Author + information
- Received November 24, 1997
- Revision received February 26, 1998
- Accepted March 5, 1998
- Published online June 1, 1998.
- Miguel Zabalgoitia, MD, FACCa,* (, )
- Jonathan L Halperin, MD, FACC∗,
- Lesly A Pearce, MS†,
- Joseph L Blackshear, MD, FACC‡,
- Richard W Asinger, MD, FACC§,
- Robert G Hart, MDa,
- for the Stroke Prevention in Atrial Fibrillation III Investigators
- ↵*Address for correspondence: Dr. Miguel Zabalgoitia, Department of Medicine/Cardiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7872
Objectives. This study explored the mechanisms linking clinical and precordial echocardiographic predictors to thromboembolism in atrial fibrillation (AF) by assessing transesophageal echocardiographic (TEE) correlations.
Background. Clinical predictors of thromboembolism in patients with nonvalvular AF have been identified, but their mechanistic links remain unclear. TEE provides imaging of the left atrium, its appendage and the proximal thoracic aorta, potentially clarifying stroke mechanisms in patients with AF.
Methods. Cross-sectional analysis of TEE features correlated with low, moderate and high thromboembolic risk during aspirin therapy among 786 participants undergoing TEE on entry into the Stroke Prevention in Atrial Fibrillation III trial.
Results. TEE features independently associated with increased thromboembolic risk were appendage thrombi (relative risk [RR] 2.5, p = 0.04), dense spontaneous echo contrast (RR 3.7, p < 0.001), left atrial appendage peak flow velocities ≤20 cm/s (RR 1.7, p = 0.008) and complex aortic plaque (RR 2.1, p < 0.001). Patients with AF with a history of hypertension (conferring moderate risk) more frequently had atrial appendage thrombi (RR 2.6, p < 0.001) and reduced flow velocity (RR 1.8, p = 0.003) than low risk patients. Among low risk patients, those with intermittent AF had similar TEE features to those with constant AF.
Conclusions. TEE findings indicative of atrial stasis or thrombosis and of aortic atheroma were independently associated with high thromboembolic risk in patients with AF. The increased stroke risk associated with a history of hypertension in AF appears to be mediated primarily through left atrial stasis and thrombi. The presence of complex aortic plaque distinguished patients with AF at high risk from those at moderate risk of thromboembolism.
Nonvalvular atrial fibrillation (AF) carries a substantial risk of arterial thromboembolism, but the absolute rate varies widely within the spectrum of patients with this arrhythmia. Clinical and precordial echocardiographic predictors of thromboembolism in AF have previously been identified (1–4), but the mechanisms linking these predictors with thromboembolic risks are incompletely defined. For example, hypertension is a strong, consistent, independent risk factor for stroke in patients with AF, increasing stroke rates far beyond that associated with hypertension in patients without AF (1,3,4), but the pathophysiologic mechanism underlying this multiplicative effect is obscure.
Transesophageal echocardiography (TEE) offers unique imaging resolution of the left atrium and its appendage and the thoracic aorta. Thus, TEE has been extensively used as a tool to detect potential sources of embolism. In the Stroke Prevention in Atrial Fibrillation (SPAF) III study, patients with AF with high, moderate and low rates of thromboembolism receiving aspirin therapy were successfully stratified on the basis of their clinical and precordial echocardiographic features (4,5). In the present analysis, we identified TEE correlates of thromboembolic risk in a broad range of patients with AF. In addition, TEE features associates with individual predictors of increased thromboembolic risk were examined to explore links with mechanisms.
The design and the main results of the SPAF III study have been described in detail elsewhere (5,6). Patients with AF receiving aspirin therapy were prospectively stratified into risk groups using the scheme presented in Figure 1. High risk patients were characterized by one or more of the following: 1) women >75 years of age, 2) systolic hypertension >160 mm Hg measured on two occasions at entry, 3) impaired left ventricular function (clinical congestive heart failure within 100 days of entry or M-mode echocardiographic fractional shortening ≤25%), or 4) previous thromboembolism. Patients without these risk factors were further divided into those with a history of hypertension (moderate risk) and those without a history of hypertension (low risk) on the basis of a priori planned secondary analysis (6). Longitudinal follow-up of low and moderate risk patients with AF receiving aspirin, and high risk participants receiving aspirin plus low doses of warfarin (which proved ineffective in protecting against stroke) or adjusted-dose warfarin, confirmed prospectively the validity of this risk stratification scheme (4,5). Classification and treatment assignment were determined before the TEE examination and not influenced by its findings.
Participation required signed informed consent according to federal and local regulations governing research involving humans.
Participants in the SPAF III study were encouraged to undergo TEE within 3 months of study entry, and 41% (n = 786) agreed to do so (48%, 42% and 37% of high, moderate and low risk participants, respectively). TEE studies were performed on average at 26 days after entry according to specific protocols for acquisition and interpretation (7). Commercially available ultrasound equipment was used, with biplane or multiplane transducers operating at a standard frequency of 5.0 MHz on gray-scale imaging. The TEE features were recorded according to standardized criteria among all 18 participating centers, and are described in detail elsewhere (7). Left atrial appendage (LAA) area was obtained by planimetry from the transverse (zero degree) view. Spontaneous echo contrast (SEC) was defined as a pattern of slowly swirling intracavitary echodensities imaged with gain settings adjusted to distinguish background noise and classified as dense when continuously present at standard gain. Aortic plaque was categorized as either simple (sessile) or complex based on features of mobility, ulceration, pedunculation or thickness ≥4 mm and could be located in the ascending, transverse or proximal descending segment (i.e., not just proximal to the origins of the cerebral vessels) (7). Analyses reported here are based on image interpretation at the local clinical laboratories. All TEE characteristics were concealed from the echocardiographers during recruitment and data acquisition, avoiding bias at the time of imaging interpretation.
About half of participants undergoing TEE were receiving warfarin before study entry (Table 1), and half of high risk patients were assigned to warfarin after enrollment. In order to characterize the frequency of LAA thrombus in the absence of warfarin effect (11), TEE studies carried out within 14 days of a patient receiving adjusted-dose warfarin (n = 311), either randomized or taking at baseline, were excluded from the analyses of LAA thrombus.
Although diabetes mellitus and intermittent (as opposed to continuous) AF were not found to be independent predictors of thromboembolism during aspirin therapy in SPAF I and SPAF II trials (8), these two factors have been associated with stroke risk in AF by other investigators (3,9). Thus, we took this opportunity, using SPAF III data, to reanalyze the role of diabetes and intermittent AF by correlating them with TEE features and thromboembolic risks.
Patient characteristics were compared across the three risk groups using a Mantel-Hantsel test for trend for categorical variables and analysis of variance for continuous variables. Individual groups were then compared using a chi-square test (or Fisher exact test if any expected cell value was <5) or two-tailed sample ttest. TEE characteristics independently predictive of risk group were determined by fitting a polychotomous logistic regression model with the moderate risk group as the reference group (EGRET statistical software, Cytel Corporation). All variables were placed in the model and terms that were statistically insignificant (log likelihood ratio test) were then eliminated (or set equal). A separate analysis was also done using a forward stepwise logistic regression model (log likelihood ratio test) to identify features of moderate and high risk patients (combined group) relative to low risk (SPSS/PC, SPSS Inc.). Significance was accepted at the p = 0.05 level and all tests were two-tailed. No adjustment was made for multiple comparisons.
Among the 786 participants undergoing TEE at entry, patient features differed substantially according to risk stratum (Table 1). As expected, high risk patients more frequently had the clinical and precordial echocardiographic features used as criteria for increased thromboembolic risk.
Correlates of thromboembolic risk
As indicated in Table 2, LAA thrombi increased in frequency from 3% to 8% to 15% (p < 0.001) between participants categorized as low, moderate and high risk, respectively. Dense SEC and peak LAA flow velocities were also univariately associated with risk stratum (p < 0.001), but the cross-sectional area of the LAA was not. The presence of aortic plaque, particularly plaque classified as complex, was more frequent in high risk patients with AF than those at low or moderate risk (Table 2). Figure 2illustrates the frequency of TEE findings versus thromboembolic risks. LAA abnormalities (presence of at least one of thrombus, dense SEC or reduced flow velocities, p < 0.001), and complex aortic plaque (p < 0.001) were associated with increased thromboembolic risk (Figure 2).
Independent correlates of thromboembolic risk by multivariate analysis
As illustrated in Table 3, LAA thrombus (relative risk [RR] 2.7, p < 0.001) and reduced LAA peak flow velocity (RR 1.8, p = 0.003) were associated with moderate risk (history of hypertension without high risk features) relative to low risk status. Complex aortic plaque (RR 2.9, p < 0.001) and dense SEC (RR 2.7, p < 0.001) were more frequent in high risk than in moderate risk patients with AF. In patients with uncontrolled systolic hypertension as their only high risk feature, complex aortic plaque was significantly more frequent than in those with a history of hypertension (35% vs. 16%, p = 0.002). Independent TEE correlates of low versus moderate or high risk were LAA thrombus (RR 2.5, p = 0.04), dense SEC (RR 3.7, p < 0.001), LAA peak flow velocity ≤20 cm/s (RR 1.7, p = 0.008) and complex aortic plaque (RR 2.1, p < 0.001).
Characteristics associated with individual high risk features
In high risk patients, TEE features did not differ significantly among individual criteria conferring high risk status (Table 4). Figure 3illustrates the frequency of TEE findings grouped as LAA abnormalities (presence of at least one of thrombus, dense SEC or reduced flow velocities) and complex plaque in patients with a single high risk factor.
Influence of diabetes, intermittence of AF and age among low risk participants
Low risk patients with and without diabetes had no significant differences in TEE features: the presence of LAA thrombi was 0% versus 3%, dense SEC was 0% versus 5% and complex aortic plaque was 17% versus 15%, between those with and without diabetes, respectively. Similarly, intermittent AF was not significantly associated with TEE features (Table 5). Among low risk patients with AF, age (assessed as a continuous variable) was associated with complex aortic plaque (72 vs. 65 years, p < 0.001) and to a lesser extent with dense SEC (72 vs. 66 years, p = 0.08). There were too few patients with LAA thrombus to assess its relation with age among low risk patients for meaningful comparison.
TEE features correlate with thromboembolic risk in nonvalvular AF and provide clues linking risk factors to mechanisms. Patients categorized as moderate risk on the basis of a history of hypertension had a substantially higher frequency of LAA thrombi, reduced atrial appendage velocity, and dense SEC than low risk patients. Hence, the association between hypertension and increased thromboembolic risk in patients with AF appears to be mediated, at least in part, by emboli originating in the LAA (10). The prevalence of complex plaque in the thoracic aorta differed between patients with AF at high versus moderate risk. Because most of these plaques were located distal to the origins of the cerebral vessels, making them unlikely sources of embolism, this observation suggests that an extracardiac pathologic mechanism, directly or indirectly, is an important mediator of thromboembolism in high risk patients with AF (11).
Dense SEC is associated with reduced flow velocity in the left atrium and with atrial thrombi formation (11)and is a marker of blood flow stasis in patients with AF. When comparing patients at low risk with those at moderate or at high risk, LAA thrombus, reduced LAA flow velocities and dense SEC were each independent TEE predictors, further confirming risk stratification. Thus, patients with AF at moderate or high risk were distinguished by abnormalities found within the left atrium (thrombus, dense SEC and reduced appendage emptying velocity), and by complex aortic plaque. In support of this observation, follow-up of these high risk patients treated with low doses of warfarin plus aspirin confirmed the predictive value of dense SEC, LAA thrombi and complex aortic plaque in the subsequent development of stroke (11).
Previous studies have shown little correlation between left atrial diameter by precordial echocardiography with thromboembolism in nonvalvular AF (8), and our results additionally revealed a lack of association between LAA cross-sectional area and stroke risk in patients with AF. Taken together, these data suggest that functional attributes of the left atrium are more important than its size in predicting thromboembolic risk.
TEE correlates of individual high risk criteria, undertaken to explore its mechanistic links, were not illuminating. For example, it remains unclear why elderly women without other risk factors carry a high risk of thromboembolism. On the other hand, left ventricular dysfunction is a consistent predictor of thromboembolism in patients with AF (12), and both atrial and aortic abnormalities were more frequent in these patients.
In multivariate models, the estimates of predictive strength of features with a low prevalence (e.g., LAA thrombi in low risk patients with AF) may be influenced by less specific but more prevalent variables (e.g., dense SEC). Hence, our estimates of the strength of correlations of LAA thrombi and dense SEC with thromboembolic risk may be affected by this interaction. Similarly, the low frequency of severe mitral regurgitation impaired the ability to accurately characterize its relation to thromboembolic risk. Even so, it seems clear that abnormalities of the left atrium predisposing to stasis or thrombus formation, or both, are important differences between patients with AF at low and those at high risk of thromboembolism.
These TEE correlations strongly support a relation between left atrial stasis, thrombus formation and stroke risk in patients with nonvalvular AF and suggest that factors outside of the atrium may contribute to the thromboembolic risk, particularly in high risk patients with AF. It is possible that efforts to restore and maintain sinus rhythm in high risk patients with AF may not completely mitigate the increased risk of stroke if embolism from extracardiac sources is the cause.
☆ This study was supported by Grants R01-NS-33351 and R01-NS-24224 from the Division of Stroke and Trauma, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.
- atrial fibrillation
- left atrial appendage
- relative risk
- spontaneous echo contrast
- Stroke Prevention in Atrial Fibrillation
- transesophageal echocardiography (echocardiographic)
- Received November 24, 1997.
- Revision received February 26, 1998.
- Accepted March 5, 1998.
- by the American College of Cardiology
- 4.↵Stroke Prevention in Atrial Fibrillation Investigators. Prospective identification of atrial fibrillation patients at low-risk of stroke during treatment with aspirin. JAMA. In press.
- Stroke Prevention in Atrial Fibrillation Investigators
- Stroke Prevention in Atrial Fibrillation Investigators
- Petersen P,
- Godtfredsen J
- 11.↵The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Transesophageal echocardiographic correlates of thromboembolism in high-risk patients with nonvalvular atrial fibrillation. Ann Intern Med. In press.
- Hart R.G,
- Pearce L.A,
- Halperin J.L,
- Miller V.T