Approximately 6.6 million Americans older than 20 years of age have had a stroke with resultant focal cerebral, retinal or spinal infarction with or without neurologic dysfunction. In addition, 795,000 people in the United States experience an ischemic or hemorrhagic stroke each year and 240,000 people experience a transient ischemic attack (TIA) with transient neurologic dysfunction caused by focal cerebral, retinal, or spinal cord ischemia, without acute infarction [1, 2, 3]. Approximately one in five patients with TIAs eventually develop a stroke [5,6]. As a consequence, $45 billion dollars is spent each year on the diagnosis and treatment of patients with strokes or TIAs [3,4].

Unfortunately, approximately 150,000 people die in the United States each year as a consequence of a stroke. Moreover, stroke is a leading cause of disability in adults with one-third of patients with stroke experiencing significant physical disabilities one year after a stroke. In addition, one in seven stroke survivors requires institutional care [2].

Atherosclerotic plaque formation with narrowing or blockage by plaque accumulation in the common carotid artery bifurcation and/or the proximal internal carotid artery is an important cause for ischemic strokes and TIAs in individuals [4,7]. In this regard, over 800 million people throughout the industrialized world have atherosclerotic plaque formation in the carotid artery and 58 million have some degree of carotid artery stenosis [8]. These patients are at increased risk for ischemic stroke or TIAs. Moreover, the incidence of carotid artery stenosis in the general population is significantly increasing due to the general popularity of high fat and high salt diets, sedentary lifestyles, and the increasing age of the population [9]. In an analysis of 59 studies from 21 countries, the incidence of carotid artery atherosclerotic plaque formation among people aged 55-59 years increased by 34% in men and by 21% in women between the years 2000 and 2020 [10].

Currently, 5 to 10% of the general population over 65 years of age have asymptomatic carotid artery stenosis of 50% or greater [11, 12, 13]. Above the age of 80 years, atherosclerotic carotid vascular disease affects approximately 7.5% of men and 5.0% of women. The highest incidences of carotid artery stenosis are found in Native Americans and Caucasians, while Asian women and African-American men have the lowest incidences of carotid artery stenosis [10].

Of major importance to cardiovascular physicians is the fact that in individuals with coronary artery disease or lower extremity peripheral vascular disease are at significant risk for carotid artery stenosis [14]. In this regard, the prevalence of coronary artery disease can be as high as 50 to 75% in individuals with carotid artery stenosis. Consequently, the diagnosis and treatment of patients with asymptomatic or symptomatic atherosclerotic carotid artery stenosis must be familiar to all cardiovascular specialists in order to limit the significant morbidity, mortality and financial costs associated with carotid artery stenosis and resultant TIAs and strokes.

Table 1 lists four important common risk factors and the respective odds ratios for carotid artery stenosis in individuals over time. Table 1 is adapted in part from Reference [6,14].

Important additional risk factors for carotid artery stenosis include the presence of diabetes mellitus, advanced glycation end products (AGEs) from a high glycemic diet, chronic kidney disease, and increased C-Reactive Protein which can augment reactive oxygen free radical formation. Patients with peripheral atherosclerotic vascular disease or with atherosclerotic risk factors are also at increased risk for carotid artery atherosclerosis as shown in Table 2, which is adapted in part from References [1,5,6,14, 15, 16].

Clinically significant carotid artery stenosis >50% occurs in 5.9% patients with normal or mild coronary artery disease, 6.6% of the patients with 1 vessel disease, 13% with two vessel disease, 17.8% with three vessel disease, and 31.3% among patients with left main coronary artery disease. Severe (>70%) carotid stenosis has been found in 2.1%, 3.1%, 3.6%, 7%, and 10.8% of patients with normal or mild coronary artery disease, 1, 2, 3 vessel disease, and left main disease, respectively [15,16].

Conversely, in patients with carotid artery stenosis the prevalence of coronary artery disease (CAD) can be as high as 25 to 60% as demonstrated by provocative tests results for myocardial ischemia or angiographic evidence of severe CAD [17]. Moreover, patients with asymptomatic carotid artery stenosis have a three-fold higher risk of myocardial infarction or death compared with patients without carotid stenosis, and the risk is greater than three-fold among patients with symptomatic carotid artery stenosis and coronary artery disease. In the international Reduction of Atherothrombosis for Continued Health (REACH) Registry, patients with ≥3 atherosclerotic vascular risk factors or established peripheral, coronary, or carotid vascular disease with asymptomatic carotid artery stenosis have a 1-year >6% absolute risk of myocardial infarction, stroke, or death compared to individuals without carotid artery stenosis [18]. Consequently, vascular screening for asymptomatic carotid artery stenosis should be considered for patients with (1) symptomatic peripheral arterial disease, coronary artery disease, or atherosclerotic aortic aneurysm or (2) two or more of atherosclerotic risk factors such as hypertension, hyperlipidemia, and tobacco smoking [19].

The right common carotid artery originates from the brachiocephalic trunk while the left common carotid artery originates from the aortic arch. However, bovine arch anatomy is common where the left common carotid artery arises from the brachiocephalic trunk. The external carotid artery arises from the common carotid artery bifurcation commonly at the level of cervical vertebrae 3-4 and gives off branches supplying the head and neck regions. The internal carotid artery arises at the common carotid artery bifurcation, in the region of the superior border of the laryngeal cartilage, forming the anterior and middle cerebral arteries and contributes to the circle of Willis at the base of the cerebral hemispheres. SEE Fig. 1 which is adapted in part from Reference [20]. The hypophyseal arteries (superior and inferior) and the ophthalmic artery are the initial branches that arise from the internal carotid artery.

Blood flow at the bifurcation of the carotid artery into the internal and external carotid arteries departs from a laminar unidirectional flow pattern with reduction of blood flow velocity, the formation of vortices, and oscillatory shear stress that can facilitate in these areas vascular endothelial cell dysfunction and atherosclerotic plaque development in patients with risk factors for atherosclerotic vascular disease such as hyperlipidemia [21].

Hyperlipidemia increases the formation free oxygen radicals/reactive oxygen species that escalate the expression of cell adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule, on carotid vascular endothelial cells and the adherence of monocytes to carotid vascular endothelial cells. The monocytes differentiate into macrophages which develop receptors for oxidized low density lipoproteins (LDL). Low density lipoproteins are taken up by the macrophage LDL receptors to form foam cells. The formation of foam cells, the proliferation and migration of vascular smooth muscle cells, and the synthesis of collagen and elastin connective tissue contribute to the development and progression of atherosclerotic plaque in the common carotid and internal carotid arteries [22]. Interleukin 6 (IL-6) is the main pro-inflammatory and pro-coagulant cytokine that is increased in in patients with carotid artery stenosis and contributes to the recruitment of inflammatory cells, increased endothelial cell permeability, smooth muscle proliferation, atherosclerotic plaque development and unstable carotid plaques [23,24].

The American Heart Association (AHA) classifies carotid artery atherosclerosis to reflect the natural history of carotid vascular plaque formation as follows: [25]•

Type I: Monocytes and atherogenic lipoproteins infiltrate the carotid arterial endothelium and contribute to vascular medial thickening of the carotid artery.

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Type II: Fatty streaks composed of foam cells (i.e. macrophages containing cholesterol) occur in the vascular intima in the proximal portion of the internal carotid artery.

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Type III: Lipid particles disrupt the integrity of the vascular smooth muscle cells in the internal carotid artery.

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Type IV: Atheroma form with a large lipid core that contains cholesterol crystals, cellular debris, and calcium deposits.

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Type V: Atheroma develop fibrous caps on the surface of the plaque, covering the fatty core within the arterial wall.

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Type VI: Intraplaque hemorrhage from microvessels occurs, which can lead to rapid expansion of the lipid core and atheroma progression as well as rupture into the artery lumen with thrombus formation and/or debris embolization to the middle or anterior cerebral arteries.

Carotid atherosclerotic plaques that are at high risk for rupture and thrombosis or cerebral embolization with resultant TIAs or stroke are characterized by large lipid cores, intraplaque hemorrhage, fibrous caps less than 165 μms and often 70 ± 47 μms, and fibrous caps infiltrated by macrophages (CD68 positive) and T cells (CD3 positive) or surface ulcer(s) or fissures [4]. The larger the lipid rich core in the carotid plaque the greater the risk of atheroma fibrous cap thinning, plaque fissuring and ultimately plaque rupture. Plaques with lipid necrotic cores that exceed 40% of the plaque are considered high risk plaques [26, 27, 28]. In addition, the incidence of intraplaque hemorrhage occurs in as many as 84% of patients with symptomatic carotid stenosis [26,27].

Patients at increased risk for carotid plaque rupture also have high serum total cholesterol, a high ratio of total to high-density lipoprotein cholesterol, increased concentrations of high sensitivity C-reactive protein, hypertension, tobacco use, and are often women >50 years of age [29, 30, 31].

Important imaging features of carotid artery disease are the severity of the carotid artery stenosis and the character of the atherosclerotic plaque in the carotid bifurcation and internal carotid artery. Imaging of carotid artery stenosis typically includes magnetic resonance angiography (MRA), computed tomographic angiography (CTA), or in some circumstances digital subtraction catheter angiography (DSA).

Magnetic resonance imaging can determine the severity of the carotid artery stenosis and also the characteristics of atherosclerotic plaque such as plaque ulceration or fissures which can lead to increased embolization [32]. In general, the sensitivity of MRA for stenosis detection and atherosclerotic plaque characterization is 91-95% and the specificity is 88-99%. The sensitivity of CTA is 77% and specificity is 95% [33]. However, the sensitivity and specificities of these imaging procedures are unique to each medical institution that evaluates patients with carotid artery stenosis. Therefore, each physician must determine the optimal carotid imaging procedure at his/her institution. Common angiographic criteria used for measurement of carotid artery stenosis is derived from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) shown in Fig. 2A where the diameter of the internal carotid stenosis “B” is subtracted from the diameter of the normal internal carotid diameter “A” and the result divided by the normal internal carotid diameter “A”. An alternate NASCET formula uses the equation: 1-B/A [34,35]. See Fig. 2. Fig. 2A is adapted in part, from Reference 35. Fig. 2B and 2C is courtesy of the General Hospital.

Based on the NASCET criteria, carotid artery stenosis is graded as follows [34,36,37]:•

Mild: 0∼49% stenosis

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Moderate: 50–69% stenosis

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Severe: 70–99% stenosis

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Complete occlusion: 100% stenosis

MR and CT angiography should not be used for widespread population screening due to their significant cost and the degree of radiation exposure with CT angiography. When carotid endarterectomy or carotid stenting is planned, MR or CT angiography is used to image the extra- and intracranial circulation, the carotid plaque, the great vessels, and the aortic arch, after an initial carotid Doppler ultrasound examination. CT angiography is recommended over MRI angiography in patients with carotid artery vascular calcification. However, large amounts of calcification can result in significant “blooming artifact’’ and overestimation of the size of carotid plaque.

Carotid Doppler ultrasound has become the noninvasive imaging modality used for the initial diagnosis and the monitoring of carotid artery stenosis in symptomatic and asymptomatic patients. The rationale for use of ultrasound examination include the low cost, ease of performance, and 89% sensitivity and 84% specificity when used by sonographers with extensive experience with the technique [38]. The standard ultrasound examination includes grayscale B-mode imaging, color Doppler imaging, and spectral Doppler velocity evaluation of the blood flow waveform at the site of greatest arterial narrowing [39]. Ultrasound devices that can be readily used at the patient's bedside for carotid artery stenosis evaluation include the Butterfly IQ3 ultrasound device and the Clarius PAL HD3 ultrasound device.

Carotid plaques also can be graded by 2D/3D ultrasound based on the maximal plaque height value as no plaque, grade 1 low risk with plaque height <1.5 mm, grade 2 intermediate risk with plaque height ≥1.5mm or carotid intima medial thickness ≥1.5mm, and grade 3 high risk with plaque height ≥2.5mm + echolucency and neovascularization when visualized with contrast media [40].

Unstable plaques often have a plaque area >80-95 mm2 and a juxtaluminal black area >6-8 mm2 that represents fresh thrombotic components on the plaque surface adjacent to the lumen and which lack a visible echogenic cap [41]. In addition, the recommended measurements on spectral Doppler evaluation include the peak-systolic blood flow velocity (PSV) and end-diastolic velocity (EDV) at the internal carotid artery (ICA) and the distal common carotid artery (CCA). The highest ICA PSV at the site of stenosis together with plaque and lumen visualization on grayscale and Doppler images are the parameters used to diagnose and grade the carotid stenosis [42,43]. In addition, the presence of post-stenotic turbulence on color flow and spectral Doppler, as well as the morphology of the waveform distal to the area of the most severe stenosis, can be utilized for further identification of high-risk carotid lesions.

The Society of Radiologists in Ultrasound recommend the following blood flow velocity criteria for diagnosis of carotid stenosis [44,45]:•

50-69% ICA carotid stenosis: An ICA PSV of 125-230 cm/sec with carotid plaque visible sonographically. Additional criteria include an ICA/CCA PSV ratio of 2.0 to 4.0 and an ICA EDV of 40 to 100 cm/sec.

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≥70% ICA stenosis but less than total occlusion: An ICA PSV >230 cm/sec and visible plaque and luminal narrowing seen on grey-scale and color Doppler. Additional criteria include ICA/CCA PSV ratio >4 and ICA EDV >100 cm/sec.

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100% occlusion of the ICA: No detectable blood flow with color, spectral, or power Doppler ultrasound and no detectable luminal patency with grey-scale ultrasound.

However, extensive carotid artery tortuosity, tandem carotid artery obstructions, and plaque calcification can confound interpretation of carotid ultrasound results [45]. Additional limitations of carotid ultrasound include the dependence on the experience/expertise of the sonographer performing the examination, limitations secondary to patient habitus and anatomy, flow dependence which can limit evaluation with patient low cardiac output, irregular heart rhythms, or a hyperdynamic cardiac state, and inability to discern low levels of stenosis [46,47]. Moreover, the presence of contralateral severe carotid stenosis or occlusion may falsely elevate carotid Doppler ultrasound velocities [48]. Conversely, the presence of collateral flow through the Circle of Willis or the ophthalmic artery can decrease the post-stenotic pressure in the carotid artery and, consequently, decrease the intrastenotic velocity [49].

Because of the possibility of overestimating or underestimating the severity of a carotid stenosis with Doppler ultrasound, additional imaging with MRA or CTA should be performed when the severity of the carotid stenosis is uncertain or a carotid artery revascularization procedure is being considered. In addition, each ultrasound laboratory must validate their diagnostic criteria with CTA or MRA angiography in their facility and determine uniform diagnostic criteria for carotid artery stenosis.

High risk carotid plaques on carotid ultrasound can be further evaluated with transcranial Doppler cerebral artery techniques by detecting during the study the release of cholesterol crystal and other particle debris from an unstable carotid artery plaque(s) that embolize to the middle or anterior cerebral arteries.

Currently, studies in both symptomatic and asymptomatic patients with carotid artery stenosis should not only evaluate carotid artery stenosis assessed at the narrowest diameter but should also incorporate determinants of atherosclerotic plaque vulnerability and stroke risk [50]. In this regard, the Carotid PlaqueRADS scale is a recently introduced multi-imaging modality scoring system that incorporates the variables maximum carotid wall thickness, lipid rich necrotic core, intraplaque hemorrhage, fibrous cap rupture, carotid plaque neovascularity, plaque burden, stenosis progression and calcification to produce an overall assessment of plaque vulnerability and stroke risk. Table 3 lists the Carotid PlaqueRADs scale and is adapted in part from Reference [50]:

Carotid artery stenosis can be asymptomatic or symptomatic with TIAs and/or ischemic strokes. Asymptomatic carotid artery stenosis occurs when the presence of a significant carotid artery stenosis does not cause cerebral ischemia or infarction. In most cases, asymptomatic carotid artery disease is detected during the auscultation of a carotid artery bruit in the neck or as an incidental finding on CTA or MRA imaging. In addition, patients with carotid stenosis can have a chronic total carotid artery occlusion that is not associated with symptoms due to collateral brain circulation from the Circle of Willis [51,52]. The anterior communicating artery or the posterior communicating artery, or both can preserve blood flow to the brain in the event of cervical carotid artery stenosis or occlusion in many patients. In addition, the human body is capable of forming collateral blood vessels from the external carotid artery to the internal carotid artery in order to preserve blood flow to a cerebral hemisphere. See Fig. 1.

Between 9.0% and 29.1% of patients with asymptomatic carotid stenosis can develop progressive carotid stenosis and can become symptomatic [51,52]. The mean time to progression for affected carotid arteries is approximately 28.0 months and is most evident in patients >73 years of age with diabetes mellitus or a history of vasculitis [53, 54, 55]. The risk of stroke in patients with asymptomatic carotid stenosis varies from 1.6% annually to 3.2% annually and is related, in part, to the degree of the carotid artery stenosis less than or greater than 60% and also the characteristics of the stenotic carotid plaque [56].

Unfortunately a carotid bruit is not a sensitive finding for significant carotid artery stenosis. In NASCET, an ipsilateral carotid bruit was associated with a sensitivity of 63% and specificity of 61% for carotid artery stenosis of 70 & 99% [38]. Nevertheless, carotid ultrasound should be performed in patients with cervical carotid bruits to evaluate the severity of the carotid artery stenosis and the characteristics of any stenotic artery plaque. In a study of 127 asymptomatic patients with carotid artery stenosis, carotid plaques at greatest risk of rupture and subsequent stroke tended to have atheroma with thin fibrous caps and/or thrombus in addition to carotid stenosis >70% [30]. Table 4 lists the clinical and imaging features and risk of stroke in patients with asymptomatic 50 to 99% carotid stenosis treated with medical therapy. Table 4 is adapted in part from References [57, 58, 59].

Current recommendations for imaging patients with asymptomatic carotid artery disease suggest that is reasonable for asymptomatic patient with ≥50% carotid stenosis be imaged at least every 12 months [34].

In patients with symptomatic carotid artery stenosis, symptoms of TIAs or stroke are dependent on the severity of the vascular stenosis, the adequacy of collateral circulation, and whether or not a carotid plaque ulcerates or ruptures with thrombus formation or cholesterol/fibrin debris that embolizes to the retinal artery or the middle or anterior cerebral arteries. Ulceration of carotid artery plaques is most often seen in the proximal (upstream) part of the plaque where shear stress is the highest [60,61].

Natural history studies suggest that the incidence of recurrent stroke after a TIA can be as high as 5% to 8% at 48 hours, 4% to 17% at 72 hours, 8% to 22% at seven days, and 11% to 25% at 14 days [34,62]. The short-term risk of ipsilateral stroke after a TIA can be derived from the five components of an ABCD score which includes patient age ≥60=1 point, blood pressure ≥140/90 1 point, clinical features including unilateral weakness (2 points) and speech impairment without unilateral weakness (1 point), duration of symptoms less than or equal to or greater than 60 minutes (1-2 points) and the presence of diabetes mellitus (1 point). A patient with an ABCD score of 0–3 has 1.0% risk of stroke in 2 days as opposed to a patient with a score of 6–7 who has an 8.1% risk of stroke. The ABCD score can also estimate stroke risks at ≥7 days after presentation with symptoms of a TIA [62].

Acute complete occlusion of the internal carotid artery due to plaque rupture and thrombus formation is associated with a large cerebral infarction, poor functional outcome, and is poorly responsible to intravenous thrombolysis [34,63, 64, 65].

Carotid artery stenosis with plaque rupture and cerebral embolism of cholesterol/debris can manifest as a stroke, TIA, or transient ipsilateral blindness (amaurosis fugax). The distribution of the cerebral ischemia and the resulting symptoms are usually from obstruction of the middle cerebral artery, the anterior cerebral artery, or the retinal artery which is one of the initial branches off the internal carotid artery. Table 5 lists the symptoms and signs of anterior cerebral circulation ischemia/infarction and is adapted in part from Reference [1,65,66].

A right middle cerebral artery syndrome is typically characterized by sudden right gaze deviation and left hemiparesis whereas a left middle cerebral artery syndrome is typically characterized by left gaze deviation, aphasia, and right hemiparesis i.e. the patient looks to the side of the cerebral artery obstruction.

Amaurosis fugax is a symptom of ipsilateral atherosclerotic carotid artery stenosis causing emboli to the ophthalmic or retinal arteries. The finding of a retinal artery cholesterol embolus, or Hollenhorst plaque, on fundoscopic examination of the retina correlates with the presence of significant carotid bifurcation/internal carotid artery atheroma and warrants carotid artery evaluation [67]. Fig. 3 shows a Hollenhorst plaque, which resulted in decreased and blurred vision

Transient ocular or hemispheric symptoms can recur in rapid succession or “crescendo symptoms” with multiple events within a 24-hour period that do not respond to antiplatelet or low molecular weight heparin treatment. Crescendo symptoms suggests ongoing cerebral embolization from an unstable carotid artery atheroma [68].

With crescendo TIAs or stroke in evolution, CT scan or MRI of brain is important to assess for brain hemorrhage or ischemic infarction, and evidence of subacute or chronic strokes. Thereafter either a CT or MRI angiogram is helpful in imaging areas of stenosis or occlusions from the aorta up to the brain in order to explain the patient symptoms and determine the extent of brain tissue damage versus the extent that is at risk. The differential diagnosis of the cause of symptomatic TIAs or cerebral ischemia/infarction also includes carotid artery dissection, carotid artery fibromuscular dysplasia, brain embolus from left atrial fibrillation, left ventricular mural thrombosis, or valvular heart disease, Takayasu vasculitis, giant cell arteritis, and complicated migraine.

If CT or MRI angiography is not immediately available, a carotid ultrasound is recommended within 24 hours of a new carotid territory transient ischemic attack, non-disabling ischemic stroke, ipsilateral amaurosis fugax, or retinal artery occlusion/infarction in order to search for high-grade stenosis of the carotid bifurcation and internal carotid artery.