Published online before print December 18, 2008, doi: 10.1161/STROKEAHA.108.527507
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Stroke. 2009;40:419.)
© 2009 American Heart Association, Inc.
Original Contributions |
Atherosclerotic Burden Findings in Young Cryptogenic Stroke Patients With and Without a Patent Foramen Ovale
From the Quebec Heart Institute (J.R.-C., M.N., E.B., E.L., P.P., P.B., O.F.B.), Laval Hospital, Québec, Canada; the Department of Neurology (A.M., A.M., S.V.), Hôpital de l’Enfant Jesus, Québec, Canada; the Department of Neurology (D.R., M.P.), Hôtel Dieu de Lévis, Lévis, Canada; and the Centre Hospitalier Universitaire Laval (C.H.), Québec, Canada.
Correspondence to Josep Rodés-Cabau, MD, FESC, Quebec Heart Institute, Laval Hospital, 2725, chemin Ste-Foy, G1V 4G5 Quebec, Canada. E-mail josep.rodes{at}crhl.ulaval.ca
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background and Purpose— To further determine the mechanisms of cryptogenic stroke or transient ischemic attack in young patients, we evaluated indices of atherosclerosis in patients
55 years old diagnosed with cryptogenic cerebrovascular event comparing those with patent foramen ovale (PFO) with those without PFO.
Methods— This was a prospective study including 100 consecutive patients 55 years old (mean age, 45±8 years; 56 males) diagnosed with cryptogenic stroke/transient ischemic attack. PFO was identified in 59 of these patients with the use of transesophageal echocardiography with contrast study. The following surrogate markers of atherosclerosis were evaluated in all patients: carotid intima media thickness as measured by carotid ultrasonography and endothelial function as determined by brachial flow-mediated vasodilation. The same measurements were obtained in a control group of 50 age- and sex-matched control subjects.
Results— Patients without PFO were more likely to be current smokers and obese and more frequently had a history of hypertension and dyslipidemia. Carotid intima media thickness measurements were higher (P<0.0001) in patients without PFO (1.03±0.31 mm) compared with those with PFO (0.75±0.20 mm) and control subjects (0.79±0.17 mm). The absence of PFO was also associated with lower brachial flow-mediated vasodilation (without PFO: 5.04±3.39%; with PFO: 7.16±4.09%; control subjects: 7.33±4.07%; P=0.02). There were no differences in carotid intima media thickness and flow-mediated vasodilation between patients with stroke/transient ischemic attack with PFO and control subjects. The presence of PFO was independently associated with reduced carotid intima media thickness (P<0.0001) and increased flow-mediated vasodilation (P=0.019).
Conclusions— In patients 55 years old diagnosed with cryptogenic stroke/transient ischemic attack, the presence of PFO was associated with a lower atherosclerotic burden as measured by carotid intima media thickness and endothelial function with no differences compared with a control group without cerebrovascular event. These results suggest that an atherosclerotic-mediated mechanism may be involved in cryptogenic stroke/transient ischemic attack in patients without PFO, whereas a nonatherosclerotic mechanism may mediate the cerebrovascular event in the presence of PFO.
Key Words: atherosclerosis • carotid arteries • patent foramen ovale • stroke
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Approximately 40% of ischemic strokes are cryptogenic (ie, no clearly definable cause is found after extensive workup). Although atherothrombosis remains one potential cause of stroke in these patients, few data are available regarding the role of an atherosclerosis-mediated mechanism in cryptogenic stroke. Some studies have evaluated the presence of significant atheromatosis of the aortic arch in patients with cryptogenic stroke, but the association between aortic arch atheroma and cryptogenic stroke has been limited to patients >60 years old.1,2 In fact, the role of atherosclerosis in young adults with cryptogenic stroke has been mostly limited to the evaluation of the prevalence of cardiovascular risk factors in these patients.3–5 Also, a role for patent foramen ovale (PFO) in the pathogenesis of cryptogenic stroke in patients
55 years old has been suggested on the basis of case–control studies that have shown a higher prevalence of PFO among these patients compared with stroke-free control subjects,6 but no studies have determined whether or not the atherosclerotic burden in young patients with cryptogenic stroke might vary depending on the presence of a PFO. The B-mode ultrasound measurement of the intima media thickness of the carotid artery (CIMT) and the evaluation of endothelial function by the flow-mediated vasodilation (FMV) of the brachial artery have been shown to be reliable noninvasive imaging markers of global atherosclerotic burden.7–9 Also, several studies have associated CIMT and endothelial dysfunction with the occurrence of ischemic stroke of atherothrombotic origin.10–14
To further explore the mechanisms involved in cryptogenic stroke/transient ischemic attack (TIA) in young adult patients, we performed a prospective study evaluating the atherosclerotic burden as measured by CIMT and endothelial function test in patients 55 years old diagnosed with cryptogenic stroke/TIA comparing those with and those without PFO and with a control group of subjects matched for age and sex.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Study Population
This prospective study included a series of 100 consecutive patients
55 years old diagnosed with a cryptogenic stroke or TIA from June 2003 to March 2007 in 3 neurology departments of the province of Quebec, Canada. The diagnosis of stroke or TIA was made by a neurologist according to the National Institute of Neurological Disorders and Stroke Classification III.15 TIA was defined as a reversible episode of neurological deficit that resolved completely within 24 hours and was attributed to inadequate blood supply. Patients with transient focal neurological symptoms whose clinical features were not sufficiently clear to affirm the diagnosis of definite TIA were excluded. The diagnosis of cryptogenic stroke/TIA was established after a systematic etiologic workup, including brain CT and/or MRI, routine blood tests, detailed coagulation study (including protein C, protein S, antithrombin III, antiphospholipid antibodies, factor V Leiden, prothrombin variant G20210A), 12-lead electrocardiogram, echocardiography, 24-hour electrocardiogram Holter, extracranial Doppler ultrasonography with frequency analysis and B-mode imaging, and cerebral CT and/or MR angiography. Definite causes of stroke included significant large artery atherosclerosis (
50% stenosis), small vessel occlusion, cardioembolic causes,16 complex atheroma of the aortic arch, nonatherosclerotic arteriopathies, and coagulopathies. Transesophageal echocardiography with a contrast study and Valsalva maneuver was performed in all patients to determine the presence or not of a PFO. All echocardiographic images were recorded and evaluated offline by a cardiologist unaware of clinical data in the core laboratory of the Quebec Heart Institute/Laval Hospital. The presence and diameter of PFO, the severity of the right-to-left shunt, and the presence of atrial septal aneurysm were determined. The presence of PFO was diagnosed on the basis of the observation of a right-to-left passage of contrast bubbles through a valve-like structure either spontaneously or after provocative maneuver (Valsalva) within 3 cardiac cycles after the complete opacification of the right atrium. The degree of right-to-left shunt was considered small if <20 microbubbles appeared and large if 20 microbubbles appeared.17,18 Atrial septal aneurysm (ASA) was diagnosed when the atrial septum exhibited an excursion into the left or right atrium 11 mm or a total excursion 15 mm and the base of the aneurysmal septum was at least of 15 mm in diameter.19
Traditional cardiovascular risk factors were systematically recorded in all patients and included smoking status, history of hypertension defined as blood pressure 140/90 mm Hg or treatment with antihypertensive medication, history of dyslipidemia defined as low-density cholesterol levels >3.50 mmol/L or treatment with lipid-lowering medication, and history of diabetes defined as serum fasten blood sugar >6.9 mmol/L or treatment with oral hypoglycemic agents or insulin. The body mass index and the waist circumference were measured in all cases. Fasting blood samples were collected in all patients 3 months after the stroke/TIA to avoid any influence of the cerebrovascular event on laboratory tests. The following measurements were systematically performed: glucose, total cholesterol, low-density cholesterol, high-density cholesterol, ratio total cholesterol/high-density cholesterol, triglycerides, lipoprotein a, apolipoprotein B, homocysteine, high-sensitivity C-reactive protein, fibrinogen, and D-dimer. Care was taken to obtain blood samples in the absence of any infectious condition within the previous 10 days. In patients receiving warfarin therapy, this treatment was withdrawn and replaced by antiplatelet treatment with aspirin at least 4 days before blood sampling.
Carotid Ultrasound Examination and Measurements
Carotid B-mode ultrasound examination was performed in all patients by 2 experienced sonographers using a Hewlett-Packard ultrasound system equipped with high-resolution transducers and digital acquiring capability. Standardized carotid ultrasound scanning and reading protocols were used.20 A transverse scan followed by a full circumferential longitudinal scan were performed to obtain appropriate images of the near and far wall of 3 predetermined carotid artery segments of both carotid arteries, including the proximal 10 mm of the internal carotid artery, the carotid bifurcation beginning at the tip of the flow divider and extending 10 mm below this point, and the arterial segment extending 10 mm below the bifurcation in the common carotid artery. The images of each study were digitally stored and measured offline by an experienced technician blinded to the clinical data. The maximum CIMT was identified and measured in each of the 6 artery segments of each carotid artery, and the mean of the maximum CIMT measurements of a total of 12 carotid segments was calculated for each patient.
Endothelial Function Testing
Endothelial function was evaluated by means of a brachial test as previously described.21 The tests were performed 3 months after the cerebrovascular episode in all patients after an overnight fast, between 7 and 8 AM, after a 15-minute rest in the supine position in a quiet dimly light room. Subjects had to have consumed no caffeine, alcohol, or chocolate and were not to have smoked in the last 12 hours. The patient had to be free of any clinically significant infectious condition within the 10 days before the test.
At each test, a 3-lead electrocardiogram was applied with continuous monitoring. The right brachial artery was imaged longitudinally just above the antebrachial fossa. Images were captured at the same time of the cardiac cycle (peak of R wave) with a high-resolution ultrasound apparatus (Hewlett-Packard 7-MHz linear-array vascular probe coupled to a Hewlett-Packard 5500 ultrasound machine). Still frames were recorded one per 5-second interval with the frames of the first and last 5 seconds of the subsequence discarded. A blood pressure cuff was then inflated on the upper arm to 220 mm Hg for 5 minutes. Immediately after release of the cuff, the brachial artery was continuously imaged, and 1 minute after release of the cuff, a set of 12 images was recorded during the next 90 seconds. Sublingual nitroglycerin of 0.3 mg was administered, and 9 more images were recorded 3 minutes later.
Recorded images were analyzed by an experienced technician blinded to clinical data using dedicated image analysis software (Dynamic Endothelial Assessment V2.0; Vasometrix). The mean calibrated diameter of the artery segment was calculated from an average of 120 computerized diameter measurements per digitalized frame. The average of all frames of each subsequence was then computed. The percent changes in arterial caliber after FMV and after nitroglycerin-mediated vasodilation from their respective basal states were determined. FMV was used as an index of endothelium-dependent dilation and nitroglycerin-mediated vasodilation as an index of endothelium-independent dilation.
Control Group
A control group of 50 subjects matched with the study population for age and sex underwent the same examinations under the same conditions as patients with cryptogenic stroke/TIA, including blood sample measurements, CIMT, and endothelial function testing. The control group consisted of volunteers with no history of cardiac or cerebrovascular event.
The study was approved by the ethics committee of the hospital, and all patients and control subjects gave written, informed consent.
Statistical Analysis
The 
2 test or Fisher exact test was used to compare qualitative variables. Comparisons among numeric variables were performed using one-way analysis of variance and further 1:1 comparisons between groups were performed using the Tukey’s post hoc test. Differences in total cholesterol and low-density lipoprotein cholesterol levels among groups were adjusted for lipid-lowering treatment status. Stepwise regression analysis was performed to determine the predictors of increased atherosclerotic burden (higher CIMT and lower brachial FMV values) in patients with cryptogenic stroke/TIA. Differences were considered statistically significant at probability values <0.05. The data were analyzed using the statistical package program SAS v9.1.3 (SAS Institute Inc, Cary, NC).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Patients and Clinical Atherosclerotic Risk Factors
From 217 consecutive patients
55 years old with ischemic stroke or TIA, a total of 100 patients (46%) were diagnosed with cryptogenic stroke or TIA and constituted the study population. The definite causes of stroke/TIA in the other 117 patients were distributed as follows: large artery atherosclerosis (17 patients [8%]), cardioembolic (18 patients [8%]), small vessel occlusion (26 patients [12%]), nonatherosclerotic arteriopathies (31 patients [14%]), and miscellanea, including coagulopathies (25 patients [12%]). Mean age of the study population was 45±8 years and 44% were females. Seventy-two patients had a stroke and 28 patients were diagnosed of TIA with evidence of an ischemic lesion at MRI in 10 of them. PFO was diagnosed in 59 patients. The clinical characteristics of the study population grouped according to the presence or absence of PFO and compared with the control group are shown in Table 1. Blood samples were obtained at a median of 4 months (range, 3 to 9 months) after the stroke/TIA episode in both patients with and without PFO. The results of the laboratory tests grouped according to the presence or absence of PFO and compared with the control group are shown in Table 2. Low-density lipoprotein cholesterol levels were higher in patients with PFO and control subjects compared with patients without PFO, but these differences were no longer significant after adjusting for lipid-lowering treatment status (P=0.63).
|
|
Surrogate Markers of Atherosclerosis
CIMT and endothelial function measurements were obtained after a median of 4 months (range, 3 to 9 months) after the event. The mean values of CIMT and endothelial function measurements grouped according to the presence or absence of PFO and compared with the control group are shown in Table 3. The mean of the maximum CIMT measurements was significantly higher in patients without PFO compared with those with PFO (mean difference, 0.28 mm; 95% CI, 0.15 to 0.41) and control subjects (mean difference, 0.24 mm; 95% CI, 0.11 to 0.36). There were no differences in CIMT measurements between patients with PFO and control subjects. Patients without PFO exhibited an impaired endothelial function expressed as a lower brachial FMV compared with patients with PFO (mean difference, 2.12%; 95% CI, 0.05 to 4.18) and control subjects (mean difference, 2.29%; 95% CI, 0.03 to 4.78). There were no differences in FMV measurements between patients with PFO and control subjects, and there were no differences among groups in the values of endothelium-independent (nitroglycerin-mediated) vasodilation.
|
On univariate analysis, the variables associated with increased CIMT in patients with cryptogenic stroke were age (r2=0.31, P=0.002), systolic blood pressure (r2=0.31, P=0.003), homocysteine level (r2=0.24, P=0.02), body mass index (r2=0.22, P=0.056), and the absence of PFO (1.03±0.31 mm versus 0.75±0.20 mm, P<0.0001). On multivariate analysis, the independent variable associated with increased CIMT were systolic blood pressure (P=0.049) and the absence of PFO (P<0.0001). The 2 variables associated with reduced brachial FMV values on univariate analysis were current smoking (4.95%±3.47% versus 6.81%±4.04%, P=0.046) and the absence of PFO (5.04%±3.39% versus 7.16%±4.09%, P=0.015). On multivariate analysis, the only independent variable associated with low FMV values was the absence of PFO (P=0.019).
Echocardiographic Characteristics of Patent Foramen Ovale
Mean PFO diameter was 2.8±1.5 mm and the degree of the right-to-left shunt was evaluated as large in 88% of the patients. A eustachian valve was associated with PFO in 16 patients (27%) and atrial septal aneurysm was diagnosed in 17 patients (29%). The clinical, laboratory, echocardiographic, and atherosclerotic burden characteristics of the patients with PFO associated with atrial septal aneurysm compared with those with PFO alone are shown in Table 4. There were no significant differences in cardiovascular risk factors or surrogate markers of atherosclerosis between patients with and without atrial septal aneurysm.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The results of the present study showed that young adult patients with cryptogenic stroke or TIA exhibited significant differences in atherothrombotic burden profile depending on the presence or absence of PFO, suggesting that different pathogenic mechanisms are involved in the occurrence of a cerebrovascular event in patients with and without PFO. Patients without PFO had a higher prevalence of traditional cardiovascular risk factors compared with patients with PFO and compared with a control group of subjects with a cardiovascular risk factor prevalence representative of the general population of the same age and sex. Patients with cryptogenic stroke/TIA and no PFO had a higher atherosclerotic burden as determined by higher CIMT and impaired endothelial function compared with patients with PFO and control subjects. Furthermore, PFO was independently associated with a lower atherosclerotic burden. Finally, no differences were observed in patients with stroke/TIA and PFO according to the presence or absence of ASA.
Lamy et al4 have shown that young patients with cryptogenic stroke exhibited significant differences in stroke risk factors depending on the presence or absence of PFO. In accordance with the results of the present study, patients with PFO were younger and less likely to have traditional cardiovascular risk factors as hypertension, hypercholesterolemia, or current smoking. In addition, the present study also demonstrated a higher prevalence of obesity and higher waist circumference values among patients without PFO compared with those with PFO. These 2 risk factors for atherosclerosis have recently been associated with carotid atherosclerosis and with a higher risk of ischemic stroke.22–24 Importantly, the prevalence of cardiovascular risk factors among patients with cryptogenic stroke/TIA without PFO was also significantly higher than that observed in a control group with a prevalence of cardiovascular risk factors similar to that reported by the Heart and Stroke Foundation of Canada for the general population of the Quebec province in the same range of age and sex.25 However, it is well known that traditional cardiovascular risk factors may only partially explain the atherosclerotic burden and cardiovascular risk for a specific patient, and noninvasive tools for obtaining a more precise evaluation of the presence and severity of atherosclerosis, the so-called surrogate markers of atherosclerosis, have been extensively developed in recent years.7–14 Data on atherosclerotic burden in patients with cryptogenic stroke have been mostly limited to the evaluation of the presence of atherosclerotic aortic arch plaques by transesophageal echocardiography.26–30 These studies reported an incidence of 10% to 39% of relevant aortic plaques in patients with cryptogenic stroke, but the patients included in these studies were significantly older than our study population and the presence of aortic atherosclerotic plaques was mainly limited to patients >60 years with an incidence as low as 4% in patients <60 years. Interestingly, Handke et al30 have recently shown that the absence of PFO was associated with a higher thickness of atherosclerotic aortic plaque in patients 55 years old diagnosed with cryptogenic stroke. The present study assessed, for the first time, the atherosclerotic burden in young adult patients with cryptogenic stroke/TIA by using 2 noninvasive surrogate markers of atherosclerosis and also evaluated the potential influence of the presence of PFO on these atherosclerotic markers. The absence of PFO was independently associated with a higher atherosclerotic burden as determined by higher CIMT and impaired endothelial function. Previous studies have demonstrated an association between CIMT measurements and endothelial dysfunction with cerebrovascular events due to large vessel atherosclerotic disease,10–14 similar to that observed in the present study in patients with cryptogenic stroke/TIA without PFO. These data strongly suggest atherothrombosis as the most plausible pathophysiological mechanism involved in the cryptogenic stroke of young adult patients without PFO.
PFO was diagnosed in 59% of the patients included in the study, and this high rate of PFO was consistent with previous studies showing that approximately half of the patients 55 years old diagnosed with cryptogenic stroke had a PFO.6 Patients with PFO exhibited a prevalence of cardiovascular risk factors similar to that observed in a control group of subjects of the same age and sex without cerebrovascular event and was significantly lower than that observed in patients without PFO for all traditional cardiovascular risk factors except diabetes. Also, patients with PFO had similar CIMT and endothelial function values compared with the control group and much lower values than those obtained in patients without PFO. The lack of differences in atherosclerotic burden between patients with cryptogenic stroke/TIA with PFO and the control group and the pronounced differences of both groups compared with patients without PFO suggest that the pathogenic mechanism responsible for cerebrovascular events in the presence of PFO is not an atherosclerotic-mediated one. A cardioembolic link between PFO and stroke due to a paradoxical embolism from a thrombotic process in the venous system has been suggested.6,31,32 Other proposed alternative mechanisms of cardioembolism linking PFO and stroke have been embolism from a mural thrombus formed locally at the atrial septum within the PFO conduit19 or a greater potential for atrial arrhythmias and thrombus formation in the presence of atrial septal abnormalities.33 Much of the controversy regarding the role of PFO in the pathogenesis of stroke has been generated by 2 large prospective studies, the PFO-ASA study19 and the PFO In Cryptogenic Stroke Study (PICCS),34 which compared patients with cryptogenic stroke with and without PFO, and showed no differences in cerebrovascular event recurrence between the 2 groups at midterm follow-up. The results of the present study would support the notion of cryptogenic stroke in young adult patients with PFO as a distinct entity for which specific therapeutic research programs must be carried out to improve clinical outcomes. The presence of ASA associated with PFO has been associated with a higher risk of recurrent cerebrovascular events19 and a higher rate of multiple cerebral ischemic lesions as determined by diffusion-weighted imaging.35,36 We failed to demonstrate any significant differences in atherosclerotic burden according to the presence or absence of ASA, and this suggests that the mechanisms of stroke might be similar in patients with PFO with and without ASA.
Limitations
The study protocol did not include a systematic screening for silent vein thrombosis in the study population. This was left to the discretion of the physician responsible for the patient and was only performed in a minority of patients, precluding knowledge of the exact incidence of venous thrombosis in these patients. However, previous studies have shown a very low incidence of venous thrombosis of lower extremities in such patients,37 and larger studies including patients with cryptogenic stroke have already obviated the need for systematic screening for venous thrombosis in these cases.19 The number of patients with PFO and ASA was limited and further larger studies will be required to better understand the role of ASA in patients with cryptogenic stroke and PFO. Finally, echocardiographic studies were not performed in subjects without stroke/TIA (control group) precluding knowledge of the prevalence of PFO in this group.
|
Acknowledgments |
|---|
We thank Serge Simard, MSc, for statistical analysis.
Source of Funding
This study was supported by a grant of the Fondation de l’Institut de Cardiologie de Québec.
Disclosures
None.
Received May 30, 2008; accepted June 24, 2008.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Molina CA, Santamarina E, Alvarez-Sabin J. Cryptogenic stroke, aortic arch atheroma and patent foramen ovale. Cerebrovasc Dis. 2007; 24 (suppl 1): 84–88.[CrossRef][Medline] [Order article via Infotrieve]
2. Macleod MR, Amarenco P, Davis SM, Donnan GA. Atheroma of the aortic arch: an important and poorly recognised factor in the aetiology of stroke. Lancet Neurol. 2004; 3: 408–414.[CrossRef][Medline] [Order article via Infotrieve]
3. Kristensen B, Malm J, Carlberg B, Stegmayr B, Backman C, Fagerlund M, Olsson T. Epidemiology and etiology of ischemic stroke in young adults aged 18 to 44 years in northern Sweden. Stroke. 1997; 28: 1702–1709.
4. Lamy C, Giannesini C, Zuber M, Arquizan C, Meder JF, Trystram D, Coste J, Mas JL. Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale. The PFO-ASA study. Stroke. 2002; 33: 706–711.
5. Serena J, Marti-Fabregas J, Santamarina E, Rodríguez JJ, Pérez-Ayuso MJ, Masjuan J, Segura T, Gállego J, Dávalos A. Recurrent stroke and massive right-to-left shunt: results from the prospective Spanish multicentre study (CODICIA study). Stroke. 2008; 39: 3131–3136.
6. Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case–control studies. Neurology. 2000; 55: 1172–1179.
7. De Groot E, Hovingh GK, Wiegman A, Duriez P, Smit AJ, Fruchart JC, Kastelein JJ. Measurement of arterial wall thickness as a surrogate marker for atherosclerosis. Circulation. 2004; 109: III33–38.[Medline] [Order article via Infotrieve]
8. Faulx MD, Wright AT, Hoit BD. Detection of endothelial dysfunction with brachial artery ultrasound scanning. Am Heart J. 2003; 145: 943–951.[CrossRef][Medline] [Order article via Infotrieve]
9. Lane HA, Smith JC, Davies JS. Noninvasive assessment of preclinical atherosclerosis. Vasc Health Risk Manag. 2006; 2: 19–30.[CrossRef][Medline] [Order article via Infotrieve]
10. Pruissen DM, Gerritsen SA, Prinsen TJ, Dijk JM, Kappelle LJ, Algra A. Carotid intima-media thickness is different in large- and small-vessel ischemic stroke: the SMART study. Stroke. 2007; 38: 1371–1373.
11. Cupini LM, Pasqualetti P, Diomedi M, Vernieri F, Silvestrini M, Rizzato B, Ferrante F, Bernardi G. Carotid artery intima-media thickness and lacunar versus nonlacunar infarcts. Stroke. 2002; 33: 689–694.
12. Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam study. Circulation. 1997; 96: 1432–1437.
13. Targonski PV, Bonetti PO, Pumper GM, Higano ST, Holmes DR, Lerman A. Coronary endothelial dysfunction is associated with an increased risk of cerebrovascular events. Circulation. 2003; 107: 2805–2809.
14. Perticone F, Ceravolo R, Pujia A, Ventura G, Iacopino S, Scozzafava A, Ferraro A, Chello M, Mastroroberto P, Verdecchia P, Schillaci G. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation. 2001; 104: 191–196.
15. Special Report from the National Institute of Neurological Disorders and Stroke. Classification of cerebrovascular disease III. Stroke. 1990; 21: 637–676.
16. Ferro JM. Cardioembolic stroke: an update. Lancet Neurol. 2003; 2: 177–188.[CrossRef][Medline] [Order article via Infotrieve]
17. Windecker S, Wahl A, Nedeltchev K, Arnold M, Schwerzmann M, Seiler C, Mattle HP, Meier B. Comparison of medical treatment with percutaneous closure of patent foramen ovale in patients with cryptogenic stroke. J Am Coll Cardiol. 2004; 44: 750–758.
18. Bédard E, Rodés-Cabau J, Houde C, Mackey A, Rivest D, Cloutier S, Noël M, Marrero A, Côté JM, Chetaille P, Delisle G, Leblanc MH, Bertrand OF. Enhanced thrombogenesis but not platelet activation is associated with transcatheter closure of patent foramen ovale. Stroke. 2007; 38: 100–104.
19. Mas JL, Arquizan C, Lamy C, Zuber M, Cabanes L, Derumeaux G, Coste J. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med. 2001; 345: 1740–1746.
20. Lonn EM, Yusuf S, Dzavik V, Doris I, Yi Q, Smith S, Moore-Cox A, Bosch J, Riley W, Teo KK. Effects of ramipril and vitamin E on atherosclerosis. The study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamine E (SECURE). Circulation. 2001; 103: 919–925.
21. Bogaty P, Brophy JM, Noel M, Boyer L, Simard S, Bertrand F, Dagenais GR. Impact of prolonged cyclooxygenase-2 inhibition on inflammatory markers and endothelial function in patients with ischemic heart disease and raised C-reactive protein. A randomized placebo-controlled study. Circulation. 2004; 110: 934–939.
22. Hu G, Tuomilehto J, Silventoinen K, Sarti C, Männistö S, Jousilahti P. Body mass index, waist circumference, and waist–hip ratio on the risk of total and type-specific stroke. Arch Intern Med. 2007; 167: 1420–1427.
23. Lakka TA, Lakka HM, Salonen R, Kaplan GA, Salonen JT. Abdominal obesity is associated with accelerated progression of carotid atherosclerosis in men. Atherosclerosis. 2001; 154: 497–504.[CrossRef][Medline] [Order article via Infotrieve]
24. Kurth T, Gaziano M, Rexrode KM, Kase CS, Cook NR, Manson JE, Buring JE. Prospective study of body mass index and risk of stroke in apparently healthy women. Circulation. 2005; 111: 1992–1998.
25. Heart and Stroke Foundation of Canada. The Growing Burden of Heart Disease and Stroke in Canada 2003. Ottawa: Heart and Stroke Foundation of Canada; 2003.
26. Amarenco P, Cohen A, Tzourio C, Bertrand B, Hommel M, Besson G, Chauvel C, Touboul PJ, Bousser MG. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med. 1994; 331: 1474–1479.
27. Jones EF, Kalman JM, Calfiore P, Tonkin AM, Donnan FA. Proximal aortic atheroma. An independent risk factor for cerebral ischemia. Stroke. 1995; 26: 218–224.[Medline] [Order article via Infotrieve]
28. Stone DA, Hawke ME, LaMonte M, Kittner SJ, Acosta J, Corretti M, Sample C, Price TR, Plotnick G. Ulcerated atherosclerotic plaques in the thoracic aorta are associated with cryptogenic stroke. A multiplane transesophageal echocardiographic study. Am Heart J. 1995; 130: 105–108.[CrossRef][Medline] [Order article via Infotrieve]
29. Castellanos M, Serena J, Segura T, Pérez-Ayuso MJ, Silva Y, Davalos A. Atherosclerotic aortic arch plaques in cryptogenic stroke: a microembolic signal monitoring study. Eur Neurol. 2001; 45: 145–150.[CrossRef][Medline] [Order article via Infotrieve]
30. Handke M, Harloff A, Olschewski M, Hetzel A, Geibel A. Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med. 2007; 357: 2262–2268.
31. Srivastava TN, Payment MF. Images in clinical medicine. Paradoxical embolism–thrombus in transit though a patent foramen ovale. N Engl J Med. 1997; 337: 681.
32. Cramer SC, Rordorf G, Maki JH, Kramer LA, Grotta JC, Burgin S, Hinchey JA, Benesch C, Furie KL, Lutsep HL, Kelly E, Longstreth WT. Increased pelvic vein thrombi in cryptogenic stroke. Results of the Paradoxical Emboli from Large Veins in Ischemic Stroke (PELVIS) study. Stroke. 2004; 35: 46–50.
33. Berthet K, Lavergne T, Cohen A, Guize L, Bousser MG, Le Heuzey JY, Amarenco P. Significant association of atrial vulnerability with atrial septal abnormalities in young patients with ischemic stroke of unknown cause. Stroke. 2000; 31: 398–403.
34. Homma S, Sacco RL, DiTullio MR, Sciacca RR, Mohr JP. Effect of medical treatment in stroke patients with PFO: PFO In Cryptogenic Stroke Study. Circulation. 2002; 105: 2625–2631.
35. Bonati LH, Kessel-Schaefer A, Linka AZ, Buser P, Wetzel SG, Radue EW, Lyrer PA, Engelter ST. Diffusion-weighted imaging in stroke attributable to patent foramen ovale. Significance of concomitant atrial septal aneurysm. Stroke. 2006; 37: 2030–2034.
36. Santamarina E, Gonzalez-Alujas MT, Munoz V, Rovira A, Rubiera M, Ribo M, Alvarez-Sabin J, Molina CA. Stroke patients with cardiac septal abnormalities: differential infarct patterns on DWI. J Neuroimaging. 2006; 16: 334–340.[Medline] [Order article via Infotrieve]
37. Stollberger C, Finsterer J, Slany J. Why is venous thrombosis only rarely detected in patients with suspected paradoxical embolism? Thromb Res. 2002; 105: 189–191.[CrossRef][Medline] [Order article via Infotrieve]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||