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(Stroke. 1999;30:834-840.)
© 1999 American Heart Association, Inc.

Original Contributions

Aortic Plaque in Atrial Fibrillation

Prevalence, Predictors, and Thromboembolic Implications

Joseph L. Blackshear, MD; Lesly A. Pearce, MS; Robert G. Hart, MD; Miguel Zabalgoitia, MD; Arthur Labovitz, MD; Richard W. Asinger, MD; Jonathan L. Halperin, MD for the Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography

From the Mayo Clinic Jacksonville, Jacksonville, Fla (J.L.B); Statistics and Epidemiology Research Corporation, Seattle, Wash (L.A.P.); University of Texas Health Science Center, San Antonio, Tex (R.G.H., M.Z.); St Louis University Medical Center, St Louis, Mo (A.L.); Hennepin County Medical Center, Minneapolis, Minn (R.W.A.); and Mt Sinai Medical Center, New York, NY (J.L.H.).

Correspondence to Joseph L. Blackshear, MD, Division of Cardiovascular Diseases, Mayo Clinic Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224. E-mail jlb16{at}exjax.mayo.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—Thoracic aortic plaque identified by transesophageal echocardiography heightens the risk of stroke associated with atrial fibrillation (AF). We sought to identify the prevalence, predictors, and implications of aortic plaque in patients with nonvalvular AF.

Methods—Thoracic aortic plaque was prospectively sought in 770 persons with AF with the use of transesophageal echocardiography and classified as simple or complex on the basis of thickness 4 mm, ulceration, or mobility. Clinical and echocardiographic features of thromboembolism were correlated by multivariate analysis.

Results—Aortic plaque was detected in 57% of the cohort, and complex plaque was detected in 25%. Both were found more frequently in the descending than in the proximal aorta. Potentially etiologic patient characteristics independently associated with complex plaque included advanced age, history of hypertension, diabetes, and past or present tobacco use. Comorbidities associated with aortic plaque were prior thromboembolism, increased pulse pressure, ischemic heart disease, stenosis or sclerosis of the aortic valve, mitral annular calcification (>10%), elevated serum creatinine concentration, spontaneous echo contrast in the left atrium or appendage, and left atrial appendage thrombus. The prevalence of complex plaque in patients aged <70 years with <10% mitral annular calcification, without ischemic heart disease, or without pulse pressure 65 mm Hg was 4% (95% CI, 1% to 6%).

Conclusions—Aortic plaque is prevalent in patients with AF and is associated with atherosclerosis risk factors and with left atrial stasis or thrombosis, which are themselves independent stroke risk factors. Since the predominant location of complex plaque was in the descending aorta, the role of aortic plaque as a source of embolism in AF is uncertain.

Key Words: aorta • atherosclerosis • atrial fibrillation

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Atherosclerotic plaque in the thoracic aorta identified by transesophageal echocardiography (TEE) is a risk factor for stroke in patients with sinus rhythm^{1 2 3} and raises the risk of thromboembolism associated with atrial fibrillation (AF).⁴ The absence of plaque in AF patients otherwise considered to be at high risk for thromboembolism was associated with a low stroke rate (1.2%/y; 95% CI, 0.2% to 8.7%) even when adequate anticoagulation was not given.⁴ These observations suggest that some strokes in patients with AF may arise from aortic or arterial disease rather than from the left atrium or atrial appendage^{5 6} and suggest that assessment of aortic plaque by TEE may contribute to stratification of thromboembolic risk in patients with AF.

We report the prevalence and predictors of aortic plaque and plaque with complex features in the largest cohort of AF patients prospectively evaluated for plaque. The results suggest a confluence of cardioembolic and vascular factors that contribute to thromboembolism in patients with AF.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The Stroke Prevention in Atrial Fibrillation (SPAF) III study included a randomized trial of adjusted-dose warfarin versus low, fixed doses of warfarin plus aspirin in combination for high-risk patients (n=1044) and a separate prospective cohort study of patients at low intrinsic risk treated with aspirin alone (n=892). High-risk participants had 1 of the following risk factors: prior thromboembolism, systolic blood pressure >160 mm Hg, recent heart failure or fractional shortening 25%, or female sex and aged >75 years. Details of the design, patient selection criteria, and main results have been reported elsewhere.^{4 7 8 9}

All patients were encouraged to undergo TEE within 3 months of enrollment, and consent was obtained from 382 of 1044 high-risk patients and 404 of 892 low-risk patients. The technique for TEE acquisition and criteria for interpretation,¹⁰ interobserver reliability for assessment of variables, including aortic plaque, and TEE correlates of thromboembolic risk have also been published.^{4 11} Atherosclerotic plaque in the thoracic aorta was categorized in terms of location and morphology. The aorta was divided into ascending, transverse, and descending segments, and plaque was classified as simple (sessile) or complex on the basis of thickness 4 mm, ulceration, pedunculation, or mobile elements.¹⁰

Risk factors for atherosclerosis and risk factors for thromboembolism in AF patients were identified and divided into potentially etiologic patient characteristics and associated patient characteristics for atherosclerotic plaque before the start of analyses. Results for all variables evaluated are reported. Characteristics were compared between groups with Student's t test for continuous variables and a ² test for categorical variables. Two series of multivariate analyses comparing any versus no plaque, and no plaque versus simple versus complex plaque, were done to identify (1) independent potentially etiologic predictors and (2) independent associated characteristics. A third series was done to identify independent etiologic and associated characteristics to derive a predictive scheme for complex plaque. Stepwise logistic regression and stepwise polychotomous logistic regression techniques were used (likelihood ratio test). The 75th percentile was used as the cut point for any continuous variable in the predictive scheme. Statistical significance was accepted at the 0.05 level, and all tests were 2-sided.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Among 786 completed TEE studies, 770 yielded images of the thoracic aorta sufficient to assess or exclude atherosclerotic plaque. Comparisons of patients and characteristics in this TEE population versus those who did not undergo TEE are presented in Table 1. Very small but highly significant differences in patient characteristics were noted. Plaque was detected in 57% of patients, and plaque with features classified as complex was detected in 25% of patients. Plaque was more prevalent in the descending aorta (simple in 30% and complex in 21%) than in the segments proximal to the origins of the cerebral arteries (simple in 21% and complex in 12%) (Figure 1). During a total of 1254 patient-years of follow-up after TEE, no peripheral embolic events occurred, while 16 strokes occurred in persons with complex plaque, 16 strokes in those with simple plaque, and 10 strokes in those with absent plaque.

View this table: [in this window] [in a new window]   Table 1. SPAF III Patients Who Did or Did Not Undergo TEE

View larger version (19K): [in this window] [in a new window]   Figure 1. Prevalence of any aortic plaque or plaque with complex features (see text) in 770 persons with nonvalvular AF. Values are percentage of total cohort. Event rates (stroke or systemic embolism, mean, 95% CI) irrespective of antithrombotic regimen were as follows: Ascending aortic plaque: absent (n=686): 3.0%, 2.2% to 4.3%/y, present (n=84): 5.8%, 2.9% to 12%/y, complex (n=13): 4.6%, 0.6% to 32%/y. Transverse aorta: absent (n=535): 3.1%, 2.1% to 4.4%/y, present (n=235) 4.1%, 2.4% to 6.7%/y, complex (n=84): 3.2%, 1.2% to 8.5%/y. Ascending or transverse aorta: absent (n=515): 3.1%, 2.1% to 4.5%/y, present (n=255): 3.9%, 2.4% to 6.4%/y, complex (n=381): 3.0%, 1.1% to 8.0%/y. Descending aorta: absent (n=389): 1.6%, 0.9% to 3.0%/y, present (n=389): 5.3%, 3.7% to 7.6%/y, complex (n=165): 6.7%, 4.1% to 11%/y.

Patients at high risk of thromboembolism on the basis of clinical and precordial echocardiographic criteria were more likely to have aortic plaque than low-risk patients (complex in 35% versus 15%; P<0.001). Univariate variables potentially related to aortic plaque are listed in Table 2. Multivariate analysis identified age as an independent, potentially etiologic predictor of simple and complex plaque, while tobacco smoking, hypertension, and diabetes were independently associated with complex plaque alone (Table 3). Complex plaque was not related to sex, random serum cholesterol levels, or fibrinogen. Of the associated patient characteristics, increased pulse pressure, aortic valve disease, and left atrial spontaneous echo contrast and thrombus were associated with both simple and complex plaque (Table 3). Prior thromboembolism (relative risk, 2.9; 95% CI, 1.9 to 4.6; P<0.001) and mitral annular calcification >10% (relative risk, 3.3; 95% CI, 1.8 to 6.0; P<0.001) were strongly associated with complex plaque alone.

View this table: [in this window] [in a new window]   Table 2. Patient Features According to Presence of Aortic Plaque

View this table: [in this window] [in a new window]   Table 3. Independent Predictors of Aortic Plaque and Associated Features

Multivariate analysis of both etiologic features and comorbidities (Table 4) confirmed the strong association of tobacco smoking, prior thromboembolism, and mitral annular calcification >10% with complex aortic plaque (all P<0.001). Although the prevalence of plaque varied by segment, these predictors of simple and complex plaque were confirmed at all sites. The prevalence of complex plaque was 4% (95% CI, 1% to 6%) among patients <70 years of age without the following: ischemic heart disease, pulse pressure 65 mm Hg, or mitral annular calcification >10% (31% of the cohort). Current tobacco smoking in a patient with any of these 4 predictive characteristics raised the prevalence of complex plaque to >50% to approach that associated with prior thromboembolism (Figure 2). Increased left ventricular mass appeared associated with reduced plaque, but this finding was restricted to persons aged >70 years who lacked other characteristics associated with aortic plaque.

View this table: [in this window] [in a new window]   Table 4. Independent Predictors of Aortic Plaque: Multivariate Analysis Combining Etiologic and Associated Features

View larger version (49K): [in this window] [in a new window]   Figure 2. Predictive scheme for complex aortic plaque. Presence of 3 or 4 characteristics identified a group (n=74) with a 55% (95% CI, 44% to 67%) prevalence of complex plaque. Addition of 1 of these characteristics to current smoker (n=33) or patients with prior thromboembolism (n=128) identified a prevalence of complex aortic plaque of 55% and 51%, respectively, moderate to severe. MAC indicates mitral annular calcification >10%.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Atherosclerotic plaque in the thoracic aorta identified by TEE was first linked with clinical thromboembolism in 1990.¹² The magnitude of stroke risk associated with this ultrasound finding (12%/y) can be estimated only within broad confidence limits, however, both in patients with AF¹¹ and in those without this dysrhythmia.^{13 14 15} The sonographic morphology of these atherosclerotic lesions is related to the risk of stroke¹³ in that patients with complex plaques are at almost twice the risk of those without this configuration. In patients with AF at high risk of thromboembolism who have complex aortic plaque, the rate of stroke among those treated by anticoagulation with adjusted-dose warfarin was one fourth the rate seen with a low-intensity combination of warfarin and aspirin.⁴ While this reduction in stroke among anticoagulated AF patients may have been due to disappearance of thrombus in the left atrial appendage,¹⁶ the rate of thromboembolism was also low (<2% annually; 95% CI, 0.2% to 8.7%/y) in similar high-risk AF patients without plaque who were not adequately anticoagulated.⁴ This implies a role but does not define a site for cardiac or arterial thrombosis in the risk of stroke associated with complex aortic plaque in the AF population.

Classification, Prevalence, and Location of Aortic Plaque
Complex aortic plaques are so designated by thickness or in terms of surface abnormalities. Mobile components are usually thrombi^{17 18} that vary with time and location. Aortic plaque was found proximal to the left subclavian artery on postmortem examination in 60% of elderly stroke victims,¹⁹ and despite a sonographic "blind spot" in the upper ascending aorta, this was almost the same prevalence at which it was detected by TEE in patients with nonfatal stroke (55% to 57%).^{1 3} Atheromatous lesions are more common in the descending versus ascending or transverse arch portions of the thoracic aorta. Amarenco et al¹ found plaque in the descending aortas of >90% of patients with prior stroke; the prevalence of complex plaque in this segment was 24%. The recurrent stroke rate in patients with complex lesions in the proximal aorta was >10%/y, and vascular events in these patients (stroke, myocardial infarction, peripheral embolism, death from vascular cause) occurred at approximately twice the rate of recurrent embolism.^{14 15} Among patients undergoing TEE during coronary bypass or valvular heart surgery, >50% displayed plaque in the aorta, 33% in the proximal and transverse segments, and >40% in the descending limb. Complex lesions occurred in 16%, and perioperative stroke rates correlated with the prevalence of complex plaque in the descending aorta.^{20 21} The prevalence of complex plaque in the ascending and transverse aortic segments in our AF patients, 12%, falls near the lower end of the range described in studies of stroke patients (14% to 42%),^{1 3 22 23} and parallels thromboembolic risk defined on the basis of clinical criteria. Complex plaque at any site was detected in 15% of low-risk patients and 35% of high-risk patients, similar to the prevalence reported in patients with AF referred for TEE (half of whom had prior clinical thromboembolism) (Table 5).^{24 25 26} In contrast, carotid artery stenosis has been reported less frequently in AF patients (8%; range, 4% to 17%).²⁷

View this table: [in this window] [in a new window]   Table 5. Any Aortic Plaque and Complex Plaque in AF

Predictors of Aortic Plaque
In unselected stroke patients, complex plaque in the ascending or transverse segments was associated with peripheral and carotid arterial disease as well as with age, tobacco smoking, and diabetes.^{3 14} In patients undergoing cardiac surgery because of ischemic or valvular disease, serum cholesterol, plasma fibrinogen, and small body mass were additional predictors of complex plaque.^{21 28} In our broad population of AF patients, we determined that age, tobacco smoking, pulse pressure, and thrombus in the left atrial appendage were independently associated with plaque, both simple and complex. Additional patient features that predicted complex plaque included prior thromboembolism, ischemic heart disease, diabetes, and moderate to severe mitral annular calcification, all variables independently associated with stroke in patients with or without AF.^{4 29 30 31} Calcific disease of the aortic valve was also independently associated. Aortic valve disease has previously been linked to atherosclerotic risk factors, but not stroke risk.³² AF patients aged >70 years with ischemic heart disease, mitral annular calcification >10%, and arterial pulse pressure 65 mm Hg were most likely to display complex aortic plaque.

Although hypertension and increased pulse pressure were strongly associated with complex aortic plaque, left ventricular mass was inversely related in older patients without other characteristics associated with complex plaque. This paradox is consistent with observations at autopsy. In victims of cryptogenic cerebral infarction,¹⁹ cardiac mass was lower (388±109 versus 427±108 g; P=0.08) and proximal aortic plaque was more prevalent (61% versus 22%; odds ratio, 5.7; 95% CI, 2.5 to 13.6) than in those in whom an embolic source was identified. An inverse relationship between aortic plaque and cardiac mass might mean that AF patients who adapt to aging with development of myocardial hypertrophy have a reduced tendency to develop aortic atherosclerosis versus those who do not develop hypertrophy. Opposite responses in cardiac muscle and arterial wall might reflect genetically mediated adaptive differences, which are now under active investigation.^{33 34 35 36}

Study Limitations
TEE was performed in willing patients at entry into this clinical trial, but fewer than 50% of the total patients underwent TEE, raising the possibility that our findings may not represent either the SPAF III population overall or an AF population in general. The SPAF III TEE population is not dissimilar to the Atrial Fibrillation Investigators population of 4253 AF patients in terms of mean age (69 years), history of hypertension (45%), angina (23%), or congestive heart failure (20%).³⁷ These data suggest that the SPAF III TEE population is similar in most respects to prior AF clinical trial populations, who are, admittedly, selected populations.³⁸

The existence of a sonographic blind spot in the aorta (upper ascending aorta) is an additional limitation in an analysis that seeks to define plaque prevalence and describe a source of embolism. Finally, the potentially etiologic and associated variables selected for analysis were based on current concepts of pathogenesis. Chance association of selected variables with plaque or failure of selection of relevant variables for analysis cannot be excluded.

Implications of Aortic Plaque in AF
Although the prevalence of complex aortic plaque in patients with AF raises the possibility that plaque-associated thrombus may be a direct cause of embolism in AF, such a mechanism has not been proven. In prior studies in which most plaques were found in the proximal aorta, both cerebral and peripheral emboli occurred, while in our patients with complex plaque limited to the descending aorta, clinical ischemic events exclusively involved the central nervous system (Figure 3).^{13 14 15 39 40} The paucity of peripheral ischemic events in our treated patients suggests that plaque-related embolism is not the dominant mechanism of thromboembolism in AF. Endocardial and left atrial abnormalities (thrombus, spontaneous echo contrast, and reduced appendage flow velocity) were more prevalent in patients with complex aortic plaque than in those without plaque. The rate of thromboembolism was low among patients without plaque treated with the relatively ineffective combination of low-dose warfarin plus aspirin (1.2%/y; 95% CI, 0.2% to 8.7%).⁴ In contrast, those with complex plaque had a high risk of stroke (16%/y; 95% CI, 8.7% to 28%), unless treated more intensively with adjusted-dose warfarin (4.0%/y; 95% CI, 1.3% to 12%).⁴ This association of complex plaque with thromboembolic risk may be mediated by left atrial or endocardial abnormalities in patients with AF.

View larger version (22K): [in this window] [in a new window]   Figure 3. Distribution of embolic events in prior studies of patients with complex aortic plaque. Peripheral embolism accounted for 23% to 71% of embolic events in these series but none of the embolic events in SPAF TEE. Even in SPAF TEE patients with complex plaque only in the descending thoracic aorta (line 2 labeled SPAF TEE), the events noted during follow-up were cerebrovascular, not peripheral. *This study included some patients with rheumatic or prosthetic heart valves.

	Acknowledgments

 
This study was supported by grants R01-NS-33551 and R01-NS-24224 from the National Institute of Neurological Disorders and Stroke (National Institutes of Health).

Received October 19, 1998; revision received December 22, 1998; accepted December 28, 1998.

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