Aortic atheroma has been a known source of systemic emboli since the first half of the 20th century. Its potential causal role in stroke had also been suggested in the late 1950Õs and early 1960Õs with collected case reports (1,2 ). However it wasnÕt until the development of transesophageal echocardiography that the true prevalence and frequency of atheromatous lesions was recognized in stroke patients. Tunick and Kronzon in 1990 first reported the findings of Ò large, protrusive plaquesÉ which have mobile projections that move freely with the blood flowÓ in three patients with stroke and systemic embolization (3). They later reported a case-controlled study of 122 patients with stroke, TIA or peripheral emboli, demonstrating that protruding aortic atheroma was an independent risk factor for embolic events (4).
In 1992 Amerenco et al. published a landmark autopsy study demonstrating the prevalence of ulcerated atheromatous plaques to be 28 percent in patients with cerebrovascular disease compared to 5 percent of patients with other neurologic disease (5). They also showed that 61 percent of patients with no known cause of stroke had ulcerated aortic plaques compared to 22 percent with a known cause. This same group went on to detail that aortic arch plaque thickness >4 mm was a strong and independent risk for ischemic stroke in patients over the age of 60 years (6). They again demonstrated a significantly higher prevalence of plague thickness >4 mm among patients with no known cause of stroke (28%) compared to those with a known cause (8.1%).
Case control studies published subsequent to these have confirmed that ascending aorta and aortic arch atheroma is an independent risk factor for ischemic stroke. Also confirmed was the higher prevalence of aortic atheroma in cryptogenic stroke and in stroke patients older than 60 years. (7,8).
In 1996 Amarenco and The French Study of Aortic Plaque in Stroke Group reported their findings that recurrent stroke and vascular events in patients with aortic atheroma was similar to the high rates seen in atrial fibrillation and symptomatic carotid stenosis (9). A cohort of 331 consecutively admitted stroke patients age>60 was followed for a mean of 2.4 years, with secondary stroke prophylaxis determined by the patientÕs primary physicians. Sixty-four percent of patients received anti-platelet therapy and 18 percent received anticoagulants. More than 30% (102/331) patients had stroke of unknown cause. Recurrent stroke and vascular events were found to increase in proportion to plaque thickness with especially high rates in those with plaques > 4mm (11.9/100 person-years) compared to plaques 1mm to 3.9mm thick (3.5/100 person-years) and those with plaque < 1mm thick (2.8/100 person-years). Once again patients with unknown cause of stroke at study entry had higher rates of recurrent stroke (16.4/100 person-years) and all recurrent vascular events (26.1/100 person-years) with plaque thickness > 4mm compared to those with smaller plaques. The incidence rates reported in this study were likely an underestimate as the majority of patients were on antiplatelet drugs, and TIAs were not considered new vascular events. The study was not powered nor designed to look at the effects of anticoagulation on recurrence of vascular events, but no differences were detected.
Since the French Aortic Plaque study many other prospective studies have shown a high incidence of recurrent stroke, vascular events and vascular death in patients with aortic atheroma (10-17). Recurrent stroke rates have varied between 12-30%. Vascular mortality has also been significantly higher on the order of 23% to 43%.
While causation in the strict sense has not been established, many factors have lead to an acceptance that aortic atheromas cause stroke. First, the striking ultrasound and pathologic similarities to carotid bifurcation plaques cannot be underestimated. Large, ulcerated or mobile plaques with or without demonstrable thrombi have been shown to correlate with ischemia in coronary, peripheral and cerebral vascular beds. Secondly, patients without other known cause of stroke more often have significant aortic atheroma. Lastly, there appears to be a dose-related effect in that larger plaques (>4mm) have a significantly higher risk of stroke and other vascular events associated with them. While treatment benefit with oral anticoagulants may be greatest for patients with larger, complex lesions, this remains to be demonstrated in prospective clinical trials. The size of aortic plaques seen on TEE in patients treated with oral anticoagulation may become smaller (18,19, 20).
In an autopsy study of 500 patients, Amarenco et al. showed the prevalence of ulcerated plaques among patients with stroke to be 26% compared to 5% of neurologic patients without stroke (5). The prevalence of ulcerated plaques was 61% among patients with no known cause of stroke compared to 22% among patients with known cause of stroke. Toyoda et al. demonstrated 26 of 42 (42%) consecutively admitted stroke patients to have complicated aortic arch lesions on transesophageal echocardiography. Amarenco et al. in a case controlled study showed aortic arch atheromatous plaques to be an independent risk factor for ischemic stroke with 14.4% of stroke patients having aortic atheromatous plaques >4mm compared to 2% of controls (6). Patients with cryptogenic stroke had an even higher rate with 28.2% of patients having aortic plaques >4mm compared to 8% of patients with known possible or likely cause.
It is well established that aortic atheroma is also an independent risk factor for recurrent stroke and vascular events. In a prospective study by The French Study of Aortic Plaques in Stroke Group (9), 331 patients consecutively admitted with stroke found to have aortic arch atheroma were followed over two to four years. The incidence of recurrent stroke was 11.9% per year in patients with aortic atheroma >4mm compared to 2.8% per year in patients with atheroma < 1mm. The recurrence of stroke was higher in the cryptogenic stroke group- 16.4% per year. Other prospective studies of stroke patients with aortic atheroma have consistently found high recurrent stroke rates of 12% to 30% in patients with aortic atheroma >4mm and those with complex morphology (ulcerated or mobile segments) (9-17).
The evaluation of the stroke patient should strive to determine cause and identify further risks in a practical, cost-effective manor. This poses a considerable challenge in an era of sophisticated and costly medical technology. Conversely reduction of subsequent stroke can yield considerable savings. This is especially true in deciding which study, TTE or TEE, to use in evaluating the stroke patient.
TEE has clearly been shown to be superior to TTE in identifying sources of cardiac emboli. TEE is also unique in its ability to identify and characterize aortic atheroma. However TEE is relatively invasive and not readily available at all centers. Furthermore it is not practical to send every stroke patient to TEE and there are some groups of stroke patients where TTE will suffice and finding other sources of emboli may not change management considerably. Defining these groups has not gained widespread attention.
As mentioned previously, the group of stroke patients without obvious cause (cryptogenic) would likely produce a higher yield on TEE than TTE for identifying aortic atheroma as a cause of stroke. Furthermore one would not expect to find significant abnormalities on TTE in this group without obvious cardiac cause (a-fib, MI, CHF). Additionally the prevalence of aortic atheroma increases with age > 60 years.
Therefore it would make sense to reserve TEE for patients > 60 years old without an obvious cardiac history suggestive of an embolic source. Additionally patients presenting with a stroke with a cardiac history (a-fib, MI, CHF) would be more likely to have TTE findings suggestive of an embolic source (LVEF <35%, mitral stenosis, LV aneurysm/clot).
This hypothesis was tested in a small group of consecutive stroke patients admitted to the University of Texas-Houston Stroke Team. Patients without lacunar stroke or obvious cardiac history underwent TTE and TEE to test the yield of each for determining the etiology for their stroke. Additionally, patients with significant carotid disease were evaluated similar to the cryptogenic stroke group, given the higher prevalence of aortic atheroma in this group. In twenty-two patients with cryptogenic stroke or carotid atherosclerosis more than 80% of patients had significant aortic atheroma (>4mm, mobile, or ulcerated features) seen on TEE. None of these patients had an obvious cause of their stroke identified by TTE. These findings on TEE led to a change in treatment from antiplatelets to full dose anticoagulation in 45% of patients studied, although recognizing that this treatment switch is not based on prospective randomized data.
Prognosis with regard to subsequent stroke, vascular event or mortality as expected is a function of plaque severity. In the French Study of Aortic Plaques the recurrent stroke rate and vascular event rate was 12% and 26% in the group with plaques>4 mm compared to 2.8% and 6% in those with plaques <1 mm, respectively. Similarly mortality was significantly higher in the group with plaques >4mm compared to those with plaques 1-3.9 mm and those with plaques < 1mm. Other groups have reported similar results. (17,27)
One of the feared complications of aortic atherosclerosis is the cholesterol emboli syndrome. This is often manifested as progressive renal failure in the setting of cutaneous or digit ischemia. This fear is based on case reports of patients developing this syndrome after initiation of anticoagulation therapy. It is believed that anticoagulation may precipitate ulceration of plaques with subsequent release of plaque material systemically. There is however little evidence to substantiate this fear. In the Stroke Prevention and Atrial Fibrillation III study where over 1000 patients were enrolled, the estimated rate of this complication during adjusted-dose warfarin anticoagulation was 0.7%/patient-year for those with any plaque and 1.3%/patient-year for those with complex plaque (16).
Though a causal role of aortic atheroma in producing embolic stroke has not been proven, several recent, non-randomized studies have shown efficacy of anticoagulation when compared to aspirin in reducing subsequent stroke and vascular mortality (11,13,15,16). In two reports on the outcome of patients in the Stroke Prevention in Atrial Fibrillation III randomized trial, there was significant benefit in reduction of stroke and embolic events in the adjusted dose warfarin group compared to the combined fixed low dose warfarin plus aspirin group (14, 16). Furthermore while the embolic event rate increased significantly in progression from no plaque to complex plaque in the combined group, the event rate remained relatively stable in the warfarin group (16). Thus the group with the highest risk aortic atheromatous plaque appears to derive the greatest benefit from full anticoagulation. This would be consistent with the presumed embolic mechanism of aortic arch atheromas.
Further study of this issue is required with regard to anticoagulation versus antiplatelet agents, duration of treatment and endarterectomy. Some results with regard to anticoagulation versus antiplatelets is expected from the subset of subjects undergoing TEE enrolled in the Warfarin versus Aspirin in Recurrent Stroke Study (WARSS) study recently published (30). Two other studies have been submitted to funding agencies in Europe, Australia and North America to address this issue; The Aortic plaque-Related Cerebral Hazard (ARCH) and the Anticoagulant Antiplatelet Aortic Atherosclerosis (4A) study (28).
A few case reports of other treatments have been reported. These have included aortic endarterectomy (4) and even thrombolytic therapy for a large atheroma (29).
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