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(Stroke. 1997;28:941-945.)
© 1997 American Heart Association, Inc.

Articles

Frequency and Severity of Asymptomatic Coronary Disease in Patients With Different Causes of Stroke

M. I. Chimowitz, MB, ChB; R. M. Poole, MD; M. R. Starling, MD; M. Schwaiger, MD; M. D. Gross, MD

From the Departments of Neurology (M.I.C., R.M.P.) and Internal Medicine, Divisions of Cardiology (M.R.S.) and Nuclear Medicine (M.S., M.D.G.), University of Michigan Medical Center and Department of Veterans Affairs Medical Center, Ann Arbor, Mich.

Correspondence to Marc I. Chimowitz, MB, ChB, Department of Neurology, Emory University Hospital, Box M23, Suite C296H, 1364 Clifton Rd, Atlanta GA 30322. E-mail mchimo{at}neuro.emory.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose We sought (1) to compare the frequency and severity of asymptomatic coronary artery disease (CAD) in patients with different causes of brain ischemia and (2) to determine profiles of patients with brain ischemia who are at highest risk of asymptomatic CAD.

Methods Sixty-nine patients with transient ischemic attack or stroke and without overt CAD underwent a cardiac stress test and a diagnostic evaluation to determine the cause of brain ischemia. The frequency of abnormal cardiac stress tests was compared in patients with large-artery cerebrovascular disease versus other causes of brain ischemia (90% of whom had penetrating artery disease or cryptogenic stroke). Additionally, the frequencies of vascular risk factors, resting electrocardiographic abnormalities, and cause of stroke (large-artery disease versus other causes) were compared in patients with abnormal stress tests versus patients with normal stress tests.

Results The frequency of abnormal stress tests was 50% (15 of 30) in patients with large-artery cerebrovascular disease versus 23% (9 of 39) in patients with other causes of brain ischemia (P=.04). Moreover, 60% of abnormal stress tests (9 of 15) in patients with large-artery cerebrovascular disease suggested severe underlying CAD that was confirmed in 7 of 7 patients who underwent coronary angiography. On the other hand, less than 25% of abnormal stress tests (2 of 9) in patients with other causes of brain ischemia suggested severe underlying CAD. Features that were more common in patients with abnormal stress tests were smoking (P=.006), large-artery cerebrovascular disease (P=.02), veteran status (P=.02), and left ventricular hypertrophy (P=.07).

Conclusions Patients with penetrating artery disease or cryptogenic stroke have a significantly lower frequency of asymptomatic CAD than patients with large-artery cerebrovascular disease. Large-artery cerebrovascular disease, smoking, veteran status, and possibly left ventricular hypertrophy may be useful features for identifying patients with transient ischemic attack or stroke who are at highest risk of harboring asymptomatic CAD.

Key Words: cardiac catheterization • carotid artery diseases • cerebral ischemia • coronary artery disease

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Previous studies have shown that 25% to 70% of patients with carotid stenosis and no overt CAD have evidence of asymptomatic CAD on provocative tests for myocardial ischemia (myocardial perfusion imaging or exercise ECG).^{1 2 3 4} However, there are virtually no data on the frequency of asymptomatic CAD in other subgroups of patients with cerebrovascular disease, eg, in patients with penetrating artery disease or cryptogenic stroke. The aims of the current study of patients with TIA or stroke and no overt CAD were (1) to compare the frequency and severity of abnormal cardiac stress tests in patients with different causes of brain ischemia and (2) to determine clinical criteria (eg, risk factor profiles, ECG findings, stroke subtypes) that identify patients with brain ischemia who are at highest risk of harboring asymptomatic CAD.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patient Eligibility and Recruitment
Consecutive patients with TIA or nondisabling ischemic stroke and no history of CAD who were evaluated by the primary author during an 18-month period were considered for the study. Exclusion criteria were age younger than 40 years; a severe neurological deficit (hemiplegia, global aphasia, neglect or denial of neurological deficit, inability to walk, dementia); history of angina, symptomatic MI, or CABG; an associated disease that limited life expectancy to less than 5 years; and inability to undergo adenosine or dipyridamole thallium myocardial perfusion imaging (eg, asthma, respiratory distress, severe hepatic dysfunction, known allergy to adenosine, dipyridamole, or thallium). Institutional review board approval was obtained before initiation of the study.

Patient Evaluation
Evaluation of all patients in the study included an assessment of vascular risk factors, a resting ECG, diagnostic tests to determine the cause of TIA or stroke, and a cardiac stress test. Risk factors that were evaluated included hypertension, smoking, diabetes mellitus, cholesterol >240 mg/dL, triglycerides >200 mg/dL, peripheral vascular disease, family history of CAD (first-degree relatives only), and left ventricular hypertrophy by ECG or echocardiographic criteria.^{5 6} Diagnostic tests to determine the cause of TIA or stroke included brain imaging (CT or MRI), cerebrovascular imaging studies (carotid and transcranial Doppler ultrasound, MRA, or intra-arterial angiography), and transthoracic or transesophageal echocardiography.

Classification of Cause of Stroke
Large-artery occlusive disease was diagnosed if ultrasound, MRA, or conventional angiography detected 50% stenosis or occlusion of a major extracranial or intracranial artery that supplied the region of the brain affected by the TIA or stroke. Cardioembolism was defined by the presence of an unequivocal cardiac source of embolism (ie, chronic or paroxysmal atrial fibrillation, mitral stenosis, prosthetic valve, endocarditis, intracardiac clot or vegetation, MI within 6 weeks, cardiomyopathy). Penetrating artery disease was diagnosed if the patient presented with pure motor hemiparesis or pure sensory stroke, brain imaging was normal or showed a small (1.5 cm) subcortical infarct that could account for the patient's deficit, and there was no evidence of large-artery occlusive disease or a cardioembolic source.⁷ Cryptogenic stroke was diagnosed if a large (>1.5 cm) subcortical infarct or a cortical infarct of any size could not be attributed to large-artery occlusive disease, a cardioembolic source, or other identifiable cause. If a patient had large-artery occlusive disease and another possible cause of stroke (eg, atrial fibrillation), the patient was assigned to the group with large-artery occlusive disease.

Evaluation for CAD
All patients underwent a resting ECG and a cardiac stress test (adenosine or dipyridamole thallium myocardial perfusion imaging, exercise thallium myocardial perfusion imaging, or exercise ECG) with standard protocols.^{8 9 10} All ECGs were evaluated by a cardiologist for the presence of Q waves, poor R wave progression, and ST-T wave changes. Pathological Q waves were defined as Q waves in two contiguous leads of 0.04 second in duration that were 25% of the R wave in the same lead. Patients whose resting ECG showed pathological Q waves (ie, suggesting an asymptomatic MI) or whose echocardiogram showed a regional wall motion abnormality were not excluded from the study.

Each thallium myocardial perfusion imaging study was reviewed independently by two investigators who were blinded to the patient's clinical data. Studies were classified as normal (no perfusion defect) or abnormal (presence of a perfusion defect). A subtle perfusion defect restricted to the inferior wall of the left ventricle was considered normal (attributed to diaphragmatic attenuation). If there was disagreement between the two primary reviewers regarding the presence of a perfusion defect, a third investigator provided the deciding opinion. All perfusion defects were classified further according to location (anterior, lateral, or inferior), reversibility on a 4-hour delay resting image (presence or absence), and size. The size of a perfusion defect was not specifically quantitated. Instead, a subjective assessment of nine left ventricular segments was made to categorize the size of a defect: a small defect was limited to a singular vascular territory and encompassed one myocardial segment only; a large defect involved four or more myocardial segments or more than one vascular territory; all other defects were considered of moderate size. Exercise ECG was considered abnormal if there was a flat depression of the ST segment 1.0 mm below the baseline or if there was a 1.5-mm upsloping ST segment 80 milliseconds after the J-point.⁸ All patients with abnormal thallium myocardial perfusion imaging studies or exercise ECG were referred to a cardiologist who decided on further evaluation (eg, cardiac catheterization). Patients undergoing cardiac catheterization were considered to have severe CAD if they had 50% stenosis of the left main coronary artery or 70% stenosis of one or more of the following arteries: LAD, circumflex artery, or RCA.

Statistical Analysis
The frequency and severity of abnormal stress tests in patients with large-artery occlusive disease versus other causes of brain ischemia (penetrating artery disease, cardioembolism, and cryptogenic stroke) were compared with the use of ² or Fisher's exact tests. To identify clinical features that were associated with asymptomatic CAD, patients with an abnormal cardiac stress were compared with patients with normal stress tests regarding the rates of vascular risk factors, resting ECG abnormalities, and cause of stroke (large-artery versus other causes). ² or Fisher's exact tests were used for categorical variables, and t tests were used for continuous variables. A stepwise logistic regression analysis was used to determine factors that were independently associated with abnormal cardiac stress tests.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Stroke Evaluation, Classification, and Risk Factors
Of 69 patients enrolled in the study, 53 had a nondisabling stroke and 16 had TIA. Fifty-seven patients (83%) were recruited from a university hospital, and 12 patients (17%) were recruited from a Veterans Affairs Medical Center. Brain CT or MRI was performed in 66 patients (96%) (2 patients with transient monocular visual loss and 1 patient with a hemisphere TIA did not undergo brain imaging); ultrasound, MRA, or angiographic imaging of the symptomatic carotid or vertebrobasilar circulation was performed in 66 patients (96%) (3 patients with a posterior circulation infarct did not undergo cerebrovascular imaging: 2 had atrial fibrillation and 1 had a thalamic lacune); echocardiography was performed in 58 patients (84%). The cause of brain ischemia was attributed to large-artery occlusive disease in 30 patients (43%) and other causes in 39 patients (57%) (penetrating artery disease in 15 patients [22%], cryptogenic stroke in 20 patients [29%], cardioembolism in 4 patients [6%]; all 4 patients had nonvalvular atrial fibrillation).

Peripheral vascular disease was significantly more common in patients with large-artery cerebrovascular occlusive disease than in patients with other causes of brain ischemia (P=.04), whereas hypertension was significantly more common in patients with other causes of brain ischemia (P=.03). The frequencies of all other vascular risk factors were not significantly different between these two groups (Table 1).

View this table: [in this window] [in a new window]   Table 1. Risk Factors in Patients With Large-Artery Cerebrovascular Occlusive Disease vs Patients With Other Causes of Brain Ischemia

Overall Results of Stress Tests and Interobserver Agreement
Adenosine or dipyridamole thallium myocardial perfusion imaging was performed in 55 patients (80%), exercise thallium myocardial perfusion imaging was performed in 10 patients (14%), and exercise ECG alone was performed in 4 patients (6%). Of these 69 patients, 24 (35%) had abnormal cardiac stress tests (23 had abnormal adenosine or dipyridamole thallium myocardial perfusion imaging, 1 patient had an abnormal exercise ECG). The interpretations of the thallium myocardial imaging studies (presence or absence of a perfusion defect) by the two primary reviewers were concordant in 82% of patients.

Frequency and Severity of Abnormal Stress Tests in Patients With Different Causes of Brain Ischemia
Frequency of Abnormal Stress Tests
Fifteen of 30 patients (50%) with large-artery cerebrovascular occlusive disease versus 9 of 39 patients (23%) with other causes of brain ischemia (4 of 20 with cryptogenic stroke, 3 of 15 with penetrating artery disease, 2 of 4 with nonvalvular atrial fibrillation) had abnormal stress tests (P=.04). In the 30 patients with large-artery occlusive disease, cardiac stress tests were abnormal in 8 of 16 patients (50%) with isolated extracranial carotid stenosis (3 of 4 with unilateral stenosis, 5 of 12 with bilateral stenoses), in 2 of 8 patients (25%) with isolated stenosis of a major intracranial artery (eg, middle cerebral artery, basilar artery), and in 5 of 6 patients (83%) with coexistent extracranial carotid and intracranial stenoses.

Severity of Myocardial Perfusion Defects and Underlying CAD at Angiography
Nine of 30 patients (30%) with large-artery cerebrovascular disease had large or multiple myocardial perfusion defects on thallium imaging (8 patients) or exercise ECG changes in several anterior leads (1 patient) suggesting severe underlying CAD. On the other hand, only 2 of 39 patients (5%) with other causes of brain ischemia had large or multiple myocardial perfusion defects (P=.007) (1 of 20 [5%] with cryptogenic stroke, 1 of 15 [7%] with penetrating artery disease, 0 of 4 [0%] with nonvalvular atrial fibrillation). The topography of the myocardial perfusion defects in patients with large-artery cerebrovascular disease suggested multivessel CAD in 8 of 30 patients (27%) and single-vessel CAD in 7 of 30 patients (23%) (6 RCA, 1 LAD). The topography of the perfusion defects in patients with other causes of brain ischemia suggested multivessel CAD in 1 of 39 patients (2.5%) and single-vessel CAD in 8 of 39 patients (21%) (5 LAD, 2 RCA, 1 circumflex artery). The perfusion defects in patients who had a 4-hour delay resting imaging study were fully or partially reversible in 12 of 14 patients (86%) with large-artery cerebrovascular disease and in 6 of 8 patients (75%) with other causes of stroke.

Cardiac catheterization was performed in 7 patients with large-artery cerebrovascular disease (5 with suspected multivessel CAD, 1 with suspected LAD disease, 1 with suspected RCA disease) and in 1 patient with cryptogenic stroke (with suspected RCA disease). All 7 patients with large-artery cerebrovascular disease had severe CAD confirmed at angiography, and the patient with cryptogenic stroke had normal coronary arteries (Table 2).

View this table: [in this window] [in a new window]   Table 2. Coronary Angiography Findings in Eight Patients With TIA or Stroke, No History of CAD, and Abnormal Cardiac Stress Tests

Clinical Criteria Associated With Abnormal Cardiac Stress Tests
Table 3 shows the frequencies of vascular risk factors, resting ECG abnormalities, and causes of brain ischemia (large-artery occlusive disease versus other causes) in patients with abnormal cardiac stress tests versus patients with normal cardiac stress tests. Of these clinical features, smoking (P=.006), large-artery occlusive disease as the cause of TIA or stroke (P=.02), and veteran status (P=.02) were significantly more common in patients with abnormal cardiac stress tests. There was a trend for left ventricular hypertrophy (P=.07) to be more common in patients with abnormal stress tests. Logistic regression analysis showed that smoking (odds ratio, 6.5; 95% confidence interval, 1.3 to 32.1) and large-artery cerebrovascular disease (odds ratio, 2.9; 95% confidence interval, 1.0 to 8.7) were independently associated with abnormal cardiac stress tests.

View this table: [in this window] [in a new window]   Table 3. Risk Factors, Demographics, ECG Findings, and Stroke Subtypes in Patients With Abnormal Cardiac Stress Tests vs Patients With Normal Cardiac Stress Tests

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This study of patients with TIA or stroke and no history of CAD showed that patients with large-artery cerebrovascular disease had a significantly higher frequency of abnormal cardiac stress tests than patients with other causes of brain ischemia despite similar frequencies of vascular risk factors in both groups (hypertension was actually significantly more common in patients with other causes of brain ischemia). Moreover, 60% of the abnormal stress tests (9 of 15) in patients with large-artery cerebrovascular disease suggested severe underlying CAD that was confirmed in 7 of 7 patients who underwent coronary angiography. On the other hand, less than 25% of abnormal stress tests (2 of 9) in patients with other causes of brain ischemia suggested severe underlying CAD.

Since atherosclerosis invariably is the pathological substrate of large-artery cerebrovascular occlusive disease, it is not surprising that there is a strong association between large-artery cerebrovascular occlusive disease and asymptomatic CAD. Previous postmortem studies have shown that atherosclerosis usually involves different arterial trees at different ages. The aorta is involved first, followed by the coronary arteries, peripheral arteries, extracranial carotid and vertebral arteries, and finally the intracranial arteries.¹¹ Our findings that 50% of patients with large-artery cerebrovascular occlusive disease and, in particular, that 83% of patients with coexistent extracranial carotid and intracranial large-artery occlusive disease had abnormal cardiac stress tests indicate that the presence of CAD is highly likely once severe atherosclerosis has involved the extracranial carotid and intracranial arteries. This finding has been corroborated in a large prospective study of veterans that showed that intracranial occlusive disease and peripheral vascular disease were independently associated with cardiac events in patients with carotid stenosis and no history of CAD.¹²

Three clinical features occurred significantly more frequently in patients with abnormal cardiac stress tests versus patients with normal stress tests in this study. These features were large-artery occlusive disease as the cause of brain ischemia, smoking, and veteran status. There was also a trend for left ventricular hypertrophy to occur more commonly in patients with abnormal stress tests. Multivariate analysis showed that smoking and large-artery cerebrovascular disease were independently associated with abnormal stress tests. The relatively low power of the study, however, does not exclude the possibility that other factors (eg, resting ECG abnormalities) may also be associated with abnormal cardiac stress tests in patients with TIA or stroke and no history of CAD (Table 3).

While the results of this study and previous studies have established that patients with large-artery cerebrovascular disease and no overt CAD have a high frequency of abnormal cardiac stress tests, only one study has evaluated cardiac outcome in patients with large-artery cerebrovascular disease and abnormal cardiac stress tests. Urbinati et al⁴ followed 106 patients who underwent cardiac stress tests before carotid endarterectomy and found that 8 of 27 patients (29.6%) with abnormal thallium myocardial perfusion imaging studies had MI or unstable angina during an average of 5.4 years of follow-up compared with only 1 of 79 patients (1.3%) with normal myocardial studies (P<.01).

Other studies have evaluated cardiac outcome in patients with carotid stenosis and no overt CAD, but cardiac stress tests were not performed in these patients. In one study of 93 patients without overt CAD who underwent carotid endarterectomy, the cumulative incidence of important cardiac events (cardiac death, MI, CABG, pulmonary edema, or ventricular tachycardia) at 8 years after endarterectomy was 25% (ie, 3% per year).¹³ In another larger study of 244 male veterans with carotid stenosis and no history of CAD, 60 patients (25%) had fatal MI/sudden death (38 patients) or nonfatal MI (22 patients) during a mean follow-up of 47.9 months (ie, 6% per year).¹²

Considering that patients with carotid stenosis and no symptoms of CAD consist of a subgroup without CAD and a subgroup with asymptomatic CAD (50% of the entire group) and that virtually all of the cardiac events would have occurred in the subgroup with asymptomatic CAD, the results of these two studies suggest that the rate of major cardiac events in patients with carotid stenosis and asymptomatic CAD is approximately 6% to 12% per year.^{12 13} The higher cardiac event rate in the Veterans Administration study may be due to a higher frequency of asymptomatic CAD in veterans compared with nonveterans. This is supported by the findings in the present study, in which 8 of 12 veterans (66%) had abnormal cardiac stress tests compared with 16 of 57 nonveterans (28%) (P=.02).

Although patients with large-artery cerebrovascular disease and no overt CAD have a high frequency of abnormal cardiac stress tests and a high rate of major cardiac events, there is no consensus on the appropriate evaluation and treatment of asymptomatic CAD in these patients. The major reason for the lack of consensus is that until recently there were no prospective data indicating which, if any, therapy is most effective for preventing cardiac events in patients with silent myocardial ischemia. However, recent studies of noncerebrovascular patients who had mild cardiac symptoms and silent myocardial ischemic episodes during daily life have shown that medical therapy (ß-blockers or calcium channel blockers) is significantly more effective than placebo for preventing MI or sudden death in these patients.^{14 15} One study has also shown that revascularization, particularly CABG surgery, is significantly more effective than medical therapy for preventing major cardiac events in patients with silent myocardial ischemia.¹⁶

The results of these recent studies on the treatment of silent myocardial ischemia substantially strengthen the case for identifying and treating asymptomatic CAD in cerebrovascular patients; however, noninvasive screening for asymptomatic CAD in all patients with cerebrovascular disease is unlikely to be cost-effective. The results of the current study suggest that large-artery cerebrovascular disease (especially if there is coexistent extracranial and intracranial occlusive disease), smoking, veteran status, and possibly left ventricular hypertrophy may be useful features for identifying patients with TIA or stroke who are at highest risk of harboring asymptomatic CAD. Given the relatively small sample size in this single-institution study, we cannot make a firm recommendation regarding the use of these criteria for screening patients for asymptomatic CAD until a large multicenter study confirms these findings.

	Selected Abbreviations and Acronyms

 

CABG = coronary artery bypass graft CAD = coronary artery disease ECG = electrocardiogram, electrocardiography LAD = left anterior descending coronary artery MI = myocardial infarction MRA = magnetic resonance angiography RCA = right coronary artery TIA = transient ischemic attack

Received October 28, 1996; revision received January 23, 1997; accepted February 24, 1997.

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