Atherosclerotic Disease of the Proximal Aorta

Frequency of Aortic Plaques in the General Population

Atherosclerosis in the aorta develops throughout life, becoming especially evident after the fourth decade of life; the prevalence and number of atherosclerotic lesions increases continuously thereafter. In the Stroke Prevention: Assessment of Risk in a Community (SPARC) study, the prevalence of “simple” (less than 4 mm in thickness, without ulceration or mobile debris) or “complex” (≥4mm thick, or with complex features) atherosclerotic lesions, was evaluated by transesophageal echocardiography (TEE) in 588 volunteers older than the age of 44 years. Atherosclerosis of any degree was identified in the ascending aorta, aortic arch, and descending aorta in 8.4%, 31.0%, and 44.9%, respectively. Corresponding figures for complex atherosclerosis were 0.2%, 2.2%, and 6.0%. Any atherosclerosis prevalence increased from approximately 17% in the 45–54 years subgroup to more than 80% in the older than age 75 subgroup. Complex atherosclerosis was virtually absent in the younger subgroup but present in more than 20% of subjects after age 75. In a TEE study on healthy volunteers older than the age of 59, simple plaques in the aortic arch were detected in 22% and complicated plaques (≥5 mm in thickness or with irregular, ulcerated surface) in 4%. The prevalence of aortic atherosclerosis in the general population varies with the characteristics, and especially risk factors distribution, of the sample studied. In the triethnic study group of 209 stroke-free volunteers older than age 55 in the Aortic Plaque and Risk of Ischemic Stroke (APRIS) study, aortic arch atherosclerosis of any degree was present in 62.2%, large (≥4 mm) arch plaques in 23.9%. These figures, considerably higher than those of the other studies, were associated with a greater burden of atherosclerotic risk factors. Compared with SPARC, the APRIS study group had higher frequencies of diabetes (23.0% vs. 8.9%), hypertension (69.4% vs. 55.2%), and past and current smoking history (60.3% vs. 39.0% and 16.1% vs. 8.2%, respectively).

Aortic Plaques and Ischemic Stroke—Pathology Studies

A strong association between aortic arch plaques and ischemic stroke was first reported by Amarenco and colleagues in an autopsy case-control study. Patients who had died from a stroke had a far greater frequency of ulcerated proximal aortic plaques than patients who had died from other neurologic diseases (26% vs. 5%; age-adjusted odds ratio [OR] 4.0; 95% confidence interval [CI], 2.1–7.8). Importantly, the highest frequency of ulcerated plaques was observed in patients with unexplained (cryptogenic) stroke (61% vs. 28%; adjusted OR 5.7; 95% CI, 2.4–13.6), providing a potential etiologic mechanism. The lack of association between ulcerated plaques and significant carotid artery stenosis or atrial fibrillation suggested an independent role of aortic plaques on stroke risk. Among patients with ulcerated plaques, only 3% were younger than 60 years.

In another necropsy study on 120 unselected patients, complicated aortic arch plaques were significantly associated with arterial embolism (OR 5.8; 95% CI, 1.1–31.7), independent of and with similar strength as severe ipsilateral carotid artery disease and atrial fibrillation.

In Vivo Studies—Transesophageal Echocardiography

TEE is the most sensitive and widely used technique for examining the association between aortic plaques and ischemic stroke in vivo. The proximity of the esophagus to the aorta and the absence of interposed structures allow the use of high-frequency ultrasound transducers, which provide high-resolution images. The segment of aorta proximal to the take-off of the left subclavian artery is the focus of the examination. The ascending aorta can be accurately visualized by TEE from the aortic valve level to the initial curvature of the arch ( Fig. 33.1 ). The mid and distal portions of the aortic arch are also visualized in all patients ( Fig. 33.2 ). A small portion of the vessel (proximal arch) may not be visualized due to the interposition of the trachea and is a “blind spot” of the examination. By TEE, an accurate assessment is possible of the presence and thickness of plaques ( Fig. 33.3 ), as well as ulcerations ( Fig. 33.4 ) or superimposed thrombus ( Figs. 33.5–33.7 ; Video 33.1 ). TEE is highly sensitive and specific for plaque detection. ^, Its diagnostic accuracy for superimposed thrombus is also high (sensitivity 91%, specificity 90%). However, the sensitivity for detecting small ulcerations of the plaque surface, which may carry additional embolic risk, ^{, ,} is lower (approximately 75%). Reproducibility of TEE measurements of plaque thickness is very good, with agreement of 84%–88% for large (≥4 mm) plaque.

TEE is a safe, although semi-invasive, diagnostic test. Major complications are uncommon and mainly due to unsuspected preexisting esophageal disease. In more than 10,000 patients, one death was observed. In an additional 2.7%, there was unsuccessful intubation (1.9%) or patient intolerance (0.8%). Similar results were obtained in 15,381 consecutive patients, with 2 deaths (0.01%) and an incidence of complications of 1.7%. In 901 patients, intubation was unsuccessful in 1.2% of cases, with no deaths and a low incidence (0.6%) of major complications. TEE performance is feasible in the majority of stroke patients and can be safely performed in patients of very advanced age.

Plaque Morphology and Stroke Risk

The risk of stroke has been mainly established measuring the thickness of the plaque, with either 4 or 5 mm chosen as cutoffs. However, it is unclear whether plaque thickness is directly related to the stroke mechanism, or rather a marker of diffuse atherosclerosis, which could be in fact responsible for the increased risk. Differences in plaque-related stroke risk exist between genders. Aortic plaques 4 mm or greater were significantly more frequent in men than in women (31.5% vs. 20.3%; P = .025) and were associated with ischemic stroke in both men (adjusted OR 6.0; 95% CI, 2.1–16.8) and women (adjusted OR 3.2; 95% CI, 1.2–8.8). However, plaques 3–3.9 mm in thickness were significantly associated with stroke in women (adjusted OR 4.8; 95% CI, 1.7–15.0) but not in men (adjusted OR 0.8; 95% CI, 0.2–3.0). This observation suggests that plaque thickness, rather than identifying the actual culprit lesion for the stroke, may be a marker of diffuse atherosclerosis, including intracranial atherosclerosis, or of other conditions that may differ between genders, and are possibly related to the stroke mechanism. In any case, plaque progression, defined as increase in thickness over time, was found to be associated with increased incidence of vascular events. Among 117 patients with stroke or TIA, those who showed plaque progression over 1 year were significantly more likely to experience a vascular event (stroke, TIA, myocardial infarction, or death) than those with no plaque progression over a median follow-up of 1.7 years (51% vs. 11%; P < .0001).

The complex morphology of a plaque may be more directly related to the stroke mechanism than its thickness. Morphologic features of the plaque, such as ulceration or mobility, have been linked with an increased stroke risk, ^{, ,} especially for cryptogenic stroke. In 152 elderly stroke patients and 152 age-matched controls, ulcerated or mobile plaques were found to be a much stronger risk factor for stroke than large but noncomplex plaques. Plaques 4 mm or greater were indeed associated with increased stroke risk (adjusted OR 4.3; 95% CI, 2.1–8.7); however, when they were divided on the basis of the presence or absence of ulceration (discrete indentation of at least 2 mm in width and depth) or mobile components, the stroke risk associated with those complex features was exceedingly high (adjusted OR 17.1; 95% CI, 5.1–57.3), whereas large but noncomplex plaques carried only a modest risk increase (adjusted OR 2.4; 95% CI, 1.1–5.1). The same remained true even after excluding patients with other stroke sources such as atrial fibrillation, carotid stenosis 60% or greater, or intracranial atherosclerosis. Cohen and colleagues studied the impact of plaque morphology (ulceration, hypoechoic components, or calcification) on the risk of recurrent vascular events in a prospective study on 334 stroke patients older than the age of 60 followed for 2–4 years. In patients with plaques 4 mm or greater, the presence of ulcerations or hypoechoic components did not increase the risk of vascular events. However, the absence of calcification was associated with the strongest increase in risk (adjusted RR 10.3; 95% CI, 4.2–25.2), whereas the presence of calcification decreased the risk (adjusted RR 1.2; 95% CI, 0.6–2.1), possibly signaling a more stable lesion. These observations suggest that, although plaque thickness represents the most readily available marker of embolic risk, the plaque’s morphologic features strongly affect its embolic potential, possibly calling for different therapeutic approaches in individual patients. Whenever TEE identifies a protruding, mobile component on a plaque, this represents thrombus superimposed to atherosclerotic material, and usually occurs on ulcerated plaques. This observation was confirmed by several studies that correlated TEE findings with the histopathologic examination. ^{, ,} Mobile components superimposed to an aortic plaque are infrequently seen in stroke patients, ranging from 1.6% to 8.7% in different studies ^{, , , , , , ,} ( Table 33.3 ). When present, however, they represent a very strong risk factor for brain embolization. In our study, mobile components superimposed to a plaque were present in 6.6% of elderly stroke patients and were associated with a more than 20-fold increase in the risk of stroke, after adjusting for other stroke risk factors. Occasionally, mobile thrombi without severe atherosclerosis can be seen in patients younger than 60 years who present with an embolic event (23 cases out of 27,855 TEE examinations in a multicenter cardiology study). These thrombi usually have insertion on small atherosclerotic plaques and appear to represent a rare variant of atherosclerotic disease in younger patients.

The potential for brain embolism from large plaques, and even more from complex plaques, has been confirmed using transcranial Doppler monitoring. Continuous monitoring of the blood flow into the middle cerebral arteries is obtained, which can be performed simultaneously on both sides, and maintained for prolonged periods of time. The passage of small particles produces characteristic high-intensity transient signals (HITSs) ( Fig. 33.8 ), whose identification can be enhanced through the application of appropriate filters. Using this technique for 30 minutes in 46 patients with acute ischemic stroke, Rundek and colleagues demonstrated the presence of HITSs in a much larger proportion of stroke patients with plaques 4 mm or greater than with small or no plaques, even in the absence of other TEE-detected possible embolic sources (70% vs. 18%; P = .007). Moreover, all patients with large and complex plaques were found to have HITSs, compared with 39% of patients with large but noncomplex plaques ( P = .005). Similar results for plaques 4 mm or greater and HITSs were obtained in cryptogenic stroke patients in a study by Castellanos et al., in which data on plaque complexity were not reported.

In summary, arch plaque thickness 4 mm or greater has been shown to be associated with increased stroke risk and remains a useful tool for risk stratification, although part of the risk may come from superimposed thrombus included in the measurement. Plaque thickness is also a marker of diffuse atherosclerosis, which may also play an important role in the stroke mechanism. The presence of complex morphologic features, and especially mobile components, appears more directly related to stroke mechanism in individual patients. Overall, the incidence of recurrent embolic events in patients with large or mobile aortic plaques has been estimated up to 14% per year, underscoring the need for effective secondary prevention strategies.

Natural History of Aortic Plaques

The natural history of atherosclerotic plaques in the proximal aorta has not been extensively studied. However, it appears that plaque size and morphology are important in determining its evolution over time. Montgomery and colleagues followed 30 patients who had aortic atherosclerosis (12 with plaque <5 mm, 8 with plaques ≥5 mm, and 10 with mobile components) on an initial TEE, and a repeat TEE performed at 12 months. Although subjects with smaller plaques showed no significant changes, 4 of 8 patients with plaques 5 mm or greater had developed a new mobile lesion. In patients who initially had a mobile lesion, such lesions had resolved in 70% of cases, but a new mobile lesion was observed in another 70%. Overall, although 20 of 30 patients (67%) had no change in degree atherosclerosis, substantial changes were observed in plaque morphology. In a study on 78 patients with stroke or TIA, plaque progression over 9 months was observed in 37% of cases and was more frequent in the arch than in other aortic segments. Using transthoracic echocardiographic (TTE) imaging from a suprasternal window, Geraci and Weinberger studied plaque progression in 89 patients followed for up to 18 months (mean 7.7). Although only 23% of plaques less than 4 mm at baseline showed thickness changes, 52% of plaques 4 mm or greater showed upward or downward changes. It therefore appears that large aortic plaques are extremely dynamic lesions, whose appearance may change considerably over relatively short time.

Aortic Plaques in Stroke Patients of Different Race-Ethnicity

Most studies on aortic plaques and ischemic stroke were conducted in white populations. However, some information is available for black and Hispanic populations that allows a comparison of plaque frequency, important in the light of the different prevalence of atherosclerotic risk factors. In a retrospective study on 1553 ischemic stroke patients (889 white, 664 black), Gupta and colleagues found higher prevalence of aortic plaques in white patients than in black in the ascending aorta (14.7% vs. 11.1%; P = .04), aortic arch (67.7% vs. 62.2%; P = .03), and descending aorta (58.4% vs. 50.3%; P = .002). The plaque burden (sum of maximum plaque thickness at the three locations) was also significantly higher in white patients (4.97 mm vs. 4.28 mm; P = .007), and so was, but only in the aortic arch, the prevalence of plaques 4 mm or greater (25.9% vs. 18.7%; P < .001) and of complex plaques (protruding, ulcerated, mobile, or calcified regardless of plaque thickness; 26.3% vs. 19.0%; P < .001). These findings were observed despite a higher prevalence of arterial hypertension and diabetes mellitus in the black subgroup and cannot therefore be explained by differences in conventional atherosclerotic risk factors. In our case-control study in ischemic stroke patients older than age 59 from the tri-ethnic community of Northern Manhattan, plaques 4 mm or greater had similar frequency in white, black, and Hispanic populations (24.1%, 20.0%, and 22.5%, respectively). However, complex plaques were twice as frequent in whites (32.3%) than in blacks (15.6%) and Hispanics (16.3%). Complex plaques were associated with a strong increase in stroke risk in all three race-ethnic subgroups. Similar to Gupta’s study, the frequency of arterial hypertension and diabetes mellitus was significantly lower in whites than in the other two race-ethnic subgroups, and that of hypercholesterolemia was significantly lower in whites than in blacks. The prevalence of plaques 4 mm or greater in the overall study population (44.8%) was much higher than in a similar study from France (14.4%) and also higher than the frequency of plaques 5 mm or greater or complex in a similar study from Australia (22%). Therefore, even though the stroke risk associated with large or complex plaques appeared similar across the studies, the attributable risk of stroke from proximal aortic plaques may be greater in the American population, underscoring the need for effective preventive measures and risk factors reduction.

Factors Associated With Aortic Plaques in Stroke Patients

Although traditional risk factors do not seem to explain the race-ethnic differences in the frequency of aortic plaques, some of these risk factors are indeed associated with plaque presence. Age is the strongest predictor of aortic atherosclerosis. ^{, , , , , , ,} Cigarette smoking has consistently been shown to be associated with aortic atherosclerosis ^{, , , ,} and appears as the most important modifiable risk factor. Arterial hypertension is also associated with proximal aortic atherosclerosis, ^, especially in the case of ulcerated lesions. In the SPARC study, systolic and pulse pressure variables (office and ambulatory), but no diastolic variables, were associated with any atherosclerosis and complex atherosclerosis in the aorta after adjusting for age and smoking history. Using ambulatory blood pressure monitoring, we reported that systolic variables (24-hour, daytime, and nighttime blood pressure) were independently associated with arch atherosclerosis, and nighttime systolic blood pressure variability was independently associated with the presence of large plaques. The association between diabetes mellitus and aortic atherosclerosis has been supported in some studies and negated in others, ^, at least after adjusting for other risk factors. Hypercholesterolemia was associated with aortic atherosclerosis in some studies, ^{, ,} and treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) induced regression of aortic atherosclerotic lesions in humans.

Other variables have been identified as associated with aortic atherosclerosis and possibly cofactors in increasing the embolic risk. As mentioned, the plaque embolic potential is related at least in part to superimposed thrombus. It is therefore conceivable that the coexistence of a hypercoagulable state may increase the likelihood of thrombus formation and enhance the plaque’s embolic potential. Procoagulant properties have been demonstrated in atherosclerotic aortas; increased tissue factor expression and activity have been observed in the atherosclerotic intima that may lead to thrombus formation as the result of its exposure to the flowing blood. Among coagulation factors, fibrinogen level has been shown to be a risk factor for cardiovascular disease and ischemic stroke ^, and to be associated with degree of carotid stenosis, abdominal aortic atheromas, and peripheral atherosclerotic disease. ^60;61 Atherogenic effects of fibrinogen have been described, possibly as the result of its interactions with some lipoproteins. In fact, fibrinogen has been shown to modulate the atherogenic effects of lipoprotein (a) and to increase the risk of severe carotid atherosclerosis and stroke in patients with low levels of high-density lipoprotein (HDL) cholesterol. The association between fibrinogen and carotid artery disease was particularly strong in the elderly. Moreover, interracial differences have been reported in the levels of fibrinogen, with blacks having higher levels than whites and both groups having higher levels than Asians. Fibrinogen has also been shown to be independently associated with severity of aortic atherosclerosis in a group of 148 patients undergoing TEE for valvular heart disease.

Plasma homocysteine has been found to be independently associated with aortic atherosclerosis. In 82 cardiac patients, Tribouilloy and colleagues found that age, male gender, LDL cholesterol, and homocysteine levels were independently associated with severity of aortic atherosclerosis. In addition, homocysteine was independently associated with aortic arch atheroma progression over 9 months in a group of 78 patients with stroke or TIA, whereas no conventional risk factor had similar independent effect. Endothelial dysfunction causing plaque progression, or hypercoagulable state resulting in thrombus deposition, were invoked as possible mechanisms.

In the APRIS study, prothrombin fragment F 1.2, an indicator of thrombin generation, was associated with large plaque presence in stroke patients ( P = .02) but not in control subjects. Over a mean follow-up of 55.1 ± 37.2 months, stroke patients with large plaques and F 1.2 levels over the median value had significantly higher risk of recurrent stroke and death than those with similar plaques but lower F 1.2 levels (230/1000 person-years versus 85/1000 person-years; P = .05). This observation suggests that, in patients presenting with acute ischemic stroke, large aortic plaques are associated with blood hypercoagulability, suggesting a role for coagulation activation in the stroke mechanism.

The embolic potential of an aortic atheroma is also related to its lipid content. Cholesterol crystal emboli have been observed in peripheral arteries of patients with large atheromas. However, total cholesterol, or even low-density lipoprotein (LDL) levels, may not be the best predictors of arch atherosclerosis. In the APRIS study, low HDL level and high apolipoprotein ratio Apo B/A1 ratio were better predictors of aortic atherosclerosis than LDL cholesterol, and HDL and Apo A1 levels were also inversely associated with plaque thickness 4 mm or greater. Lipoprotein (a) has been shown to be an independent marker of aortic atherosclerosis. Lipoprotein (a) is a complex between LDL and apoprotein (a). Serum lipoprotein (a) levels are under strong genetic influence and are mainly determined by the synthetic rate of apo (a), a protein with remarkable similarities to plasminogen, which has prompted the speculation that lipoprotein (a) may be an important risk factor for both atherosclerosis and thrombosis. In addition, lipoprotein (a) has been detected in atherosclerotic plaques, where it combines with fibrin and attenuates the clearance of this protein, promoting atherogenesis and vascular dysfunction.

In addition to the control of traditional cardiovascular risk factors such as hypertension and dyslipidemia, other nonpharmacologic measures may be associated with lower aortic arch atherosclerotic burden. Light to moderate alcohol consumption was associated with decreased risk of any (adjusted OR 0.45; 95% CI, 0.29–0.68) or large (adjusted OR 0.51; 95% CI, 0.34–0.77) arch plaque in APRIS, suggesting a possible mechanism for the decreased stroke risk associated with this level of alcohol consumption described in observational studies.