Cardioembolic stroke: an update. (Review Article).

Abstract: Cardioembolic stroke accounts for approximately 15% of all strokes and is thought to bc one of the more preventable types of strokes. Features that have been reported to support cardioembolism as a mechanism for ischemic stroke have included documented cardiac source of embolism, maximal neurologic deficit at onset, multiple cerebrovascular territories involved, enhanced tendency toward hemorrhagic transformation, enhanced risk of syncope or seizure associated with presentation, and lower likelihood of premonitory transient ischemic attacks. Features that tend to make cardioembolic stroke less likely include significant cerebral atherosclerosis, stepwise progression of the neurologic deficit within a finite period of time, vascular distribution such as entire internal carotid artery territory with combined middle cerebral artery and anterior cerebral artery involvement or watershed distribution, and premonitory transient isehemic attacks. A number of cardiac conditions can promote thromboembolism, a nd there is risk stratification reflective of the specific condition or coexistent conditions. Anticoagulant therapy generally has been found to be the most effective means of preventing cardiogenic brain embolism, but the intensity of anticogulation needs to be optimized to reflect the risk-to-benefit ratio for the particular patient.

Key Words: atrial fibrillation, cardioembolic stroke, cerebral embolus, valvular heart disease 

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Embolic stroke implies a clot originating from one site that then promotes occlusive cerebral artery disease. The most common sources of cerebral embolism include the carotid arteries, specific cardiac disease, and atheromata of the aortic arch. It is reported that cardioembolic stroke accounts for approximately 15% of all strokes. (1) However, this percentage might be higher. A study published in 1983 (2) reported a cardioembolic mechanism in 23.5% of 540 consecutive stroke patients, whereas the German Stroke Data Bank, (3) published in 2001, reported a cardioembolic mechanism in 25.6% of patients. It is important to define the stroke mechanism as accurately as possible, because this aspect of the diagnosis has the potential to translate into more effective therapy. However, the designation of an isehemic stroke as cardioembolic is usually presumptive based on the associated supportive factors at hand. For example, the presence of atrial fibrillation in an older stroke patient makes cardioembolism the most l ikely mechanism until proved otherwise. Coexistent significant valvular heart disease would make the mechanism of cardioembolism even more likely. Conversely, a relatively normal echocardiogram and the presence of high-grade carotid stenosis ipsilateral to the infarct would make the mechanism of cardioembolism more questionable.

Potential Cardiac Sources of Cerebral Embolism

Potential sources of cardiogenic emboli are listed in Table 1. The frequency is subject to interpretation, because not every acute stroke patient with a potential cardiogenic source of embolus has embolism from the heart as a mechanism. Certain potential sources of cerebral embolism pose a much lower risk than others, as discussed below.

Atrial Fibrillation

The prevalence of atrial fibrillation is roughly 1% at age 60, 5% for patients aged 70 to 75 years, and up to 10% for patients older than 80 years of age. (4) Of note, lone atrial fibrillation (ie, that associated with a structurally normal heart) in patients younger than 60 years of age is associated with a low risk of stroke. (5) The presence of valvular heart disease other than mitral valve prolapse, however, is associated with roughly a 17-fold increased risk of stroke. (6) Overall, the risk of stroke in patients with atrial fibrillation is 4.5%/yr, but this average represents a spectrum of factors that includes the patient's age and coexistent disease. (7) For example, the proportion of strokes with atrial fibrillation in the United States is 6.2% for patients who are 50 to 59 years of age, 7.3% for patients 60 to 69 years of age, 16.5% for patients 70 to 79 years of age, and 30.8% for patients 80 to 89 years of age. (8) Of note, unlike cardiac failure, coronary heart disease, and hypertension, which dec line in impact with age, atrial fibrillation was found to have increasing importance with increasing age.

Atrial fibrillation is estimated to be associated with between 75,000 and 95,000 strokes per year in the United States. (9,10) However, it is estimated that up to 30% of patients with nonvalvular atrial fibrillation and stroke have a mechanism of stroke other than cardioembolism. (11) On the basis of the compilation of numerous reports, the Quality Standards Subcommittee of the American Academy of Neurology has come up with low-risk, moderate-risk, and high-risk patient profiles for nonvalvular atrial fibrillation. (12)

Low risk is associated with roughly a 1% risk per year of stroke without therapy and is defined as patients younger than 65 years of age with no high-risk coexistent disease. Moderate risk is associated with a roughly 2% per year risk of stroke and is defined as patients 65 years of age and older with no high-risk coexistent disease. High risk is associated with a roughly 6% or greater risk of stroke per year and is defined as patients with a history of hypertension, diabetes mellitus, prior stroke or transient ischemic attack, coronary artery disease, and/or congestive heart failure. The Stroke Prevention in Atrial Fibrillation III Investigators (13) presented some variations on a theme in which moderate risk is defined as a history of hypertension but no other risk factors, and they cited a risk factor of roughly 3.5% per year for this group. They identify a high-risk group as having a risk of 8% or greater per year associated with systolic blood pressure higher than 160 mm Hg; left ventricular dysfunction, which includes congestive heart failure within the previous 3 months or fractional shortening up to 25% evidenced on M-mode echocardiograms, prior stroke or transient ischemic attack, and women older than 75 years of age. In their schema, the yearly risk of stroke is roughly 12% for patients with prior stroke or transient ischemic attack, and there is cumulative risk, which is dependent on the number of risk factors present for a particular individual.

Of particular concern is the potential for recurrent cerebral infarction once cerebral infarction has occurred in a patient with atrial fibrillation. In a study of recurrent cerebral embolism in nonvalvular atrial fibrillation, Hart el al (14) reported a 20% recurrence rate of cerebral embolism within 11 days of the initial embolus in patients who had not undergone anticoagulant therapy. Sage and Van Uitert (15) reported a 20% annual recurrence rate during a 9-year follow-up period in patients who were not treated with anticoagulant therapy. In terms of overall risk of recurrence, Wolf et al, (16) in a population-based study, reported that the risk of recurrent stroke at 30 days was only slightly more frequent in stroke patients with atrial fibrillation (25%) than in those without atrial fibrillation (20%). However, the 6-month recurrence rate was 47% in the atrial fibrillation group compared with 20% in the group without atrial fibrillation, which is greater than a twofold difference.

Myocardial Infarct

Roughly 2.5% of patients with acute myocardial infarct experience a stroke within 2 to 4 weeks of the infarction. (1) Most emboli occur within 1 to 2 weeks of the cardiac event, and the risk varies from roughly 6% for anterior wall myocardial infarcts to approximately 1% for inferior wall infarcts. It is estimated that 38,000 strokes per year in the United States are directly related to acute myocardial infarction. (17) Factors that enhance the risk of stroke include associated severe left ventricular dysfunction with significantly impaired cardiac output, the presence of a left ventricular aneurysm and/or visualization of a left ventricular thrombus, the presence of a protruding or mobile left ventricular thrombus, and associated cardiac arrhythmia such as atrial fibrillation. (18) In a study of the relationship of left ventricular dysfunction after myocardial infarct and stroke, (17) patients with ejection fractions less than 28% had a relative risk of stroke of 1.86 compared with patients with an ejection fraction greater than 35% (P = 0.01). Of note, the use of captopril and thrombolytic agents had no significant impact on the risk of stroke in this study.

In a study of the risk of stroke in patients with acute myocardial infarct who were treated with thrombolytic and antithrombotic medication, (19) 1.14% of 20,768 patients had strokes. Of these 236 cerebral events, 0.36% were hemorrhagic, 0.48% were ischemic, and 0.30% were indeterminate. There was a small but significant increased risk of stroke with recombinant tissue plasminogen activator compared with streptokinase (1.33 versus 0.94%; adjusted odds ratio, 1.42). No benefit was found with the associated use of subcutaneous heparin. The risk of stroke was significantly enhanced in older patients, those in a higher Killip class, and those with anterior wall infarctions.

Cardiomyopathy 

Left ventricular dysfunction, when severe, can lead to thromboembolism and stasis of blood flow within the heart. Ejection fraction is the proportion of left ventricular volume emptied during systole, which provides a reliable measure of left ventricular systolic dysfunction. The degree of dysfunction correlates with the risk of congestive heart failure (CHF). It is estimated that as many as 72,000 patients per year in the United States have strokes related to CHF. (20) The annual rate of stroke in patients with CHF is roughly 2%, and the risk of stroke is 4.1 times greater in patients 50 to 59 years of age with cardiac failure than in age-matched controls without the disease. (21) However, the relative risk falls to 1.5 in Patients 80 to 89 years of age, which reflects the importance of other stroke risk factors in older patients. The risk of stroke correlates with the severity of left ventricular dysfunction. 17.22 Furthermore, the risk of recurrent stroke is reported to be approximately 20% at 1 year and a s high as 45% at 5 years. (23) As mentioned previously, coexistent disease has a cumulative effect, and the combination of recent CHF and atrial fibrillation places the patient at particularly high risk for cardioembolic stroke. (13)

Cardiomyopathy usually has an ischemic cause, but viral cardiomyopathy can result in such impairment of cardiac output that embolic events can occur. Another potential mechanism is the use of illicit drugs such as cocaine. In a case report of recurrent embolic stroke, (24) a 39-year-old man developed dilated cardiomyopathy and left ventricular thrombus formation directly related to his use of cocaine.

Valvular Heart Disease

It is well recognized that rheumatic valvular heart disease is a risk factor for stroke. The two most commonly cited valve abnormalities are mitral stenosis and calcific aortic stenosis. In the modern era of valve replacement for hemodynamically significant valvular heart disease, the major emphasis has been on the importance of coexistent factors such as atrial fibrillation or bacterial endocarditis as well as the risk of embolic disease associated with prosthetic cardiac valves. It is generally recommended that all patients with mechanical valves be treated with long-term anticoagulation. Bioprosthetic valves, however, do not routinely require long-term anticoagulation unless there has been a documented cardioembolic event.

The risk of embolic events in anticoagulated patients with mechanical valves is 3% per year for mitral valves and 1.5% for aortic valves. (1) For patients with bioprosthetic valves, the risk of embolic events without anticoagulation is 2 to 4% per year. (1) However, this risk applies to patients without coexistent atrial fibrillation, because this combination generally calls for anticoagulation.

Mitral valve prolapse has been reported to be a risk factor for ischemic stroke, (25) especially in young patients. (26) In a recent study in which the investigators examined this possible association, (27) however, no clear relationship between mitral valve prolapse and ischemic stroke in patients [less than or equal to] 45 years of age was found. Mitral annulus calcification has been cited as a possible source of cerebral embolism on the basis of anecdotal reports. However, one study that addressed this possibility (28) concluded that mitral annulus calcification was more of a marker for generalized calcific atherosclerosis than a clear source of embolus. This might also apply to idiopathic hypertrophic subaortic stenosis in which patients with this entity and stroke usually have coexistent factors that might more explain the stroke mechanism directly. (29)

Bacterial endocarditis has been recognized for a number of years as a source of septic emboli to the brain. The risk for native valve endocarditis in the United States is on the order of 1.7 to 6.2 cases per 100,000 person-years. (30) As many as 65% of embolic events in patients with infective endocarditis involve the central nervous system, (30) and Staphylococcus aureus is the bacterial organism most commonly associated with stroke. (31)

Chronic Sinoatrial Disorder

This bradycardia-tachycardia (ie, sick sinus) syndrome can be associated with cerebral embolic events. The risk is probably greatest for those patients whose conditions evolve into a paroxysmal or chronic atrial fibrillation pattern. In one study, (32) 14 of 100 patients with this disorder had brain emboli, and one had a retinal embolism. This study underscores the need to control this rhythm disturbance effectively and administer prophylactic therapy as clinically indicated.

Interatrial Septal Abnormalities

Lechat et al (33) reported a significantly higher prevalence of patent foramen ovale in patients with ischemic stroke who were younger than 55 years of age and had normal cardiac examinations compared with controls (40 versus 10%, P < 0.001). Since that report, both supportive studies (34,35) and contradictory studies (36) have been published. Cabanes et al (37) reported a relationship between both patent foramen ovale and atrial septal aneurysm greater than 10 mm excursion and cryptogenic stroke with a marked synergistic effect. This has been further supported by a meta-analysis of case-control studies. (38)

Diagnostic Evaluation

Clinical Features. It can be difficult to distinguish embolic strokes from other mechanisms on purely clinical grounds. (39) According to the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Data Bank, (40,41) features supportive of a cardiogenic source of cerebral embolism include history or presence of systemic embolism, abrupt onset, diminished level of consciousness at onset, visual field abnormalities, neglect, and aphasia. Factors that are not supportive of such a mechanism, according to NINDS, include hemiparesis without cortical or sensory deficits and pure sensorimotor strokes. A phenomenon that has been reported in connection with cardiogenic brain embolism is the so-called spectacular shrinking deficit, in which patients present with a major hemispheric stroke syndrome but then spontaneously demonstrate rapid recovery. (42) This has been attributed to migration of the embolus through the cerebral circulation. (43)

Brain Scan Findings. Computed tomography remains the traditional initial neuroimaging procedure for patients who present with manifestations of acute stroke. Findings supportive of an embolic mechanism include multiple infarcts in different vascular territories (Fig. 1) and infarction compatible with a branch occlusion of an intracerebral artery (eg, infarction of the superior or inferior division of a middle cerebral artery). (44) The term embolic encephalopathy (45) has been used to identify the phenomenon of global aphasia without contralateral hemiparesis, in which the superior and inferior divisions of the dominant hemisphere middle cerebral artery are discretely affected by separate embolic events with sparing of the motor strip. In addition, hemorrhagic transformation has been thought to be supportive of embolic stroke, and specific vascular territory involvement can help to distinguish one form of infarction mechanism from another.

Large striatocapsular infarcts seen on computed tomographic or magnetic resonance imaging brain scans are usually related to large-vessel occlusive disease of the middle cerebral artery resulting in infarction in the territories of the medial and lateral group of the lenticulostriate arteries. (46) Cardiogenic embolism is a potential mechanism in certain patients, (47) however, and middle cerebral artery stenosis as a result of in situ atherosclerosis might predispose the patient to embolic occlusion of the affected vessel. In a study in which the researchers specifically examined the mechanism of middle cerebral artery territory infarcts, (48) the presumed cause of the infarct was large-vessel occlusive disease in one-third of the patients and cardioembolism in one-fourth of the patients. This finding was similar to the percentage found for anterior cerebral artery distribution infarction. (49) In the posterior circulation, isolated brainstem infarcts are usually thrombotic in nature, (50) whereas cerebellar and more extensive posterior circulation infarcts are not uncommonly seen in association with a cardiogenic source of embolism. (51)

Cerebral Arteriography. Cerebral arteriography is often normal in patients with cerebral embolism. It can demonstrate intracranial stenosis, however, which predisposes to lodging of the embolus within the cerebral circulation. (52) Also supportive of an embolic mechanism is the finding of distal branch occlusion or occlusions in different vascular territories. (53)

Transcranial Doppler Ultrasonography. Transcranial Doppler ultrasonography has been demonstrated to be useful in detecting cerebral emboli in patients with a potential cardiogenic source of embolism. This study can provide supportive evidence for embolism as a cause of stroke in a patient who presents with symptoms of stroke. (54) In a transcranial Doppler study of patients with prosthetic cardiac valves, however, these embolic signals were found to possess no direct clinical significance. (55)

Cardiac Evaluation. Routine evaluation in stroke patients includes careful heart auscultation and performing electroencephalography. Clinical features compatible with cerebral embolism warrant further investigation for a possible cardiogenic source of the cerebral embolism. (56) Potential cardiac sources as a cause of embolism that can be detected by performing echocardiography are listed in Table 2. (57) Transesophageal echocardiography is more sensitive than transthoracic echocardiography in the detection of potential cardiogenic sources of emboli, (58) but the results are often subject to interpretation. (59) In one stroke study, (60) the sensitivity in detecting left atrial thrombi, spontaneous echo contrast, atrial septal aneurysm, interatrial shunts supportive of a possible paradoxical cerebral embolus, ventricular thrombi or aneurysm, or myxomatous mitral valve was 8% when transthoracic echocardiography was performed and 46% when transesophageal echocardiography was performed. Certain features on echoc ardiography, such as left atrial spontaneous echo contrast (61) as well as the size of the left atrium, (62) can be helpful in the support of a cardioembolic mechanism. Transesophageal echocardiography is reported to reveal a left atrial appendage thrombus in roughly 10% of patients with non-valvular atrial fibrillation and in 20 to 40% of patients with recent thromboembolism. (10) Heart monitoring can be especially useful in patients with transient symptoms, (63) although the overall yield is low. (64) Suspicion of infective endocarditis warrants blood cultures, measuring erythrocyte sedimentation rate, and echocardiography.

Preventive Therapy

It is well established that anticoagulant therapy represents the optimal management modality for the prevention of cardiogenic cerebral embolism. However, it is important to determine the level of risk for a particular patient as well as to assess the relative degree of safety for long-term anticoagulant therapy. Unfortunately, the end point for treatment failure is stroke, which can be a devastating determinant.

Warfarin, with a targeted international normalized ratio (INR) of 2.8 to 4.8, was found to reduce the risk of stroke associated with myocardial infarction by 40 to 55% during a 3-year follow-up period. (65,66) In another study of anticoagulant therapy in myocardial infarction, (67) the incidence of stroke was 0.7 per 100 patient-years in patients who underwent anticoagulation versus 1.2 in the placebo group. However, this benefit was partially offset by the higher intracranial hemorrhage rate seen in patients treated with warfarin, in whom the INR was 3.0 or greater. Warfarin, with a targeted INR of 2.0 to 3.0, is associated with an overall risk reduction of 68% in patients with atrial fibrillation, (12) but this mode of therapy should be restricted primarily to patients with moderate to high risk of embolic events, as previously discussed. Low-dose warfarin, with a targeted INR of 1.5 to 2.1, has been proposed by Yamaguchi et a1 (68) for older patients because of their enhanced risk of intracranial hemorrhag e if administered high-dose warfarin. However, the investigators in the Stroke Prevention in Atrial Fibrillation III randomised clinical trial (13) found that low-dose warfarin, with a targeted INR of 1.2 to 1.5, even in combination with 325 mg/d aspirin, was not effective compared with warfarin with n targeted INR of 2.0 to 3.0. Aspirin is generally recommended for low-risk patients with atrial fibrillation, and the overall risk reduction is 20%, (12) which represents the risk reduction in patients in general who are at risk for stroke. Obviously, antiarrhythmic therapy designed to suppress atrial fibrillation also serves to reduce the risk of embolic events significantly. (69)

The mortality risk reduction with warfarin in patients with CHF has been reported to range from a significant 24% (66) to a nonsignificant 10%. (65) This ratio is thought to be reflective, at least in part, of a reduction in vascular events, including cardioembolic stroke. This has not been studied in a convincing, controlled fashion, however, and comparison has been made with aspirin therapy, which has the demonstrated potential to reduce mortality secondary to myocardial ischemia. (70)

As mentioned previously, oral anticoagulation for mechanical heart valves is clearly indicated, and the generally recommended INR is 3.5 to 4.5. (71) This protection can be enhanced with the addition of low-dose aspirin to warfarin therapy with a targeted INR of 3.0 to 4.5, (72) but this regimen is associated with a 55% increase in the relative risk for bleeding and a relative risk increase of 27% for major bleeding.

The risk of stroke associated with interatrial septal defects such as a patent foramen ovale is a subject of controversy. Preliminary information reported by Mohr et a1 (73) indicated no additional protection with the use of warfarin in patients with patent foramen ovale. An alternative approach is surgical closure of the patent foramen ovale to prevent paradoxical cerebral embolism. (74) In a preliminary report of percutaneous closure of patent foramen ovale, this procedure seemed to hold promise for stroke prevention in patients who were particularly susceptible to paradoxical cerebral embolism. (75)

Conclusions

Cardioembolic stroke can be prevented in the majority of susceptible patients. Clinical features help to identify patients who are at particular risk for this ischemic stroke mechanism. The major concern is intracranial hemorrhage as a complication of anticoagulant therapy. Anticoagulation at conventional intensities is associated with a 7- to 10-fold increased risk of intracranial hemorrhage, which translates to roughly 1%/yr. (76) Predisposing factors for anticoagulant-related intracranial hemorrhage include advanced age, intensity of the anticoagulation, prior ischemic stroke, and hypertension. Thus, patient selection for chronic anticoagulant therapy is of utmost importance. With newer diagnostic techniques and with information gleaned from recent controlled clinical trials of anticoagulant therapy in stroke prevention, an enhanced perspective on optimal management in patients at risk for cardioembolic stroke has been gained.

Table 1

Potential cardiogenic sources of cerebral emboli (a)

                               Estimated percentage
Cardiac disorder                 of yearly stroke

Atrial fibrillation                     7
Cardiac failure                         4
Myocardial infarct                      2
Other (eg, prosthetic                   2
 heart valve, interatrial
 septal defect, endocarditis)

(a) Based on yearly stroke rate of approximately 750,000 in the United
States and an estimated overall frequency of cardioembolic stroke of
15%.

Table 2

Potential cardiogenic sources of cerebral emboli detectable on
echocardigrams

Define
 Left ventricular thrombus with or without
 aneurysm
 Left atrial appendage thrombus
 Left atrial myxoma
 Valvular vegetation (septic or nonseptic)
 Protruding aortic atheromata
Probable
 Dilated cardiomyopathy with severely
 impared ejection fraction
 Interatrial septal defect with right-to-
 left shunting
 Spontaneous contrast in the left atrium
Possible
 Mitral valve prolapse
 Mitral annulus calcification
 Wall motion abnormality of the left
 ventricle
 Valvular disease

Accepted November 7, 2002.

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RELATED ARTICLE: Key Points

* Cardioembolic stroke accounts for roughly 15% of all strokes.

* The risk profile for a potential cardiogenic source of embolism needs to be stratified.

* Clinical features that support cardioembolic stroke include sudden onset of maximal neurological deficit, multiple cerebral vascular territories involved, a predilection for branch occlusion not necessarily associated with in situ cerebral atherosclerosis, and the presence of a documented cardiogenic source of embolism.

* The use of anticoagulant therapy tends to be the most effective means of preventing cardiogenic emboli, but the efficacy of protection must clearly outweigh potential complications of the long-term therapy.

From the Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA.

Reprint requests to Roger B. Kelley, MD, Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71103.

Copyright [c] 2003 by The Southern Medical Association

0038-4348/03/9604-0343