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Significance of aortic atheroma in elderly patients with ischemic stroke
Clinical Neurology and Neurosurgery 109 (2007) 311–316
Significance of aortic atheroma in elderly patients with ischemic stroke A hospital-based study and literature review Mohamad Bagher Sharifkazemi ∗ , Amir Aslani, Mahmood Zamirian, Ali Reza Moaref Cardiology Department, Shiraz University of Medical Sciences, Shiraz, Iran Received 11 September 2006; received in revised form 20 November 2006; accepted 8 December 2006
Abstract Objectives: Cardioembolism accounts for 15–30% of ischemic strokes. Transesophageal echocardiography (TEE) is useful in detecting potential sources of cardiac embolism. Aortic atheromas have recently been recognized as important causes of stroke. The aim of this study was to evaluate TEE findings in elderly patients with ischemic stroke. A review of literature was done to highlight the significance of aortic atherosclerotic disease in patients with ischemic stroke. Methods: One hundred consecutive patients with ischemic stroke aged ≥55 years underwent TEE for evaluation of cardiac sources of embolism. Patients with significant carotid artery stenosis (stenosis of >50% in common or internal carotid arteries) were excluded. Results: The most noteworthy finding was the high prevalence of complex atheromatous plaques in the ascending aorta and/or aortic arch (25%). Conclusion: The present study demonstrates that TEE is helpful to detect cardiovascular sources of embolism in elderly patients with ischemic stroke. Aortic atheroma is present in 25% of elderly patients with ischemic stroke and without significant carotid artery stenosis. Aortic atherosclerosis may be an important cause of ischemic stroke in this population. © 2007 Elsevier B.V. All rights reserved. Keywords: Stroke; Aortic atheroma; Transesophageal echocardiography
1. Introduction Cardioembolism accounts for 15–30% of ischemic strokes [1]. Transesophageal echocardiography (TEE) is useful in detecting potential sources of cardiac embolism [2–8] and is often performed in patients who have suffered from ischemic stroke or systemic embolic events. However, it is still controversial whether all such patients should undergo TEE. Transthoracic echocardiography (TTE), although a powerful noninvasive tool for the assessment of cardiac chamber size, function, and valvular disease, is insensitive in detecting intra-thoracic sources of embolism [9]. Left atrial spontaneous echo contrast, left atrial thrombus, and mobile pedunculated aortic atheroma, risk factors for thromboembolism [10,11] are usually not visualized by TTE [2–8]. ∗
Corresponding author at: Cardiology Department, Namazee Hospital, Shiraz, P.O. Box 71935-1334, Iran. Tel.: +98 917 111 0514; fax: +98 711 627 9733. E-mail address: [email protected] (M.B. Sharifkazemi). 0303-8467/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2006.12.003
Over the past decade, it has been shown that morphologically complex atheromatous plaques in the ascending aorta or aortic arch can indicate a high risk of cerebral infarction [12]. Such atherosclerotic plaques in the thoracic aorta are risk factors for stroke in patients with sinus rhythm [13–15] and increase the risk of thromboembolism associated with atrial fibrillation (AF) [16]. The aim of this hospital-based study was to evaluate TEE findings in elderly patients with ischemic stroke without significant carotid artery atherosclerosis. A review of articles was done to highlight the significance of aortic atherosclerotic disease in patients with ischemic stroke. 2. Materials and methods 2.1. Study population Patients aged ≥55 years who were admitted for their first ischemic stroke were enrolled in this prospective study from
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May 2005 until June 2006 if no significant carotid artery stenosis (stenosis of >50% in common or internal carotid arteries) was present. TEE was performed within the first week after diagnosis of ischemic stroke. Neuroimaging by computed tomography (CT) scan (in 80% of patients) and magnetic resonance imaging (MRI) (in 20% of patients) was done to confirm the clinical diagnosis. Clinical and electrocardiographic data were obtained by patient interview and chart review. NIHSS score (The National Institutes of Health Stroke Scale Score) was recorded on admission in each subject.
2.4. Exclusion criteria
2.2. Vascular imaging
2.5. Statistical analysis
In all patients, the common carotid arteries, carotid bulbs, and internal carotid arteries were assessed for stenosis using color Doppler and pulse Doppler techniques. A significant carotid artery stenosis was defined as a stenosis of >50% in common or internal carotid arteries.
Descriptive statistics are presented as the mean value ± 1 S.D. or frequency (%). Comparison between the data in two groups was performed with t-test for continuous variables and χ2 statistics with the Fisher correction when appropriate for categorical variables. A value of p < 0.05 was considered as statistically significant.
Reasons for exclusion in this study were: (1) if the diagnosis of ischemic stroke was not confirmed by an expert neurologist; (2) patients with antecedents of stroke before the stroke that the patient was admitted for; (3) those with significant carotid artery stenosis (stenosis of >50% in common or internal carotid arteries); (4) patients who were not able to tolerate TEE (due to altered mentality or severe dementia); (5) patients with microangiopathic stroke.
2.3. Echocardiographic studies All consecutive patients underwent TEE for detection of potential sources of cardiac embolism. Echocardiographic examination was performed with Vivid 3 (GE Corporation) cardiac ultrasound machine equipped with 5-MHz transesophageal multiplane transducer. The presence of the following potential sources of embolism was specifically examined: (1) left atrial spontaneous echo contrast and left atrial thrombus; (2) atheromatous plaques in the ascending aorta and/or aortic arch; (3) patent foramen ovale, atrial septal defect, and atrial septal aneurysm; (4) other causes, including valvular vegetations and intracardiac masses. Left atrial spontaneous echo contrast was diagnosed by the presence of characteristic dynamic smoke-like swirling echo in the left atrium or the atrial appendage, distinct from background white noise due to excessive gain [17]. Left atrial thrombus was diagnosed by the presence of an echo-dense mass in the left atrium or the left atrial appendage, distinct from the endocardium and the pectinate muscles of the left atrial appendage [18]. Atheromatous plaques were classified as simple (sessile) or complex. Plaques with thickness of ≥4 mm, ulceration, pedunculation, or mobile elements were considered as complex [19]. The inter-atrial septum was examined for patent foramen ovale, atrial septal defect, and atrial septal aneurysm. Contrast study with agitated saline was performed in all patients to look for inter-atrial shunting. Bubbles appearing in the left atrium within the first three cardiac cycles after injection of the agitated saline or observation of bubbles traversing the inter-atrial septum following cough or Valsalva maneuver were considered as a positive diagnostic study for shunting. Atrial septal aneurysm was defined as a thin-walled area in the region of the fossa ovalis with a base of at least 1.5 cm and an excursion with the cardiac cycle of at least 1.5 cm [20]. Special attention was paid to distinguish a true atrial septal aneurysm from a hyper mobile inter-atrial septum.
3. Results 3.1. Baseline characteristics A total of 100 consecutive patients met all study criteria. TEE was performed in all patients without any complications. Clinical patient characteristics are listed in Table 1. The mean patient age was 69 ± 9 years, and the population displayed a male predominance (56%). The most frequent cardiovascular risk factor was hypertension (34%) followed by hyperlipidemia (20%), smoking (17%), ischemic heart disease (10%), and diabetes mellitus (9%). Atrial fibrillation was detected in 30 patients (30%). 3.2. Results of TEE TEE detected a minimum of one potential source of embolism in 88 patients (88%). The prevalence of the cardiovascular sources of embolism diagnosed by TEE is shown in Table 1. The most noteworthy finding was the high prevalence of complex atheromatous plaques (25%) and simple aortic atheroma (32%) in the ascending aorta and/or aortic arch. Left atrial spontaneous echo contrast was detected in 22 of 30 patients (73%) with AF and 8 of 70 patients (11%) with sinus rhythm (p < 0.01). Five patients (5%) had a thrombus in the left atrium, of which 3 were located in the left atrial appendage, 1 in the left atrial cavity, and 1 thrombus was located both in the left atrial appendage and cavity. Left atrial thrombus was detected in 5 of 30 patients (16%) with AF and none in patients with sinus rhythm (p < 0.01). A patent foramen ovale was detected in 13 (13%), atrial septal aneurysm in 2 (2%) and atrial septal defect in 1 patient (1%). Left ventricular thrombus, intra-cardiac tumors or valvular vegetations were not observed in this study population.
M.B. Sharifkazemi et al. / Clinical Neurology and Neurosurgery 109 (2007) 311–316 Table 1 Clinical and transesophageal echocardiographic findings of the study patients Age (years) Female (%)
69 ± 9a 44 (44%)
Baseline NIHSS score 1–7 8–14 15–21 >21
69 (69%) 14 (14%) 10 (10%) 7 (7%)
History of hypertension (%) History of hyperlipidemia (%) Cigarette smoking (%) History of ischemic heart disease History of diabetes mellitus (%)
34 (34%) 20 (20%) 17 (17%) 10 (10%) 9 (9%)
Current use of Aspirin Warfarin Statins ACE-Inhs
61 (61%) 30 (30%) 5 (5%) 3 (3%)
Atrial fibrillation (%) LV dysfunction (EF ≤ 50%) LA spontaneous echo contrast (%) LA/LAA thrombus (%) Simple atheroma (%) Complex atheroma (%) PFO (%) Atrial septal aneurysm (%) Atrial septal defect (%) Valvular vegetations (%) Intracardiac tumor LV thrombus (%)
30 (30%) 3 (3%) 30 (30%) 5 (5%) 32 (32%) 25 (25%) 13 (13%) 2 (2%) 1 (1%) 0 0 0
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cardiac sources of embolism [21]. The present study demonstrates that TEE is helpful to detect cardiovascular sources of embolism in elderly patients with ischemic stroke. 4.1. Cardiac sources of embolism Atrial fibrillation is a well-known risk factor for ischemic stroke [21]. In the present study, AF was present in 30% of all ischemic strokes, which is consistent with previous studies [21]. Patent foramen ovale was found in 27–35% of autopsy series [22,23]. However, using tranesophageal contrast echocardiography, PFO has been reported to be present in only 3.2–22% of normal subjects [23]. In the present study, PFO was present in 13% of cases. The reason for the lower prevalence of PFO compared with autopsy series is uncertain. Webster et al. suggested that in half of the PFO cases in autopsy series, the size of PFO was too small to be detected by contrast methods [23]. Atrial septal aneurysm (ASA) has also been considered as an independent risk factor for stroke, although the mechanism of thrombus formation has not been clarified [24]. The average frequency of ASA in a meta-analysis of TEE studies in patients with cerebral embolism was 8.8% [24]. In the present study, ASA was present in 2% of elderly patients with ischemic stroke. 4.2. Prevalence of aortic atheroma
NIHSS: The National Institutes of Health Stroke Scale; LV: left ventricular; LA: left atrial; LAA: left atrial appendage; PFO: patent foramen ovale. a Mean ± 1 S.D. Table 2 Correlation between stroke characteristics and atheroma classification NIHSS score
Simple atheroma (n = 32)
Complex atheroma (n = 25)
P value
1–7 8–14 15–21 >21
21 (66%) 5 (16%) 4 (12%) 2 (6%)
17 (68%) 4 (16%) 3 (12%) 1 (4%)
NS NS NS NS
NIHSS: The National Institutes of Health Stroke Scale; NS: non-significant.
3.3. Correlation between stroke characteristics and atheroma classification As noted earlier, atheromatous plaques were classified as simple or complex. Plaques with thickness ≥4 mm, ulceration, pedunculation, or mobility were considered as complex. There was no correlation between baseline NIHSS score and atheroma classification (Table 2).
The present study showed a relatively high incidence of atherosclerotic plaques in elderly patients with stroke; 32% had simple and 25% had complex atheroma in the ascending aorta and/or aortic arch. The prevalence of atheroma in the aortic arch in patients with embolic disease, reported by three different groups of investigators, was remarkably consistent: 27% [25], 21% [26] and 26% [27]. In contrast, significant atheroma was found in only 9%, 4% and 13% of control subjects, respectively. Most studies of aortic plaque included patients who had stroke that were referred for diagnostic investigation. However, the Stoke Prevention: Assessment of Risk in a Community (SPARC) study enrolled patients at random and therefore was not subject to referral bias [28]. Of 588 patients with average age of 66.9 years, aortic plaque in any location was present in 43.7%, of which complex plaque (defined as ≥4 mm or mobile) was present in 7.6% of patients. 8.4% of aortic plaques were present in the ascending aorta, but complex plaques were noted in the ascending aorta in only 0.2% of the cases. Plaques were present in the aortic arch in 31%, but complex arch plaques were present in only 2.2% of the cases. 4.3. Aortic atheroma and the risk of stroke
4. Discussion Previous reports comparing TTE and TEE in patients with stroke showed the superiority of TEE in detecting
Retrospective case–control studies documented a significant association between stroke and the presence of aortic atheroma seen in TEE [25–27], autopsy [29,30] and intraoperative epi-aortic ultrasound [31]. The French Aortic
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Plaque in Stroke (FAPS) group evaluated a large number of patients with varying plaque thickness and found not only that increasing plaque thickness contributed to the increasing risk of stroke but also that the odds ratio for ischemic stroke was significantly elevated in patients with a plaque thickness of ≥4 mm [13]. In contrast, in the SPARC study, a prospective population-based longitudinal study, the authors found that aortic atherosclerotic plaques are not associated with future cardiac or cerebrovascular events and aortic atherosclerosis may not be an independent risk factor for vascular events in the general population [28]. In a population based study, Petty et al. [32] found that complex atherosclerotic aortic debris were not a risk factor for cryptogenic ischemic stroke and embolization from the aorta is not a common mechanism of ischemic stroke.
4.7. Plaque morphology and embolic risk From the earliest studies, the presence of mobile lesions (thrombi) superimposed on aortic atheroma has been recognized to impart a high embolic risk. In one study, the presence of ulceration in aortic plaques seen on TEE was significantly correlated with cryptogenic stroke [35]. In a study that included 334 stroke patients aged >60 years, the highest risk of recurrent stroke on follow up for 2–4 years was found in patients with non-calcified plaques >4 mm on TEE [36]. The lack of calcification was associated with a higher risk of stroke, regardless of the other morphologic features of the plaque. It is possible that non-calcified plaques represent more lipid-laden and therefore “vulnerable” lesions. 4.8. Aortic atheroma as a marker for coronary artery disease
4.4. Aortic atheroma and carotid artery disease The association between atheroma and embolic disease in the studies discussed earlier was independent of other risk factors for stroke, most prominently carotid disease and atrial fibrillation. Although aortic atheromas are independent risk factors for stroke and peripheral emboli, it is not surprising that patients with significant carotid atherosclerosis also have a higher prevalence of aortic arch atherosclerosis than those without carotid disease, and therefore they have more than one potential source of embolization. In one retrospective study, aortic arch atheroma was significantly more common in patients with ischemic stroke and carotid stenosis compared to patients who had ischemic stroke without carotid stenosis (38% versus 17%) [33]. 4.5. Aortic atheroma and atrial fibrillation The Stroke Prevention in Atrial Fibrillation (SPAF) investigators have reported a series of 382 patients with “high risk” non-valvular atrial fibrillation (age >75 years with hypertension and previous strokes) in whom TEE was performed [16]. In this population, 134 (35%) had a complex aortic plaque (defined as mobile, ulcerated, size ≥4 mm). These patients had 12–20% increases in stroke risk. The risk was dramatically lower (only 1.2%) in the patients with high risk non-valvular atrial fibrillation without significant aortic atherosclerosis regardless of therapy with warfarin or aspirin. 4.6. Plaque size and embolic risk The earliest case series and case–control studies in the United States used a cutoff point of ≥5 mm plaque thickness to classify significant aortic atheroma [12,25,34]. However, the French Aortic Plaque in Stroke (FAPS) group found not only that increasing plaque thickness contributed to increased risk, but also that with a plaque thickness of ≥4 mm the odds ratio for ischemic stroke was significantly increased [13].
Aortic plaque seen on TEE has been correlated with a higher prevalence of coronary artery disease [36] and the presence of significant angiographic coronary artery stenosis [37]. In addition, lack of aortic plaque on TEE has also been shown to be predictive of the absence of coronary artery disease [38]. 4.9. Treatment of aortic atheroma Since severe aortic atherosclerosis is associated with embolization of thrombus, initially treatment consisted of anticoagulation. Three reports dealt with the issue of whether warfarin is beneficial in patients with aortic plaque. The first study described 31 patients with mobile thrombi in the aorta as documented on TEE [39]. Warfarin reduced the incidence of vascular events in these patients: ischemic stroke occurred in 3 of 11 patients not treated with warfarin and in none of the patients on warfarin. A second group reported an observational study of 129 patients with severe aortic plaque on TEE [40]. Treatment with oral anticoagulation, aspirin or ticlopidine was not randomized. In this study, there was a reduction in the number of embolic events in patients with plaques ≥4 mm who received oral anticoagulants. For patients with mobile thrombi, there was a significant reduction in mortality on anticoagulants, although the trend toward fewer embolic events did not reach statistical significance in this group. Both studies were small, observational, and retrospective. The third study that evaluated the use of anticoagulation in aortic atherosclerosis was reported by the SPAF Investigators Committee on Echocardiography. This was a randomized trial that included patients with high-risk non-valvular atrial fibrillation [16]. TEE showed severe aortic plaque in 134 patients. The risk of stroke in 1 year in patients with severe aortic plaque was reduced from 15.8% (11 events) in those treated with fixed low-dose warfarin plus aspirin (international normalized ratio, 1.2–1.5) to only 4% (3 events) in those treated with adjusted-dose warfarin (international normalized ratio, 2–3). Therefore, there was a 75% risk reduction
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in patients with plaque who received “therapeutic-range” warfarin dosage. Based on these three reports, warfarin seems to be reasonably safe (no increased risk of cholesterol crystal atheroemboli and bleeding complications) and efficacious in reducing ischemic stroke in patients with aortic plaque. One concern in the literature is that anticoagulation has been reported in association with new or worsening atheroemboli, possibly because of bleeding into the plaques [41]. However, this complication was rarely found in the SPAF trial [16]. Statins have shown to reduce the stroke rate in the Cholesterol and Recurrent Events (CARE) trial [42]. In this trial involving older patients with myocardial infarction, the use of statins was associated with a significant reduction in the risk for stroke and coronary events. To date, no randomized trial on the use of statins in patients with severe aortic plaque has been published. In an observational study of 519 patients with severe aortic plaque on TEE [43] however, a relative risk reduction for ischemic stroke of 59% was found in patients that were treated with statins. It seems likely that statin therapy decreases the risk of stroke. The pathophysiology may include many of the multiple effects attributed to statins, including plaque regression and stabilization, decreased inflammation and inhibitory effects on the coagulation cascade. Prophylactic aortic arch endarterectomy before coronary bypass or valve surgery appears to be dangerous and is not indicated [44]. However, there have been case reports of successful aortic endarterectomy in a few desperate cases of recurrent embolization from a large aortic thrombus superimposed on plaque [45,46].
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
5. Conclusions The present study demonstrates that in elderly patients with ischemic stroke without significant carotid disease, TEE reveals cardiovascular sources of embolism in a majority of patients. The most noteworthy finding was the high prevalence of complex atheromatous plaques in the ascending aorta and/or aortic arch. Aortic atheroma may be responsible for many so-called cryptogenic strokes. Although evidencebased treatment of aortic atherosclerosis is largely deficient, patients may benefit from the use of statins.
[17]
[18]
[19]
[20]
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Significance of aortic atheroma in elderly patients with ischemic stroke A hospital-based study and literature review Mohamad Bagher Sharifkazemi ∗ , Amir Aslani, Mahmood Zamirian, Ali Reza Moaref Cardiology Department, Shiraz University of Medical Sciences, Shiraz, Iran Received 11 September 2006; received in revised form 20 November 2006; accepted 8 December 2006
Abstract Objectives: Cardioembolism accounts for 15–30% of ischemic strokes. Transesophageal echocardiography (TEE) is useful in detecting potential sources of cardiac embolism. Aortic atheromas have recently been recognized as important causes of stroke. The aim of this study was to evaluate TEE findings in elderly patients with ischemic stroke. A review of literature was done to highlight the significance of aortic atherosclerotic disease in patients with ischemic stroke. Methods: One hundred consecutive patients with ischemic stroke aged ≥55 years underwent TEE for evaluation of cardiac sources of embolism. Patients with significant carotid artery stenosis (stenosis of >50% in common or internal carotid arteries) were excluded. Results: The most noteworthy finding was the high prevalence of complex atheromatous plaques in the ascending aorta and/or aortic arch (25%). Conclusion: The present study demonstrates that TEE is helpful to detect cardiovascular sources of embolism in elderly patients with ischemic stroke. Aortic atheroma is present in 25% of elderly patients with ischemic stroke and without significant carotid artery stenosis. Aortic atherosclerosis may be an important cause of ischemic stroke in this population. © 2007 Elsevier B.V. All rights reserved. Keywords: Stroke; Aortic atheroma; Transesophageal echocardiography
1. Introduction Cardioembolism accounts for 15–30% of ischemic strokes [1]. Transesophageal echocardiography (TEE) is useful in detecting potential sources of cardiac embolism [2–8] and is often performed in patients who have suffered from ischemic stroke or systemic embolic events. However, it is still controversial whether all such patients should undergo TEE. Transthoracic echocardiography (TTE), although a powerful noninvasive tool for the assessment of cardiac chamber size, function, and valvular disease, is insensitive in detecting intra-thoracic sources of embolism [9]. Left atrial spontaneous echo contrast, left atrial thrombus, and mobile pedunculated aortic atheroma, risk factors for thromboembolism [10,11] are usually not visualized by TTE [2–8]. ∗
Corresponding author at: Cardiology Department, Namazee Hospital, Shiraz, P.O. Box 71935-1334, Iran. Tel.: +98 917 111 0514; fax: +98 711 627 9733. E-mail address: [email protected] (M.B. Sharifkazemi). 0303-8467/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2006.12.003
Over the past decade, it has been shown that morphologically complex atheromatous plaques in the ascending aorta or aortic arch can indicate a high risk of cerebral infarction [12]. Such atherosclerotic plaques in the thoracic aorta are risk factors for stroke in patients with sinus rhythm [13–15] and increase the risk of thromboembolism associated with atrial fibrillation (AF) [16]. The aim of this hospital-based study was to evaluate TEE findings in elderly patients with ischemic stroke without significant carotid artery atherosclerosis. A review of articles was done to highlight the significance of aortic atherosclerotic disease in patients with ischemic stroke. 2. Materials and methods 2.1. Study population Patients aged ≥55 years who were admitted for their first ischemic stroke were enrolled in this prospective study from
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May 2005 until June 2006 if no significant carotid artery stenosis (stenosis of >50% in common or internal carotid arteries) was present. TEE was performed within the first week after diagnosis of ischemic stroke. Neuroimaging by computed tomography (CT) scan (in 80% of patients) and magnetic resonance imaging (MRI) (in 20% of patients) was done to confirm the clinical diagnosis. Clinical and electrocardiographic data were obtained by patient interview and chart review. NIHSS score (The National Institutes of Health Stroke Scale Score) was recorded on admission in each subject.
2.4. Exclusion criteria
2.2. Vascular imaging
2.5. Statistical analysis
In all patients, the common carotid arteries, carotid bulbs, and internal carotid arteries were assessed for stenosis using color Doppler and pulse Doppler techniques. A significant carotid artery stenosis was defined as a stenosis of >50% in common or internal carotid arteries.
Descriptive statistics are presented as the mean value ± 1 S.D. or frequency (%). Comparison between the data in two groups was performed with t-test for continuous variables and χ2 statistics with the Fisher correction when appropriate for categorical variables. A value of p < 0.05 was considered as statistically significant.
Reasons for exclusion in this study were: (1) if the diagnosis of ischemic stroke was not confirmed by an expert neurologist; (2) patients with antecedents of stroke before the stroke that the patient was admitted for; (3) those with significant carotid artery stenosis (stenosis of >50% in common or internal carotid arteries); (4) patients who were not able to tolerate TEE (due to altered mentality or severe dementia); (5) patients with microangiopathic stroke.
2.3. Echocardiographic studies All consecutive patients underwent TEE for detection of potential sources of cardiac embolism. Echocardiographic examination was performed with Vivid 3 (GE Corporation) cardiac ultrasound machine equipped with 5-MHz transesophageal multiplane transducer. The presence of the following potential sources of embolism was specifically examined: (1) left atrial spontaneous echo contrast and left atrial thrombus; (2) atheromatous plaques in the ascending aorta and/or aortic arch; (3) patent foramen ovale, atrial septal defect, and atrial septal aneurysm; (4) other causes, including valvular vegetations and intracardiac masses. Left atrial spontaneous echo contrast was diagnosed by the presence of characteristic dynamic smoke-like swirling echo in the left atrium or the atrial appendage, distinct from background white noise due to excessive gain [17]. Left atrial thrombus was diagnosed by the presence of an echo-dense mass in the left atrium or the left atrial appendage, distinct from the endocardium and the pectinate muscles of the left atrial appendage [18]. Atheromatous plaques were classified as simple (sessile) or complex. Plaques with thickness of ≥4 mm, ulceration, pedunculation, or mobile elements were considered as complex [19]. The inter-atrial septum was examined for patent foramen ovale, atrial septal defect, and atrial septal aneurysm. Contrast study with agitated saline was performed in all patients to look for inter-atrial shunting. Bubbles appearing in the left atrium within the first three cardiac cycles after injection of the agitated saline or observation of bubbles traversing the inter-atrial septum following cough or Valsalva maneuver were considered as a positive diagnostic study for shunting. Atrial septal aneurysm was defined as a thin-walled area in the region of the fossa ovalis with a base of at least 1.5 cm and an excursion with the cardiac cycle of at least 1.5 cm [20]. Special attention was paid to distinguish a true atrial septal aneurysm from a hyper mobile inter-atrial septum.
3. Results 3.1. Baseline characteristics A total of 100 consecutive patients met all study criteria. TEE was performed in all patients without any complications. Clinical patient characteristics are listed in Table 1. The mean patient age was 69 ± 9 years, and the population displayed a male predominance (56%). The most frequent cardiovascular risk factor was hypertension (34%) followed by hyperlipidemia (20%), smoking (17%), ischemic heart disease (10%), and diabetes mellitus (9%). Atrial fibrillation was detected in 30 patients (30%). 3.2. Results of TEE TEE detected a minimum of one potential source of embolism in 88 patients (88%). The prevalence of the cardiovascular sources of embolism diagnosed by TEE is shown in Table 1. The most noteworthy finding was the high prevalence of complex atheromatous plaques (25%) and simple aortic atheroma (32%) in the ascending aorta and/or aortic arch. Left atrial spontaneous echo contrast was detected in 22 of 30 patients (73%) with AF and 8 of 70 patients (11%) with sinus rhythm (p < 0.01). Five patients (5%) had a thrombus in the left atrium, of which 3 were located in the left atrial appendage, 1 in the left atrial cavity, and 1 thrombus was located both in the left atrial appendage and cavity. Left atrial thrombus was detected in 5 of 30 patients (16%) with AF and none in patients with sinus rhythm (p < 0.01). A patent foramen ovale was detected in 13 (13%), atrial septal aneurysm in 2 (2%) and atrial septal defect in 1 patient (1%). Left ventricular thrombus, intra-cardiac tumors or valvular vegetations were not observed in this study population.
M.B. Sharifkazemi et al. / Clinical Neurology and Neurosurgery 109 (2007) 311–316 Table 1 Clinical and transesophageal echocardiographic findings of the study patients Age (years) Female (%)
69 ± 9a 44 (44%)
Baseline NIHSS score 1–7 8–14 15–21 >21
69 (69%) 14 (14%) 10 (10%) 7 (7%)
History of hypertension (%) History of hyperlipidemia (%) Cigarette smoking (%) History of ischemic heart disease History of diabetes mellitus (%)
34 (34%) 20 (20%) 17 (17%) 10 (10%) 9 (9%)
Current use of Aspirin Warfarin Statins ACE-Inhs
61 (61%) 30 (30%) 5 (5%) 3 (3%)
Atrial fibrillation (%) LV dysfunction (EF ≤ 50%) LA spontaneous echo contrast (%) LA/LAA thrombus (%) Simple atheroma (%) Complex atheroma (%) PFO (%) Atrial septal aneurysm (%) Atrial septal defect (%) Valvular vegetations (%) Intracardiac tumor LV thrombus (%)
30 (30%) 3 (3%) 30 (30%) 5 (5%) 32 (32%) 25 (25%) 13 (13%) 2 (2%) 1 (1%) 0 0 0
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cardiac sources of embolism [21]. The present study demonstrates that TEE is helpful to detect cardiovascular sources of embolism in elderly patients with ischemic stroke. 4.1. Cardiac sources of embolism Atrial fibrillation is a well-known risk factor for ischemic stroke [21]. In the present study, AF was present in 30% of all ischemic strokes, which is consistent with previous studies [21]. Patent foramen ovale was found in 27–35% of autopsy series [22,23]. However, using tranesophageal contrast echocardiography, PFO has been reported to be present in only 3.2–22% of normal subjects [23]. In the present study, PFO was present in 13% of cases. The reason for the lower prevalence of PFO compared with autopsy series is uncertain. Webster et al. suggested that in half of the PFO cases in autopsy series, the size of PFO was too small to be detected by contrast methods [23]. Atrial septal aneurysm (ASA) has also been considered as an independent risk factor for stroke, although the mechanism of thrombus formation has not been clarified [24]. The average frequency of ASA in a meta-analysis of TEE studies in patients with cerebral embolism was 8.8% [24]. In the present study, ASA was present in 2% of elderly patients with ischemic stroke. 4.2. Prevalence of aortic atheroma
NIHSS: The National Institutes of Health Stroke Scale; LV: left ventricular; LA: left atrial; LAA: left atrial appendage; PFO: patent foramen ovale. a Mean ± 1 S.D. Table 2 Correlation between stroke characteristics and atheroma classification NIHSS score
Simple atheroma (n = 32)
Complex atheroma (n = 25)
P value
1–7 8–14 15–21 >21
21 (66%) 5 (16%) 4 (12%) 2 (6%)
17 (68%) 4 (16%) 3 (12%) 1 (4%)
NS NS NS NS
NIHSS: The National Institutes of Health Stroke Scale; NS: non-significant.
3.3. Correlation between stroke characteristics and atheroma classification As noted earlier, atheromatous plaques were classified as simple or complex. Plaques with thickness ≥4 mm, ulceration, pedunculation, or mobility were considered as complex. There was no correlation between baseline NIHSS score and atheroma classification (Table 2).
The present study showed a relatively high incidence of atherosclerotic plaques in elderly patients with stroke; 32% had simple and 25% had complex atheroma in the ascending aorta and/or aortic arch. The prevalence of atheroma in the aortic arch in patients with embolic disease, reported by three different groups of investigators, was remarkably consistent: 27% [25], 21% [26] and 26% [27]. In contrast, significant atheroma was found in only 9%, 4% and 13% of control subjects, respectively. Most studies of aortic plaque included patients who had stroke that were referred for diagnostic investigation. However, the Stoke Prevention: Assessment of Risk in a Community (SPARC) study enrolled patients at random and therefore was not subject to referral bias [28]. Of 588 patients with average age of 66.9 years, aortic plaque in any location was present in 43.7%, of which complex plaque (defined as ≥4 mm or mobile) was present in 7.6% of patients. 8.4% of aortic plaques were present in the ascending aorta, but complex plaques were noted in the ascending aorta in only 0.2% of the cases. Plaques were present in the aortic arch in 31%, but complex arch plaques were present in only 2.2% of the cases. 4.3. Aortic atheroma and the risk of stroke
4. Discussion Previous reports comparing TTE and TEE in patients with stroke showed the superiority of TEE in detecting
Retrospective case–control studies documented a significant association between stroke and the presence of aortic atheroma seen in TEE [25–27], autopsy [29,30] and intraoperative epi-aortic ultrasound [31]. The French Aortic
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Plaque in Stroke (FAPS) group evaluated a large number of patients with varying plaque thickness and found not only that increasing plaque thickness contributed to the increasing risk of stroke but also that the odds ratio for ischemic stroke was significantly elevated in patients with a plaque thickness of ≥4 mm [13]. In contrast, in the SPARC study, a prospective population-based longitudinal study, the authors found that aortic atherosclerotic plaques are not associated with future cardiac or cerebrovascular events and aortic atherosclerosis may not be an independent risk factor for vascular events in the general population [28]. In a population based study, Petty et al. [32] found that complex atherosclerotic aortic debris were not a risk factor for cryptogenic ischemic stroke and embolization from the aorta is not a common mechanism of ischemic stroke.
4.7. Plaque morphology and embolic risk From the earliest studies, the presence of mobile lesions (thrombi) superimposed on aortic atheroma has been recognized to impart a high embolic risk. In one study, the presence of ulceration in aortic plaques seen on TEE was significantly correlated with cryptogenic stroke [35]. In a study that included 334 stroke patients aged >60 years, the highest risk of recurrent stroke on follow up for 2–4 years was found in patients with non-calcified plaques >4 mm on TEE [36]. The lack of calcification was associated with a higher risk of stroke, regardless of the other morphologic features of the plaque. It is possible that non-calcified plaques represent more lipid-laden and therefore “vulnerable” lesions. 4.8. Aortic atheroma as a marker for coronary artery disease
4.4. Aortic atheroma and carotid artery disease The association between atheroma and embolic disease in the studies discussed earlier was independent of other risk factors for stroke, most prominently carotid disease and atrial fibrillation. Although aortic atheromas are independent risk factors for stroke and peripheral emboli, it is not surprising that patients with significant carotid atherosclerosis also have a higher prevalence of aortic arch atherosclerosis than those without carotid disease, and therefore they have more than one potential source of embolization. In one retrospective study, aortic arch atheroma was significantly more common in patients with ischemic stroke and carotid stenosis compared to patients who had ischemic stroke without carotid stenosis (38% versus 17%) [33]. 4.5. Aortic atheroma and atrial fibrillation The Stroke Prevention in Atrial Fibrillation (SPAF) investigators have reported a series of 382 patients with “high risk” non-valvular atrial fibrillation (age >75 years with hypertension and previous strokes) in whom TEE was performed [16]. In this population, 134 (35%) had a complex aortic plaque (defined as mobile, ulcerated, size ≥4 mm). These patients had 12–20% increases in stroke risk. The risk was dramatically lower (only 1.2%) in the patients with high risk non-valvular atrial fibrillation without significant aortic atherosclerosis regardless of therapy with warfarin or aspirin. 4.6. Plaque size and embolic risk The earliest case series and case–control studies in the United States used a cutoff point of ≥5 mm plaque thickness to classify significant aortic atheroma [12,25,34]. However, the French Aortic Plaque in Stroke (FAPS) group found not only that increasing plaque thickness contributed to increased risk, but also that with a plaque thickness of ≥4 mm the odds ratio for ischemic stroke was significantly increased [13].
Aortic plaque seen on TEE has been correlated with a higher prevalence of coronary artery disease [36] and the presence of significant angiographic coronary artery stenosis [37]. In addition, lack of aortic plaque on TEE has also been shown to be predictive of the absence of coronary artery disease [38]. 4.9. Treatment of aortic atheroma Since severe aortic atherosclerosis is associated with embolization of thrombus, initially treatment consisted of anticoagulation. Three reports dealt with the issue of whether warfarin is beneficial in patients with aortic plaque. The first study described 31 patients with mobile thrombi in the aorta as documented on TEE [39]. Warfarin reduced the incidence of vascular events in these patients: ischemic stroke occurred in 3 of 11 patients not treated with warfarin and in none of the patients on warfarin. A second group reported an observational study of 129 patients with severe aortic plaque on TEE [40]. Treatment with oral anticoagulation, aspirin or ticlopidine was not randomized. In this study, there was a reduction in the number of embolic events in patients with plaques ≥4 mm who received oral anticoagulants. For patients with mobile thrombi, there was a significant reduction in mortality on anticoagulants, although the trend toward fewer embolic events did not reach statistical significance in this group. Both studies were small, observational, and retrospective. The third study that evaluated the use of anticoagulation in aortic atherosclerosis was reported by the SPAF Investigators Committee on Echocardiography. This was a randomized trial that included patients with high-risk non-valvular atrial fibrillation [16]. TEE showed severe aortic plaque in 134 patients. The risk of stroke in 1 year in patients with severe aortic plaque was reduced from 15.8% (11 events) in those treated with fixed low-dose warfarin plus aspirin (international normalized ratio, 1.2–1.5) to only 4% (3 events) in those treated with adjusted-dose warfarin (international normalized ratio, 2–3). Therefore, there was a 75% risk reduction
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in patients with plaque who received “therapeutic-range” warfarin dosage. Based on these three reports, warfarin seems to be reasonably safe (no increased risk of cholesterol crystal atheroemboli and bleeding complications) and efficacious in reducing ischemic stroke in patients with aortic plaque. One concern in the literature is that anticoagulation has been reported in association with new or worsening atheroemboli, possibly because of bleeding into the plaques [41]. However, this complication was rarely found in the SPAF trial [16]. Statins have shown to reduce the stroke rate in the Cholesterol and Recurrent Events (CARE) trial [42]. In this trial involving older patients with myocardial infarction, the use of statins was associated with a significant reduction in the risk for stroke and coronary events. To date, no randomized trial on the use of statins in patients with severe aortic plaque has been published. In an observational study of 519 patients with severe aortic plaque on TEE [43] however, a relative risk reduction for ischemic stroke of 59% was found in patients that were treated with statins. It seems likely that statin therapy decreases the risk of stroke. The pathophysiology may include many of the multiple effects attributed to statins, including plaque regression and stabilization, decreased inflammation and inhibitory effects on the coagulation cascade. Prophylactic aortic arch endarterectomy before coronary bypass or valve surgery appears to be dangerous and is not indicated [44]. However, there have been case reports of successful aortic endarterectomy in a few desperate cases of recurrent embolization from a large aortic thrombus superimposed on plaque [45,46].
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
5. Conclusions The present study demonstrates that in elderly patients with ischemic stroke without significant carotid disease, TEE reveals cardiovascular sources of embolism in a majority of patients. The most noteworthy finding was the high prevalence of complex atheromatous plaques in the ascending aorta and/or aortic arch. Aortic atheroma may be responsible for many so-called cryptogenic strokes. Although evidencebased treatment of aortic atherosclerosis is largely deficient, patients may benefit from the use of statins.
[17]
[18]
[19]
[20]
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