

The MCA is the most common site of ischemic stroke. The manifestations of an infarction in its territory can be extremely varied, depending on the site of occlusion. Contralateral weakness and sensory loss can occur. Often, the face and arm are more severely affected than the leg. Various types of aphasia are associated with lesions in the dominant hemisphere; hemineglect and apractic syndromes are associated with damage to the nondominant hemisphere. Contralateral visual field deficits can occur, and paresis and apraxia of conjugate gaze to the opposite side are occasionally noted. Infarctions of the ACA typically lead to contralateral leg weakness more so than weakness of the arm. Various cognitive or psychiatric disturbances have also been associated with unilateral or bilateral medial frontal lobe infarctions.

Anterior choroidal artery infarctions typically result in contralateral hemiparesis caused by involvement of the posterior limb of the internal capsule, hemisensory loss caused by involvement of the posterolateral thalamus or its connections, and hemianopia related to involvement of the lateral geniculate body or its connections in the visual pathways. The classic deficit in PCA infarctions is contralateral visual field disturbances. Other symptoms and signs may occur, depending on site of occlusion and the extent of the cerebral hemisphere supplied by the PCA.

Natural History of Extracranial Carotid Disease

As a prelude to discussing the medical management of extracranial carotid disease, knowledge of its prevalence, the importance of detecting carotid bruits, and its natural history can provide a helpful perspective. Some insight into the history of proposed treatments for extracranial carotid disease is necessary as a background to a discussion of the natural history. Armed with the thought that extracranial carotid artery disease might be a mechanism for stroke, surgeons began using carotid endarterectomy in the 1950s as a way to remove offending plaque, hoping to prevent strokes. In the 1970s, platelet antiaggregating agents such as aspirin were found to help prevent strokes. Several studies on the efficacy of aspirin in preventing stroke excluded patients who were to undergo surgical treatment such as carotid endarterectomy. Adequate prospective randomized controlled studies that compared carotid endarterectomy with “best medical care” did not appear until the 1990s. Also, initial observational studies did not control for the use of platelet antiaggregants or anticoagulants. Therefore, it is difficult to determine the actual natural history of carotid artery occlusive disease using data from these years.

Typically, patients with extracranial carotid disease reach a physician’s attention in one of three ways: (1) an asymptomatic lesion is found on some type of noninvasive screening test, most often carotid ultrasonography; (2) a carotid bruit is auscultated on physical examination; or (3) extracranial carotid disease is found during the evaluation of a patient with a previous stroke or TIA symptoms. In unselected adult populations, the frequency of ICA stenosis of more than 50% on carotid duplex scanning was less than 5% but increased with age.^22,23 The incidence is higher in patients with coronary artery disease, peripheral vascular disease, and high-risk factors for atherosclerosis.²⁴

The prevalence of asymptomatic carotid artery bruits increases with age and has been assessed in two large population-based studies. In Evans County, Georgia, 4.4% of 1620 asymptomatic individuals at least 45 years of age had a carotid bruit.²⁵ In the Framingham study, 3.5% of asymptomatic people aged 44 to 54 years and 7% of those aged 65 to 79 years had a carotid bruit.²⁶ In both studies, the incidence of TIAs and strokes was higher in individuals with carotid bruits than in those without bruits, but the correlation between the location of the bruit and the location and proposed etiology of the cerebral ischemia was poor. In two studies that correlated cerebral angiographic findings and carotid bruits, the predictive value of carotid bruit for ipsilateral extracranial carotid atherosclerosis was about 75%,²⁷ and the false-positive rate was 10%.²⁸ In the Asymptomatic Carotid Artery Study (ACAS), only about 10% of the randomized patients had an ipsilateral carotid bruit.²⁹ Auscultation of the carotid artery is useful and easy to accomplish at the bedside. Some patients, however, have no carotid bruit but have significant extracranial carotid disease, and not all patients with a carotid bruit have significant extracranial carotid disease.

The risk for stroke depends on the degree of carotid artery stenosis. Asymptomatic carotid artery stenosis of less than 75% carries an annual stroke risk of about 1%. When the stenosis is greater than 75%, the combined 1-year risk for TIA or stroke is about 10%. Most events are ipsilateral to the stenosed artery. The natural history of asymptomatic carotid artery occlusive disease was reported in studies from the 1980s. In a retrospective study of 640 neurologically asymptomatic patients with either pressure-significant ICA lesions determined by oculoplethysmography or carotid bruits without pressure-significant lesions, the annual stroke rates were 3.4% and 1.5%, respectively. However, only 56% of the strokes and TIAs occurred in a distribution ipsilateral to the oculoplethysmographic abnormality.³⁰ In a prospective study of 339 patients using serial Doppler examinations with a median follow-up of 29 months, the number of strokes varied with the degree of carotid stenosis. Two percent of those with 50% to 80% carotid stenosis, 8.3% of those with 80% to 99% stenosis, and 12.2% of those with a carotid occlusion had strokes.³¹ Again, not all strokes occurred in the distribution of the abnormal carotid artery. Neither of these studies controlled for the use of platelet antiaggregants, and both excluded patients who had undergone carotid artery surgery.

Two large randomized prospective studies evaluated the effects of carotid endarterectomy in neurologically symptomatic patients, the European Carotid Surgery Trial (ECST) and NASCET. Both studies had patients with some degree of asymptomatic carotid stenosis contralateral to the symptomatic, randomized carotid, and the risk for stroke in the distribution of the asymptomatic artery has been published. ECST found that higher degrees of stenosis tended to have a higher risk for stroke; the 3-year risk for stroke was 1.8% in the 0% to 29% stenosis group, 2.1% in the 30% to 69% stenosis group, and 5.7% in the 70% to 99% stenosis group.³² In NASCET, the risks for stroke over a 4-year period were 4.5%, 8.3%, and 14.5% for stenosis of less than 30%, 30% to 69%, and 70% to 99%, respectively.³³ These numbers should be compared carefully because the degree of carotid stenosis was measured differently in the two trials (50% NASCET stenosis equals 75% ECST stenosis).

Patients with a TIA or minor nondisabling stroke in the distribution of a carotid stenosis appear to have a higher risk for subsequent ipsilateral stroke compared with patients with no neurological symptoms with known carotid stenosis. Data from the control or medically treated arms of NASCET and ECST provided stroke rates ipsilateral to the symptomatic carotid stenosis. In NASCET, the ipsilateral stroke rates were 26%, 22%, and 19% for 70% to 99%, 50% to 69%, and less than 50% stenosis, respectively. The major ipsilateral stroke rates were 13%, 7.2%, and 4.7% for 70% to 99%, 50% to 69%, and less than 50% stenosis, respectively.^34,35 In ECST, the ipsilateral major stroke rates were 17.4%, 10.6%, and 6% for 70% to 99%, 50% to 69%, and less than 50% stenosis, respectively.³⁶ Again, interpretation must be cautious. Not only was the degree of carotid stenosis measured differently in ECST and NASCET, the duration of follow-up also varied. The mean follow-up was about 6 years in ECST, 2 years in the severe stenosis NASCET group, and 5 years in the mild and moderate stenosis NASCET group.

Medical Management of Extracranial Carotid Disease