<70 years
≥70 years
Men
4.8 %
12.5 %
Women
2.2 %
6.9 %
Similar prevalence estimates were noted across different populations across the globe. The prevalence of significant carotid stenosis ≥ 50 % in an asymptomatic Egyptian series of 617 subjects was 6.3 % [4]. The Suita study randomly sampled asymptomatic men and women aged 50–79 years in urban Japan. The prevalence of significant stenosis was 4.4 % (7.9 % in men and 1.3 % in women) [5]. The Korean Longitudinal Study on Health and Aging evaluated carotid intimal–medial thickness (IMT) among asymptomatic elderly patients >65 years. The prevalence of subclinical atherosclerosis, defined as carotid IMT > 0.8 mm was 39.2 % [6].
The prevalence of Carotid stenosis is higher in subsets of asymptomatic patients with traditional atherosclerotic risk factors. Ultrasound screening of a population of 766 asymptomatic subjects with multiple atherosclerotic risk factors, revealed significant stenosis in 14.2 % of subjects with diabetes and dyslipidemia and 29.6 % in patients with 4 risk factors [7]. In a series of 440 young (25–50 years) North Indian asymptomatic subjects, carotid atherosclerosis (IMT > 0.9 mm) was noted in 21.6 % of subjects satisfying the criteria for metabolic syndrome. A large proportion of patients with carotid atherosclerosis (71.5 %) had 4 or more components of the metabolic syndrome [8]. Compared to nondiabetics, subjects with type 2 diabetes are three times more likely to develop asymptomatic carotid stenosis. In subjects with carotid stenosis, type 2 diabetics are more likely to develop severe stenosis [9]. In an East German population of 1632 asymptomatic adults, nonsmoking subjects with poor physical activity and unhealthy diet were at higher odds (OR: 2.68) of developing severe carotid stenosis compared to nonsmokers with physical activity and optimal diet. Diet and activity did not seem to influence risk of stenosis among smokers [10]. In a Japanese series, the prevalence of significant carotid stenosis was significantly greater among rural subjects (9.6 %) compared to urban subjects (4.6 %); this difference was attributed to long standing hypertension [11].
As atherosclerosis is a systemic disease, patients with symptomatic atherosclerosis elsewhere are more likely to also have carotid stenosis. This includes patients with peripheral arterial disease (PAD) and coronary disease. A meta-analysis of 19 studies with 4573 patients with symptomatic PAD, found moderate stenosis in 25 % of subjects and severe stenosis in 14 % [12]. In a series of asymptomatic, elderly patients (60–80 years) with two or more cardiovascular risk factors, a low Ankle Brachial index (ABI) <0.9 predicted the presence of significant carotid stenosis (14.3 % vs. 4.7 % among patients with normal ABI) [13]. Doppler screening of 162 patients with PAD in the SMART (Second Manifestations of ARTerial disease) cohort revealed significant asymptomatic carotid stenosis in 14 % [14]. About two-thirds of the PAD patients with significant asymptomatic carotid stenosis have concomitant coronary artery disease, several of them fulfilling indications for coronary revascularization [15]. The screening for carotid stenosis among patients going for coronary artery bypass grafting (CABG) is a common practice in many institutions. Among 643 patients undergoing CABG, 7.7 % had severe carotid stenosis and the presence of a cervical bruit, PAD or aortic aneurysm predicted significant carotid disease [16]. In another series of 757 patients with CABG, the prevalence of ≥50 % stenosis was 26.4 % and ≥70 % stenosis was 8.6 %. High plasma levels of ApoB/ApoA1, lipoprotein(a), and homocysteine predicted carotid stenosis in this population [17]. Among patients with abdominal aortic aneurysms, severe asymptomatic carotid stenosis was found in 10.8 % [18].
Pathophysiology of the Asymptomatic Carotid Plaque
Carotid atherosclerosis is well established as an inflammatory process [19] in which the vascular endothelium plays a dynamic role [20]. Inflammation is responsible for the initiation, progression, and vulnerability of the atherosclerotic plaque. [20] Normal endothelium is quiescent and in an anti-inflammatory state, with excess production of nitric oxide, which is regarded as protective for the endothelium. Hypertension, diabetes, oxidized low density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, smoking, homocysteine, certain infections, and the mechanical shear stresses in the region of the carotid bulb convert the anti-inflammatory endothelial cell into a pro-inflammatory state [20]. The pro-inflammatory state results in excess production of oxygen-derived free radicals such as superoxide and peroxynitrites. One of their major effects is the oxidation of LDL cholesterol.
Oxidized LDL results in activation of leucocytes and intimal smooth muscle cells. It induces production of endothelium adhesion molecules, which attract monocytes to the area. It activates monocytes into macrophages, which engulf oxidized LDL molecules resulting in foamy macrophages. Oxidized LDL also reduces the expression of nitric oxide synthase, decreasing the production of protective nitric oxide [20]. Another effect of oxidative stress is the increased expression of matrix metalloproteinase 9 (MMP 9). MMP 9 results in deterioration of the extracellular matrix, promoting migration of leukocytes and smooth muscle cells into the subendothelial area. In the fully developed plaque, MMP 9 may weaken the fibrin cap, resulting in plaque rupture [20].
The various stages of atherosclerotic plaque evolution have been classified by the American Heart Association, starting with an initial lesion with activated macrophages [21]. The next stage is the fatty streak where foamy macrophages are formed. This progresses to the intermediate lesion, where foamy macrophages increase in number, and some of them die resulting in extracellular lipid formation. Plaques are usually asymptomatic up to this stage [21]. As the extracellular lipid increases in quantity, the plaque is now called an atheroma. This progresses to a fibroatheroma with a defined lipid necrotic core and a fibrous cap [21]. When sufficient amount of necrotic lipid accumulates, it may crystallize into cholesterol crystals. The jagged crystals may cause a rupture of the fibrous cap or may rupture the vasa vasorum of the artery resulting in intraplaque hemorrhage. Such a complicated lesion is the setting for initiation of thrombosis. Once a necrotic lipid core begins to form, the patient is prone to develop clinical symptoms [21].
Pathological studies on plaques removed during endarterectomy suggest that the asymptomatic plaque in patients who have never experienced symptoms have increased smooth muscle content, increased calcification and less frequent intra-plaque hemorrhage [22]. Genetic studies in the elderly patients with asymptomatic carotid plaque have identified single nucleotide polymorphisms associated with high levels of proinflammatory molecules such as interferon gamma and interleukin 6 [23]. Recent genome wide association studies have identified some novel loci, which have opened up a fertile field for future atherosclerosis research [24].
Clinical Manifestations of Asymptomatic Carotid Stenosis
The main concern with asymptomatic carotid stenosis is whether the plaque will convert to a symptomatic stenosis (i.e., the risk of future cerebrovascular events). Generally the risk of stroke in patients with asymptomatic stenosis is low. In studies from the pre-statin era, patients with an asymptomatic stenosis <75 % had a 1.3 % annual risk of stroke. With a stenosis ≥75 %, the annual risk of stroke was 2–2.5 %. With the advent of statins and aggressive antihypertensive therapy, these risks are generally lower. The risk of cerebrovascular events is markedly increased if the patient has concomitant intracranial atherosclerosis (3.6 % annual risk) [25]. The risk of stroke increases with the degree of stenosis and the rate of stenosis progression [26]. Cohort studies with sequential ultrasound follow-up show that the progression rates of asymptomatic stenosis are usually low [27]. The average rate of progression tends to be faster among diabetics, especially if they continue smoking [27].
Beyond the occurrence of a cerebrovascular event, asymptomatic carotid stenosis has several other clinical implications. Studies using transcranial Doppler ultrasound can detect asymptomatic intracranial microembolic signals from carotid plaques. In the Asymptomatic Carotid Emboli Study, patients with severe asymptomatic carotid stenosis received two single hour recordings with transcranial Doppler [28]. Of 482 subjects, 10.7 % demonstrated microemboli on 1 recording, and 16.7 % showed microemboli on at least one of two recordings. Antiplatelet therapy reduced the likelihood of detecting microembolic signals [28]. In a systematic review, 10 % of 1066 patients with asymptomatic carotid stenosis demonstrated at least one microembolic signal [29]. The presence of microembolism strongly predicted future cerebrovascular events with an OR of 13.4 [29]. In a natural history study of 821 patients with asymptomatic carotid stenosis, 17.8 % of subjects showed silent embolic infarcts on head CT [30]. This finding has been replicated in other series [31]. The presence of such infarcts, while asymptomatic, increased the risk of future symptomatic cerebrovascular events [30].
A number of cohorts have convincingly demonstrated cognitive impairment among patients with otherwise asymptomatic carotid stenosis. A cognitive evaluation of 1975 subjects in the Framingham Offspring study showed that an increased internal carotid IMT was significantly associated with poorer performance on verbal and nonverbal memory measures [32]. Carotid stenosis ≥25 % was associated with poorer performance on executive function [32]. In another recent study, 17 patients with severe asymptomatic carotid stenosis and 26 controls, underwent extensive neuropsychological testing and multimodal MR imaging [33]. Patients with severe stenosis had significantly lower scores on memory and complex visuospatial performance. Multimodal MR imaging demonstrated disruption of both interhemispheric and intrahemispheric functional connectivity in the default mode network and frontoparietal networks [33]. Patients with severe carotid stenosis had lower whole brain mean fractional anisotropy (FA) and diffuse decrement of FA, indicating poorer diffusivity and microstructural disruption of white matter integrity. Eleven of the 17 patients underwent carotid revascularization. Interestingly, MR imaging at 3 months demonstrated significantly improved FA and functional connectivity. There were improvements in cognitive scores also, although these did not reach statistical significance [33]. Multiple cohorts have shown otherwise asymptomatic carotid stenosis to be a strong predictor of early postoperative cognitive impairments following CABG [34, 35].
As mentioned above, there is a higher prevalence of asymptomatic carotid stenosis in patients undergoing CABG. There are conflicting reports about the contribution of carotid stenosis to the outcome of patients undergoing surgery. In a series of 455 patients undergoing CABG, asymptomatic carotid stenosis ≥50 % was an independent predictor of mortality after surgery (OR: 2.7) [34]. In this study, patients with carotid stenosis were about 5 times more likely to have cognitive abnormalities postoperatively. Carotid stenosis did not predict postoperative strokes [34]. In another series of 878 consecutive patients undergoing CABG, severe carotid stenosis did not predict either postoperative stroke or 30 day mortality [36]. In a meta-analysis of studies of cardiac surgery patients with asymptomatic stenosis, Naylor et al. demonstrated that prophylactic carotid revascularization prior to cardiac surgery will only benefit about 1–2 % of patients with severe and bilateral asymptomatic carotid stenosis (number needed to treat 50–100); and will not benefit patients with unilateral asymptomatic stenosis [37]. Thus, the practice of concomitant or staged carotid revascularization with CABG remains controversial.
Dizziness and syncope are common reasons for referral of patients for carotid artery screening. Fainting, without associated neurological signs is a very common symptom and can occur in about 40 % of the general population during their lifetime [38]. Fainting associated with other focal neurological symptoms and signs can be a presentation of vertebrobasilar stenosis or subclavian steal. No studies have shown carotid duplex to be valuable in the diagnosis of syncope [38]. The American Academy of Neurology listed avoidance of carotid imaging for simple syncope as one of the top five recommendations in the “Choosing Wisely” initiative [39].
Patients are often referred for Doppler evaluations of the carotid artery for an asymptomatic bruit picked up incidentally on clinical examination. However, in today’s era of medical management, the benefit of detection of asymptomatic carotid stenosis does not generally outweigh the risk of early intervention [40]. Therefore, the US Preventive Services Task Force recommends against routine carotid auscultation in the general population [40]. A meta-analysis of 28 prospective cohort studies with 17,913 patients followed over 67,708 patient-years, showed an increased rate of stroke (1.6 per 100 patient-years) and transient ischemic attacks (2.6 per 100 patient years) compared to patients without bruits [41]. The corresponding rates in patients without bruits were stroke (1.3 per 100 patient-years) and transient ischemic attack (0.9 per 100 patient-years). Among 686 multiethnic, asymptomatic subjects in the Northern Manhattan Study (NOMAS) cohort, the prevalence of carotid stenosis ≥60 % was only 2.2 % and the prevalence of bruits was 4.1 % [42]. For prediction of carotid stenosis, sensitivity of auscultation for a bruit was 56 %, specificity was 98 %, positive predictive value was 25 % and negative predictive value was 99 %. Thus, a high false negative rate suggests that absence of a bruit is not sufficient to exclude carotid stenosis [42]. Therefore, it may be reasonable to restrict screening for carotid stenosis by ultrasound in high risk populations (see Section on “Prevalence”).
Modalities for Detection of Carotid Artery Stenosis
The investigative modalities available for detection of carotid stenosis include duplex ultrasound, CT angiography, MR angiography and conventional digital subtraction angiography. Due to its noninvasive nature and lack of radiation, duplex ultrasonography is the most feasible test for severe carotid stenosis. However, the test has moderate sensitivity and specificity, and yields many false positive results. Therefore, a positive duplex result needs confirmation by another test. The sensitivity and specificity of duplex ultrasonography and MR Angiography were compared in a meta-analysis using digital subtraction angiography as a gold standard. [43] Among 64 patient series using duplex ultrasonography, the pooled sensitivity and specificity to detect 70–99 % stenosis were 86 % and 87 % respectively. The pooled sensitivity and specificity for MRA based on 21 patient series were 95 % and 90 %. Thus MRA seems to have a better discriminatory power for severe stenosis compared to duplex ultrasonography [43].
Another meta-analysis of studies using duplex sonography found a pooled sensitivity and specificity of 90 % and 94 % respectively for the detection of severe stenosis [44]. The caveat with duplex sonography is that different laboratories use widely varying measurement properties, thereby casting doubt on the reliability of this investigation [44].
Contrast enhanced MRA tends to overestimate the degree of carotid stenosis, particularly with mild or moderate stenosis. In this regard, a time of flight MRA performs better [45]. Although contrast enhanced MRA is an excellent screening technique because of reduced imaging time and improved signal to noise ratio, it is not the ideal test to assess degree of stenosis [45]. While CT angiography provides excellent detail of the carotid lesion, it is limited by the exposure to radiation, expense and the need for iodinated contrast. A meta-analysis of 28 studies looked at the value of CT angiography for detection of severe carotid stenosis [46]. The pooled sensitivity and specificity were 85 % and 93 %; equivalent to those achieved with duplex ultrasonography [46]. Digital subtraction angiography similarly is invasive, requires radiation exposure and has a small risk of neurological events in the order of 0.1–0.5 % [47].
The key question is: Which asymptomatic patients should be referred for screening of carotid stenosis? Several attempts have been made to determine a cost-effective and beneficial approach to this question. An excellent discussion of the different studies is provided by Qureshi et al. [48]. The general consensus from the different studies is that if the prevalence of carotid stenosis is 20 % or higher in a group of patients (for instance in populations over 65 years with multiple cardiovascular risk factors such as hypertension, coronary disease, cigarette smoking or dyslipidemia), screening for carotid stenosis would be beneficial, and could reduce stroke risk in a cost-effective manner [48]. For populations with intermediate prevalence of carotid stenosis, the benefit is marginal and is lost if perioperative complications exceed 5 %. Screening in unselected populations does not reduce stroke risk and is not recommended, as instead it could be harmful [48].
Prognosis and Treatment of Asymptomatic Carotid Stenosis
In terms of management for patients with asymptomatic carotid stenosis (ACS), all patients should receive medical therapy. Carotid revascularization, typically with carotid endarterectomy (CEA), can be useful for select patients. The role of carotid artery stenting (CAS) for patients with asymptomatic disease is uncertain.
With regard to medical therapy, all patients should receive the core elements of vascular disease therapy. This includes the following:
1.
Antiplatelet therapy
2.
Aggressive treatment of dyslipidemia
3.
Treatment of hypertension to national guideline targets
4.
Smoking cessation
5.
Lifestyle modification, including dietary modification and exercise
It is beyond the scope of this chapter to discuss each of these in detail but certain observations are worthwhile. For antiplatelet therapy, aspirin is typically used (81–325 mg/day). There are no data comparing alternative antiplatelet regimens (such as clopidogrel or aspirin plus extended release dipyridamole) to aspirin for patients with ACS.
The value of lipid lowering with statins in patients with ACS has been established from several sources. In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, atorvastatin 80 mg/day was compared with placebo in patients with a prior stroke or transient ischemic attack (TIA) [49]. In an analysis of patients with carotid stenosis, 1007 patients had a mean stenosis of 51 % [50]. In the atorvastatin patients, LDL was lowered from 132 mg/dl at baseline to an average of 70 mg/dl during trial follow-up. In the placebo patients, LDL decreased from 133 mg/dl to 130 mg/dl. The atorvastatin-treated patients had a 33 % reduction in any stroke, 43 % reduction in coronary events, and 56 % reduction in later carotid revascularization procedures. In the Asymptomatic Carotid Surgery Trial (ACST), there was increasing use of lipid-lowering treatment during the course of the trial [51]. For patients not on lipid lowering therapy and treated in the medical arm of the study, the 10 year risk of stroke was 24.9 %. This figure was reduced to 14.5 % for patients who were treated with lipid-lowering therapy. As a result of these observations (and other studies), treatment with high potency statins is an important component of treatment of patients with ACS.
The role of CEA in asymptomatic individuals is a matter of considerable debate. The Asymptomatic Carotid Atherosclerosis Study (ACAS) [52] and the ACST are the two largest randomized clinical trials that have investigated the value of CEA relative to medical therapy.
In ACAS, patients were randomized to receive either best medical treatment alone or medical therapy plus CEA if they had stenosis greater than 60 % but were otherwise healthy. The study was stopped early after a mean period of 2.7 years follow-up. In the surgical arm, the combined event rate for ipsilateral stroke, any perioperative stroke and death at 5 years was projected to be 5.1 %, compared with 11 % in the medical arm—a relative risk reduction of 55 % and an ARR of 5.9 % (Number Needed to Treat, NNT 17). The absolute annual benefit in ACAS of 1.2 % was considered marginal by some experts in the 1990s. The benefit seen with surgery in ACAS could be a result of the exceptionally low perioperative risk of 1.5 % achieved in the trial. Whether this low perioperative stroke rate can be uniformly achieved in “real-life” situations is doubtful. For example, in a study of over 1800 asymptomatic CEA cases from Ontario, the perioperative stroke and death rate was 4.7 % [53].
Although it is frequently reported that the ASCT findings were similar to those of the ACAS, there were important differences in the two study designs. In ACAS, the primary analysis compared strokes occurring in the territory of the operated carotid artery, while the ACST included strokes in any vascular territory. In addition, conventional angiography was not mandated for either group in ACST. After 5-years’ follow-up, the risk of recurrent stroke for the surgical group in ACST was 6.4 % and 11.8 % for those on medical treatment. This difference was more or less evident even after 10 years—13.4 % versus 17.9 % with net benefit of 4.5 % (NNT 22). The risk of perioperative stroke or death was 2.8 %. Importantly, this study showed a significant reduction of fatal or disabling strokes in the surgical arm (3.5 % vs. 6.1 % in medically treated group, ARR 2.6 %; p < 0.004). Approximately half of all ipsilateral recurrent strokes that occurred were classified as fatal or disabling. There was no clear benefit of CEA in subjects age 75 years and older in ACST.
A meta-analysis of data from 5223 patients from three major trials of CEA for asymptomatic carotid stenosis was performed by Chambers and Donnan [54]. Surgery conferred a significant benefit in terms of the composite primary outcome (any perioperative or subsequent stroke, and all-cause perioperative mortality; relative risk 0.69, 95 % CI 0.57–0.83). The overall risk of perioperative stroke or death was 2.9 %. Subgroup analysis revealed men received more benefit from surgery than did women, and younger patients benefited more than older patients. Unlike the symptomatic stenosis trials, stenosis severity did not correlate with benefit from surgery. Despite these findings, some have argued against the routine use and widespread enthusiasm for CEA in asymptomatic patients. Barnett et al. highlight that the absolute annual risk reduction of stroke in this asymptomatic group is about 1 % with a number needed to treat of 83 to prevent one stroke in 2 years [55]. Moreover, it has been estimated that approximately half the strokes in asymptomatic individuals are not related to the stenosed carotid artery but are rather lacunar strokes or caused by cardioembolic events [56].
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