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Patients who have had a transient ischaemic attack or minor stroke have an increased risk of cardiovascular events for the following 5 years. We aimed to assess 5-year functional outcomes in patients with transient ischaemic attack or minor ischaemic stroke and to determine the factors associated with long-term disability.We analysed data from patients in TIAregistry.org, an international, prospective, observational registry of patients with transient ischaemic attack or minor ischaemic stroke from 61 specialised centres in 21 countries. Patients aged 18 years or older who had a transient ischaemic attack or minor stroke within the previous 7 days between May 30, 2009, and Dec 30, 2011, with a baseline modified Rankin scale (mRS) score of 0-1, and who had been followed up for 5 years, were eligible for inclusion in this study. We evaluated whether existing comorbidities and stroke recurrence, categorised as disabling (mRS score of1, including death) or non-disabling (mRS score of 0-1), at 5 years after baseline, were associated with poor functional outcome (defined as an mRS score of1). We used multivariable generalised equation models for factors associated with poor functional outcome at 5 years and multivariable cause-specific Cox hazard regression models in case of stroke recurrence.Between May 30, 2009, and Dec 30, 2011, 3847 eligible patients were included in the study, 3105 (80·7%) of whom had an mRS evaluation at 5 years of follow-up. Median follow-up duration was 5·00 years (IQR 4·78-5·00). 710 (22·9%) of 3105 patients had an mRS score greater than 1 at 5 years. Factors associated with poor functional outcome at 5 years were older age (per 10-year increase, odds ratio [OR] 2·18, 95% CI 1·93-2·46; p0·0001), diabetes of any type (1·45, 1·18-1·78; p=0·0001), history of stroke or transient ischaemic attack before the qualifying event (1·74, 1·37-2·22; p0·0001), hypertension (1·38, 1·00-1·92; p=0·050), atrial fibrillation or flutter (1·52, 1·04-1·94; p=0·030), congestive heart failure (1·73, 1·22-2·46; p=0·0024), valvular disease (2·47, 1·70-3·58; p0·0001), stroke as qualifying event (1·31, 1·09-1·57; p=0·0037), history of peripheral artery disease (1·98, 1·28-3·07; p=0·0023), history of coronary artery disease (1·32, 1·00-1·74; p=0·049), intracranial haemorrhage during follow up (4·94, 1·91-12·78; p=0·0013), and living alone (1·32, 1·10-1·59; p=0·0031). Regular physical activity before the index event was associated with reduced risk of poor functional outcome (OR 0·52, 95% CI 0·42-0·66; p0·0001). 345 recurrent strokes had occurred at 5 years of follow-up, 141 (40·9%) of which were disabling or fatal. Stroke recurrence increased the risk of having a disability at 5 years (OR 3·52, 95% CI 2·37-5·22; p0·0001). Recurrent disabling or fatal strokes were independently associated with older age (per 10-year increase, hazard ratio [HR] 1·61, 95% CI 1·35-1·92; p0·0001), diabetes of any type (2·23, 1·56-3·17; p0·0001), National Institutes of Health Stroke Scale score of greater than 5 at discharge (5·11, 2·15-12·13; p=0·0013), history of coronary artery disease (1·76, 1·17-2·65; p=0·0063), history of stroke or transient ischaemic attack before the qualifying event (1·54, 1·03-2·29; p=0·035), congestive heart failure (1·86, 1·01-3·47; p=0·044), stroke as qualifying event (1·73, 1·22-2·45; p=0·0024), mRS score of greater than 1 at discharge (2·48, 1·27-4·87; p=0·0083), and intracranial haemorrhage during follow-up (17·15, 9·95-27·43; p0·0001). Regular physical activity before the index event was associated with reduced risk of recurrent disabling stroke at 5 years (HR 0·56, 95% CI 0·31-0·99; p=0·046), and 5-year disability without recurrent stroke (0·61, 0·47-0·79; p=0·0001).We found a substantial burden of disability (mRS score of1) at 5 years after transient ischaemic attack or minor ischemic stroke, and most predictors of this disability were modifiable risk factors. Patients who did regular physical exercise before the index event had a significantly reduced risk of disability at 5 years compared with patients who did no exercise.AstraZeneca, Sanofi, Bristol Myers Squibb, SOS Attaque Cérébrale Association.

Background and Purpose: Although statins are effective in secondary prevention of ischemic stroke, they are also associated with an increase risk of intracranial hemorrhage (ICH) in certain conditions. In the TST trial (Treat Stroke to Target), we prespecified an exploration of the predictors of incident ICH. Methods: Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned in a 1:1 ratio to a target LDL (low-density lipoprotein) cholesterol of Results: Among 2860 patients enrolled, 31 incident ICH occurred over a median follow-up of 3 years (18 and 13 in the lower and higher target group, 3.21/1000 patient-years [95% CI, 2.38–4.04] and 2.32/1000 patient-years [95% CI, 1.61–3.03], respectively). While there were no baseline predictors of ICH, uncontrolled hypertension (HR, 2.51 [95% CI, 1.01–6.31], P =0.041) and being on anticoagulant (HR, 2.36 [95% CI, 1.00–5.62], P =0.047)] during the trial were significant predictors. On-treatment low LDL cholesterol was not a predictor of ICH. Conclusions: Targeting an LDL cholesterol of Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01252875; EUDRACT identifier: 2009-A01280-57.

Background and Purpose— The TST trial (Treat Stroke to Target) evaluated the benefit of targeting a LDL (low-density lipoprotein) cholesterol of 4 mm, in a French and Korean population. The follow-up lasted a median of 5.3 years in French patients (similar to the median follow-up time in the SPARCL trial [Stroke Prevention by Aggressive Reduction in Cholesterol Level]) and 2.0 years in Korean patients. Exposure duration to statin is a well-known driver for cardiovascular risk reduction. We report here the TST results in the French cohort. Methods— One thousand seventy-three French patients were assigned to Results— After a median follow-up of 5.3 years, the achieved LDL cholesterol was 66 (1.69 mmol/L) and 96 mg/dL (2.46 mmol/L) on average, respectively. The primary end point occurred in 9.6% and 12.9% of patients, respectively (HR, 0.74 [95% CI, 0.57–0.94]; P =0.019). Cerebral infarction or urgent carotid revascularization following transient ischemic attack was reduced by 27% ( P =0.046). Cerebral infarction or intracranial hemorrhage was reduced by 28% ( P =0.023). The primary outcome or intracranial hemorrhage was reduced by 25% ( P =0.021). Intracranial hemorrhages occurred in 13 and 11 patients, respectively (HR, 1.17 [95% CI, 0.53–2.62]; P =0.70). Conclusions— After an ischemic stroke of documented atherosclerotic origin, targeting a LDL cholesterol of Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01252875.

Background: The TST trial (Treat Stroke to Target) showed the benefit of targeting a low-density lipoprotein cholesterol (LDL-C) concentration of Methods: TST-PLUS (Treat Stroke to Target–Plaque Ultrasound Study) included 201 patients assigned to an LDL-C concentration of Results: After a median follow-up of 3.1 years, the achieved LDL-C concentrations were 64 mg/dL (1.64 mmol/L) in the lower-target group and 106 mg/dL (2.72 mmol/L) in the higher-target group. Compared with the higher-target group, patients in the lower-target group had a similar incidence of newly diagnosed carotid plaque: 46/201 (5-year rate, 26.1%) versus 45/212 (5-year rate, 29.7%). The change in common carotid arteries intima–media thickness was −2.69 µm (95% CI, −6.55 to 1.18) in the higher-target group and −10.53 µm (95% CI, −14.21 to −6.85) in the lower-target group, resulting in an absolute between-group difference of −7.84 µm (95% CI, −13.18 to −2.51; P =0.004). Conclusions: In patients with ischemic stroke and atherosclerosis, an LDL-C target of Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01252875.

ObjectiveTo determine long-term vascular outcomes of Asian patients who experienced TIA or minor ischemic stroke and to compare the outcomes of Asian patients with those of non-Asian patients, in the context of modern guideline-based prevention strategies.MethodsThis is a subanalysis of the TIAregistry.org project, in which 3,847 patients (882 from Asian and 2,965 from non-Asian countries) with a recent TIA or minor ischemic stroke were assessed and treated by specialists at 42 dedicated units from 14 countries and followed for 5 years. The primary outcome was a composite of cardiovascular death, nonfatal stroke, and nonfatal acute coronary syndrome.ResultsNo differences were observed in the 5-year risk of the primary outcome (14.0% vs 11.7%; hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.88–1.37; p = 0.41) and stroke (10.7% vs 8.5%; HR, 1.17; 95% CI, 0.90–1.51; p = 0.24) between Asian and non-Asian patients. Asian participants were at higher risk of intracranial hemorrhage (1.8% vs 0.8%; HR, 2.23; 95% CI, 1.09–4.57; p = 0.029). Multivariable analysis showed that the presence of multiple acute infarctions on initial brain imaging was an independent predictor of primary outcome and modified Rankin Scale score of >1 in both Asian (HR, 1.91; 95% CI, 1.11–3.29; p = 0.020) and non-Asian (HR, 1.39; 95% CI, 1.02–1.90; p = 0.037) patients.ConclusionThe long-term risk of vascular events in Asian patients was as low as that in non-Asian patients, while Asian participants had a 2.2-fold higher intracranial hemorrhage risk. Multiple acute infarctions were independently associated with future disability in both groups.Classification of EvidenceThis study provides Class I evidence that among people who experienced TIA or minor stroke, Asian patients have a similar 5-year risk of cardiovascular death, stroke, and acute coronary syndrome as non-Asian patients.

BACKGROUND: In patients with non-cardio-embolic stroke, atorvastatin 80 mg/day reduced the relative risk of recurrent stroke by 16%, and a post hoc analysis showed that achieving an LDL-c of less than 70 mg/dL reduced the relative risk by 28% as compared to an on-treatment LDL of 100 mg/dL or more. Current guidelines from the French drug agency recommend treating with a statin after an ischaemic stroke to a target of less than 100 mg/dL, but no study directly tested LDL-c targets. The Treat Stroke to Target (TST) trial will compare the efficacy of achieving an LDL-c of less than 70 mg/dL versus an achieved LDL-c of 100 ± 10 mg/dL for secondary prevention in patients with recent ischaemic stroke of atherosclerotic origin. Main hypothesis: An achieved on-treatment LDL-c of less than 70 mg/dL will reduce by 25% the risk of recurrent ischaemic stroke, myocardial infarction, urgent coronary or carotid revascularisation following new symptoms requiring hospitalisation, and vascular death compared with on-treatment LDL-c of 100 ± 10 mg/dL. DESIGN: Patients are randomised to either LDL-c levels, and the investigator who is not blinded can use the lipid-lowering agent of his/her choice available on the market (including statins and ezetimibe), in order to achieve the assigned LDL-c level. To be eligible for enrolment, patients have a recent ischaemic stroke or TIA of atherosclerotic origin with at least one arterial stenosis of a cerebral artery, enrolled between acute phase of the qualifying stroke (once the neurological deficit is stabilised) and three months. The initial planned sample size of 3760 participants followed three years was amended to allow follow-up of all enrolled patients until 385 primary efficacy outcome events have occurred, and no later than 31 December 2019. Patients will be recruited in 76 sites in two countries (France and South Korea) between March 2010 and December 2018 (last included patient followed up to one year). Safety outcomes will include haemorrhagic strokes and new onset diabetes. All primary endpoints will be adjudicated by an endpoint committee, blinded to the assigned LDL-c level. Two sub-studies assess (1) the relative effect of assigned LDL-c levels on occurrence of new atherosclerotic plaque as detected by carotid ultrasound during follow-up, using M’ATH software for repositioning and (2) the genetic and biomarker drivers of recurrent primary endpoints according to assigned LDL-c lowering arm, in atherosclerotic strokes. SUMMARY: The TST trial is evaluating the benefits of achieving an LDL-c less than 70 mg/dL for secondary stroke prevention in ischaemic stroke patients of atherosclerotic origin. Main results are anticipated in 2020 or earlier (ClinicalTrials.gov NCT01252875).

Background After a transient ischemic attack (TIA) or minor stroke, the long-term risk of stroke and other vascular events is not well known. In this follow-up to a report on 1-year outcomes from a registry of TIA clinics in 21 countries that enrolled 4789 patients with a TIA or minor ischemic stroke from 2009 through 2011, we examined the 5-year risk of stroke and vascular events. Methods We evaluated patients who had had a TIA or minor stroke within 7 days before enrollment in the registry. Among 61 sites that participated in the 1-year outcome study, we selected 42 sites that had follow-up data on more than 50% of their enrolled patients at 5 years. The primary outcome was a composite of stroke, acute coronary syndrome, or death from cardiovascular causes (whichever occurred first), with an emphasis on events that occurred in the second through fifth years. In calculating the cumulative incidence of the primary outcome and secondary outcomes (except death from any cause), we treated death as a competing risk. Results A total of 3847 patients were included in the 5-year follow-up study; the median percentage of patients with 5-year follow-up data per center was 92.3% (interquartile range, 83.4 to 97.8). The composite primary outcome occurred in 469 patients (estimated cumulative rate, 12.9%; 95% confidence interval [CI], 11.8 to 14.1), with 235 events (50.1%) occurring in the second through fifth years. At 5 years, strokes had occurred in 345 patients (estimated cumulative rate, 9.5%; 95% CI, 8.5 to 10.5), with 149 of these patients (43.2%) having had a stroke during the second through fifth years. Rates of death from any cause, death from cardiovascular causes, intracranial hemorrhage, and major bleeding were 10.6%, 2.7%, 1.1%, and 1.5%, respectively, at 5 years. In multivariable analyses, ipsilateral large-artery atherosclerosis, cardioembolism, and a baseline ABCD2 score for the risk of stroke (range, 0 to 7, with higher scores indicating greater risk) of 4 or more were each associated with an increased risk of subsequent stroke. Conclusions In a follow-up to a 1-year study involving patients who had a TIA or minor stroke, the rate of cardiovascular events including stroke in a selected cohort was 6.4% in the first year and 6.4% in the second through fifth years. (Funded by AstraZeneca and others.)

Importance Patients who have experienced stroke with intracranial atherosclerotic disease (ICAD) may also have concomitant atherosclerosis in different arterial beds and other possible causes for ischemic stroke. However, little is known about the frequency and prognostic effect of such overlapping diseases. Objectives To describe the prevalence of systemic atherosclerotic burdens and overlapping stroke etiologies and their contributions to long-term prognoses among patients who have experienced stroke with ICAD. Design, Setting, and Participants The Asymptomatic Myocardial Ischemia in Stroke and Atherosclerotic Disease study is a single-center prospective study in which 405 patients with acute ischemic stroke within 10 days of onset were consecutively enrolled between June 2005 and December 2008 and followed up for 4 years. After excluding 2 patients because of incomplete investigations, 403 were included in this analysis. Main Outcomes and Measures Significant ICAD was defined as having 50% or greater stenosis/occlusion by contrast-enhanced/time-of-flight magnetic resonance angiography, computed tomography angiography, and/or transcranial Doppler ultrasonography. Systemic vascular investigations on atherosclerotic disease were performed with ultrasonography in carotid arteries, aorta and femoral arteries, and by angiography in coronary arteries. Coexistent stroke etiologies were assessed using the atherosclerosis, small-vessel disease, cardiac pathology, other cause, and dissection (ASCOD) grading system. We estimated the 4-year risk of major adverse cardiovascular events (MACE), including vascular death, nonfatal cardiac events, nonfatal stroke, and major peripheral arterial events. Results Of 403 participants, 298 (74%) were men and the mean (SD) age was 62.6 (13.1) years. Significant ICAD was found in 146 (36.2%). Patients with significant ICAD more often had aortic arch (70 [60.9%] vs 99 [49.0%];P = .04) and coronary artery (103 [76.9%] vs 153 [63.2%];P = .007) atherosclerosis than those without. Among patients with ICAD, concurrent stenosis in the extracranial carotid artery (24 [23.4%] vs 3 [9.0%];P = .08; adjusted hazard ratio[aHR] = 2.12) and the coronary artery (19 [29.9%] vs 8 [12.8%];P = .01; aHR = 1.90) increased the MACE risk. Furthermore, patients with ICAD who also had any cardiac pathology (ASCOD grade C1-3) were at a higher MACE risk than others (grade C0) (20 [28.2%] vs 7 [11.4%];P = .01; aHR = 2.24). By contrast, patients with ICAD with any form of small vessel disease (grade S1-3) had a lower MACE risk than those without (grade S0) (20 [17.3%] vs 6 [34.6%];P = .05; aHR = 0.23). Conclusions and Relevance Patients with ICAD often have coexisting systemic atherosclerosis and multiple potential stroke mechanisms that affect their prognosis, suggesting that extensive evaluations of overlapping diseases may allow better risk stratification.

Background and Purpose— Contrary to typical transient symptoms (TS), atypical TS, such as partial sensory deficit, dysarthria, vertigo/unsteadiness, unusual cortical visual deficit, and diplopia, are not usually classified as symptoms of transient ischemic attack when they occur in isolation, and their clinical relevance is frequently denied. Methods— Consecutive patients with recent TS admitted in our transient ischemic attack clinic (2003–2008) had systematic brain, arterial, and cardiac investigations. We compared the prevalence of recent infarction on brain imaging, major investigational findings (symptomatic intracranial or extracranial atherosclerotic stenosis ≥50%, cervical arterial dissection, and major source of cardiac embolism), and 1-year risk of major vascular events in patients with isolated typical or atypical TS and nonisolated TS, after exclusion of the main differential diagnoses. Results— Among 1850 patients with possible or definite ischemic diagnoses, 798 (43.1%) had isolated TS: 621 (33.6%) typical and 177 (9.6%) atypical. Acute infarction on brain imaging was similar in patients with isolated atypical and typical TS but less frequent than in patients with nonisolated TS, observed in 10.0%, 11.5%, and 15.3%, respectively ( P P =0.06). One-year risk of a major vascular events was not significantly different in the 3 groups. Conclusions— Transient ischemic attack diagnosis should be considered and investigated in patients with isolated atypical TS.

The objective of this study was to assess the effect of golimumab on carotid ultrasound measures and cardiovascular serious adverse events (SAEs) in patients with inflammatory arthritides.An exploratory carotid artery ultrasound substudy was performed in the GO-BEFORE study of methotrexate (MTX)-naive rheumatoid arthritis patients, with ultrasounds performed at weeks 0, 24, and 52 to measure common carotid artery intima-media thickness, distensibility coefficient, interadventitial diameter, and plaque count. Cardiovascular SAEs reported over 2 years of follow-up were assessed in 5 golimumab phase 3 clinical trials of patients with rheumatoid arthritis (GO-BEFORE, GO-FORWARD, and GO-AFTER), psoriatic arthritis (GO-REVEAL), and ankylosing spondylitis (GO-RAISE). In GO-BEFORE and GO-FORWARD, patients received placebo + MTX, golimumab 50 mg + MTX, or golimumab 100 mg +/- MTX at baseline and every 4 weeks; in the other 3 trials, patients received placebo or golimumab 50 or 100 mg.The carotid ultrasound substudy showed inconsistent changes in common carotid artery intima-media thickness in the golimumab + MTX groups over time, and there was large variability in the measurements. Increases in interadventitial diameter were observed in the golimumab 100 mg + placebo group, but not in the golimumab + MTX groups. There were no significant differences in the distensibility coefficient and plaque count between the golimumab and placebo groups. Very few patients overall experienced a cardiovascular SAE, and the incidence of cardiovascular SAEs was not statistically different between the golimumab and placebo groups.The results of the carotid ultrasound substudy were inconclusive, and no increase or decrease in cardiovascular SAEs was observed following 2 years of treatment with golimumab with or without MTX.

Background and Purpose— Transient visual symptoms (TVS) are common complaints. They can be related to transient ischemic attacks, but the nature of the symptoms often remains uncertain, and data on prognosis are scarce. We studied the prevalence, presentation, and effect of different types of TVS, paying particular attention to the association with high-risk pathology of embolism. Methods— A total of 2398 patients with suspected transient ischemic attack admitted to the SOS-TIA clinic between January 2003 and December 2008 underwent immediate evaluation and treatment. Results— Eight hundred twenty-six (34.5%) patients had TVS, including 422 (17.6%) patients with isolated TVS. Transient monocular blindness was the most frequent TVS (36.3%), followed by diplopia (13.4%), homonymous lateral hemianopia (12.3%), bilateral positive visual phenomena (10.8%), and lone bilateral blindness (4.5%). Positive diffusion-weighted imaging was found in 11.8%, 8.1%, 8.1%, and 5.0% of patients with homonymous lateral hemianopia, diplopia, lone bilateral blindness, and transient monocular blindness, respectively. Among 1850 patients (595 patients with TVS) with definite/possible transient ischemic attack or minor stroke, a major source of embolism of cardiac or arterial origin was found less frequently in patients with isolated or nonisolated TVS than in patients without TVS (19.6%; 19.7% versus 28.1%, respectively; P Conclusions— Approximately 20% of patients with TVS had a major source of embolism detected, requiring urgent management. Atrial fibrillation was particularly frequent in patients with transient homonymous lateral hemianopia.

Background and Purpose— ASCOD phenotyping (A, atherosclerosis; S, small vessel disease; C, cardiac pathology; O, other causes; and D, dissection) assigns a degree of likelihood to every potential cause (1 for potentially causal, 2 for causality is uncertain, 3 for unlikely causal but disease is present, 0 for absence of disease, and 9 for insufficient workup to rule out the disease) commonly encountered in ischemic stroke. We used ASCOD to investigate the overlap of underlying vascular diseases and their prognostic implication. Methods— A single rater applied ASCOD in 405 patients enrolled in the Asymptomatic Myocardial Ischemia in Stroke and Atherosclerotic Disease study. Results— A was present in 90% of patients (A1=43% and A2=15%), C in 52% (C1=23% and C2=14%), and S in 66% (S1=11% and S2=2%). On the basis of grades 1 and 2, 25% of patients had multiple underlying diseases, and 80% when all 3 grades were considered. The main overlap was found between A and C; among C1 patients, A was present in 92% of cases (A1=28%, A2=20%, and A3=44%). Conversely, among A1 patients, C was present in 47% of cases (C1=15%, C2=15%, and C3=17%). Grades for C were associated with gradual increase in the 3-year risk of vascular events, whereas risks were similar across A grades, meaning that the mere presence of atherosclerotic disease qualifies for high risk, regardless the degree of likelihood for A. Conclusions— ASCOD phenotyping shows that the large overlap among the 3 main diseases, and the high prevalence of any form of atherosclerotic disease, reinforces the need to systematically control atherosclerotic risk factors in all ischemic strokes.

Background Whether cerebral artery endothelial dysfunction is a key factor of symptomatic lacunar stroke and cerebral small vessel disease remains unclear. Methods Cerebral and extracerebral vasoreactivity were measured in 81 patients with recent symptomatic lacunar stroke and in 81 control subjects matched for main vascular risk factors. Cerebral vasoreactivity and carotid endothelial-dependent vasodilation were measured after five-minutes of carbon dioxide-induced hypercapnia. Brachial endothelial-dependent vasodilation was assessed after hyperemia induced by deflating a cuff around the forearm previously inflated to 200 mmHg for four-minutes. Carotid and brachial endothelial-independent vasodilation were measured five-minutes after administration of sublingual nitroglycerin 300 μg. Brain magnetic resonance imaging were analyzed in lacunar stroke patients. Results One-month after stroke onset, patients had more severely impaired cerebral vasoreactivitys than matched controls (mean ± standard deviation, 14.4 ± 12.1% vs. 19.4 ± 17.4%; P = 0.049). Severe alterations of both carotid and brachial endothelial-dependent and at a lesser degree of carotid and brachial endothelial-independent vasodilation were observed in both groups. After adjustment for confounders, subjects with a cerebral vasoreactivity value in the two lower tertiles (≤19.6%) were more likely to have had a symptomatic lacunar stroke (adjusted odds ratio, 3.78; 95% confidence interval, 1.42 to 10.08; P = 0.008). Only alteration of brachial endothelial-independent vasodilation correlated with parenchymal abnormalities, namely microbleeds and leukoaraiosis. Conclusions While abnormalities in extracerebral vasoreactivity seem related to vascular risk factors, the severity of endothelial dysfunction in cerebral arteries may be determinant in the occurrence of symptomatic lacunar stroke in patients with small vessel disease.

Intima-media thickness (IMT) provides a surrogate end point of cardiovascular outcomes in clinical trials evaluating the efficacy of cardiovascular risk factor modification. Carotid artery plaque further adds to the cardiovascular risk assessment. It is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. The scientific basis for use of IMT in clinical trials and practice includes ultrasound physics, technical and disease-related principles as well as best practice on the performance, interpretation and documentation of study results. Comparison of IMT results obtained from epidemiological and interventional studies around the world relies on harmonization on approaches to carotid image acquisition and analysis. This updated consensus document delineates further criteria to distinguish early atherosclerotic plaque formation from thickening of IMT. Standardized methods will foster homogenous data collection and analysis, improve the power of randomized clinical trials incorporating IMT and plaque measurements and facilitate the merging of large databases for meta-analyses. IMT results are applied to individual patients as an integrated assessment of cardiovascular risk factors. However, this document recommends against serial monitoring in individual patients.

Background and Purpose— There is mounting evidence that atherogenic dyslipidemia (ie, low high-density lipoprotein cholesterol combined with high triglyceride concentrations) is an independent predictor of high cardiovascular risk and possibly of stroke. Methods— All patients included in the SOS-TIA cohort underwent an initial standardized evaluation, including medical history, physical examination, routine blood biochemistry, and diagnostic testing, and were followed for 1 year. Lipid profile was evaluated under fasting conditions. Atherogenic dyslipidemia was defined as high-density lipoprotein cholesterol blood concentration ≤40 mg/dL and triglycerides ≥150 mg/dL. Results— Among 1471 consecutive patients with transient ischemic attack (TIA) or minor stroke, overall prevalence of atherogenic dyslipidemia was 5.8%, but varied from 4.6% to 11.1%, depending on final diagnosis (possible TIA or TIA with a cerebral ischemic lesion, respectively). Prevalence of atherogenic dyslipidemia was independently associated with male sex, diabetes, and body mass index, but not with ABCD2 score. Atherogenic dyslipidemia also strongly associated with symptomatic intracranial stenosis ≥50% (adjusted odds ratio, 2.77; 95% CI, 1.38–5.55), but not with symptomatic extracranial stenosis ≥50% (adjusted odds ratio, 1.20; 95% CI, 0.64–2.26). Despite appropriate secondary prevention treatment, 90-day stroke risk was greater in patients with versus without atherogenic dyslipidemia (4.8% versus 1.7%; P =0.04). Conclusions— The atherogenic dyslipidemia phenotype in patients with TIA may be associated with intracranial artery stenosis and higher risk of early recurrent stroke. Additional data are needed to confirm these findings and to assess the best way to reduce important residual risk in such patients.

According to recently published data, fibrates may reduce the risk of major cardiovascular events. Whether patients with low high-density lipoprotein cholesterol (HDL-C), high triglyceride levels, or both may have additional benefits remains under debate.We performed a meta-analysis of the 5 large trials assessing the impact of fibrates on cardiovascular end points and providing information on low HDL-C and high triglyceride levels. Subgroups were determined according to values closest to predetermined cut-offs for both HDL-C and triglycerides ( 200 mg/dL, respectively). Overall, 4671 patients (2401 in fibrate group and 2270 in placebo group) were classified as having an atherogenic dyslipidemia featuring low HDLC combined with high triglyceride levels. Across trials, the proportion of patients classified in this subgroup ranged from 11% to 33%. We found a significant difference in the magnitude of fibrate effect across dyslipidemia subgroups (P for between-group heterogeneity = 0.0002). A greater effect size was found in patients with high triglyceride levels or atherogenic dyslipidemia phenotype where fibrates were estimated to reduce the cardiovascular risk by 28% [95% confidence interval (CI), 15% to 39%; P < 0.001] or 30% (95% CI, 19% to 40%, P < 0.0001), respectively, but only by 6% (95% CI, 22% to 13%, P = 0.13) in nonatherogenic dyslipidemia patients. Targeting patients with high triglyceride levels or atherogenic dyslipidemia with fibrates may help reduce residual vascular risk.

Background and Purpose— There is an overlap between stroke and coronary heart disease, but the exact prevalence of coronary artery disease in patients with nonfatal cerebral infarction is unclear, particularly when there is no known history of coronary heart disease. Methods— We consecutively enrolled 405 patients presenting with acute cerebral infarction documented by neuroimaging who underwent carotid and femoral artery, thoracic, and abdominal aorta ultrasound examinations. Of the 342 patients with no known coronary heart disease, 315 underwent coronary angiography a median of 8 days (interquartile range, 6–11) after stroke onset. Results— Coronary plaques on angiography, regardless of stenosis severity, were present in 61.9% of patients (95% confidence interval [CI], 56.5–67.3) and coronary stenoses ≥50% were found in 25.7% (95% CI, 20.9–30.5). The overall prevalence of coronary plaque increased with the number of arterial territories (carotid or femoral arteries) involved, with an adjusted odds ratio of coronary artery disease of 1.25 (95% CI, 0.58–2.71) for presence of plaque in 1 territory, and 4.31 (95% CI, 1.92–9.68) for presence of plaque in both territories, compared with no plaque in either territory. The presence of plaque in both femoral and carotid arteries had an age- and sex-adjusted positive predictive value of 84% for presence of coronary plaque and a negative predictive value of 44%. Conclusions— There is a high burden of silent coronary artery disease in patients with nonfatal cerebral infarction and no known coronary heart disease, even in the absence of systemic atherosclerosis. The prevalence is even higher in patients with evidence of carotid and/or femoral plaque.

Background: Measurement of far wall common carotid artery intima-media thickness (CCAIMT) has emerged as a predictor of incident cardiovascular events. The Cardiovascular Risk Factor Multiple Evaluation in Latin America (CARMELA) study was the first large-scale population-based assessment of both CCAIMT and cardiovascular risk factor prevalence in 7 Latin American cities; the relationship between CCAIMT and cardiovascular risk markers was assessed in these urban Latin American centers. Methods: CARMELA was across-sectional, population-based, observational study using stratified, multistage sampling. The participants completed a questionnaire, were evaluated in a clinical visit and underwent carotid ultrasonography. Clinical measurements were obtained by health personnel trained, certified and supervised by CARMELA investigators. Mannheim intima-media thickness consensus guidelines were followed for measurement of CCAIMT. Results: In all cities and for both sexes, CCAIMT increased with higher age. CCAIMT was greater in the presence of cardiovascular risk factors than in their absence. In all cities, there was a statistically significant linear trend between increasing CCAIMT and a growing number of cardiovascular risk factors (p < 0.001). After adjustment for age and sex, metabolic syndrome was strongly associated with increased CCAIMT (p < 0.001 in all cities), as were hypercholesterolemia, obesity and diabetes (p < 0.001 in most cities). By multivariate analysis, hypertension was independently associated with an increase in CCAIMT in all cities (p < 0.01). Conclusions: CARMELA was the first large-scale population study to provide normal CCAIMT values according to age and sex in urban Latin American populations and to show CCAIMT increases in the presence of cardiovascular risk factors and metabolic syndrome.

Background and purpose The contribution of modifying non-low-density lipoprotein cholesterol (LDL-C) levels to reduce stroke risk remains uncertain. The aim of this study was to investigate the association between treatment-induced change in plasma triglyceride levels and risk of stroke and progression of carotid intima-media thickness (CIMT). Methods We performed a systematic review and meta-regression analyses of randomized controlled trials of lipid-modifying treatments selected from a PubMed search on literature published from 1966 to 2008. Results We identified 64 randomized controlled trials (active groups, n =96,807; control groups, n =98,681) that tested lipid-modifying drugs and reported triglyceride levels and stroke outcome. Extracting data from placebo groups, we found a statistically significant association between baseline triglyceride levels and stroke risk (adjusted relative risk [RR], 1.05 per 10-mg/dL increase; 95% CI, 1.03–1.07). Except for a trend in fibrate and niacin trials, there was no evidence of any relationship between degree of triglyceride change and stroke incidence. In multivariable meta-regression analysis including baseline and change in LDL-C, only change in LDL-C was associated with log risk ratio of all strokes (RR reduction, 4.5% per 10-mg/dL reduction; 95% CI, 1.7–7.2; P =.003). Similarly, taking into account 26 randomized controlled trials reporting CIMT outcome, LDL-C reduction was associated with reduced CIMT progression (−3.0μm/y per 10-mg/dL reduction; 95% CI, −5.5 to −0.4; P =.03). Conclusions In view of the limitations of meta-regression analysis and CIMT measures as surrogate endpoints in lipid-lowering drugs trials, additional studies are needed to more precisely quantify the detrimental effect of triglyceride levels on stroke risk and to establish the efficacy of triglyceride-lowering therapy in addition to LDL-C reduction.

Background and Purpose— The purpose of this study was to assess the prevalence of embolic signals (ES) in acute coronary syndromes (ACS) and their association with stroke. Methods— From December 2004 to October 2006, 209 consecutive patients with ACS (without prosthetic heart valves or previous stroke) were studied within 72 hours of symptom onset. Patients underwent ES monitoring in both middle cerebral arteries by transcranial Doppler for 30 minutes. Median follow-up was 14 months after discharge. Results— Patients were treated according to current European Society Cardiology guidelines. Specifically, 92% of patients received heparin(s), 100% aspirin, 92% clopidogrel, 67% intravenous glycoprotein IIb/IIIa inhibitors, 9% fibrinolysis, and 67% underwent angioplasty. ES were detected in 7 patients (prevalence 3.4%; 95% CI, 1.4 to 6.8). Except for a higher prevalence of ES in patients with unstable angina versus other ACS categories (8.5% versus 1.9%, P =0.047), none of the factors among baseline characteristics, clinical features, ACS treatment, and cardiac findings were associated with the presence of ES. During hospitalization, 3 patients without ES had cerebrovascular events (one stroke and 2 transient ischemic attacks), whereas no cerebrovascular events occurred in patients with ES. Conclusions— The prevalence of ES among hospitalized patients with ACS is currently low, possibly because of improvement in ACS treatment. In this ACS sample, ES did not appear associated with short-term risk of cerebrovascular events.

Objective Urgent evaluation and treatment of transient ischemic attack (TIA) patients in a dedicated TIA clinic may reduce the 90-day stroke risk by 80%. ABCD2 (Age, Blood pressure, Clinical features, Duration, Diabetes) score and magnetic resonance imaging abnormalities help to identify patients at high risk of stroke. Our aim was to determine whether the use of transcranial Doppler (TCD) examination on arrival at the TIA clinic yields additional information that facilitates the identification of patients at high risk of stroke recurrence. Methods Between January 2003 and December 2007, 1,881 patients were admitted to SOS-TIA clinic (a TIA clinic with around-the-clock access). Clinical and vascular assessment included TCD performed by a neurologist immediately after admission. Stroke prevention measures were initiated on arrival, in accordance with guidelines. All patients were followed for 1 year after presentation to the SOS-TIA clinic. Results A total of 1,823 TCD examinations were performed within 4 hours of admission. Intracranial narrowing or occlusion was found in 8.8% of patients, and was independently associated with age, hypertension, and diabetes. After 1-year follow-up on best preventive therapy, the incidence of recurrent vascular events (intracranial revascularization for TIA recurrence, stroke, myocardial infarction, and vascular death combined) was 7.0% in patients with intracranial narrowing or occlusion and 2.4% in those without (log-rank, p = 0.007). The hazard ratio of combined outcome for the presence of intracranial narrowing or occlusion was 2.29 (95% confidence interval [CI], 1.15-4.56; p = 0.02) in multivariate analysis including age, gender, hypertension, and diabetes, and was 2.50 (95%CI, 1.24–5.05; p = 0.01) in multivariate analysis including ABCD2 score ≥4. Interpretation Immediate TCD examination on arrival at the TIA clinic is feasible and could help to identify patients at high risk of vascular events recurrence. This study supports a systematic intracranial vascular examination in the initial management of TIA. ANN NEUROL 2010;68:9–17

Objective Intracranial arterial dolichoectasia (IADE), also called dilatative arteriopathy of the brain, is defined as an increase in length and diameter of intracranial arteries. Abdominal aortic aneurysm and ectasia of coronary arteries have been reported in association with IADE. In both conditions, a dysfunction of matrix metalloproteinases (MMP)-2, -3, and -9 have been found. Our aim was to investigate these MMP pathways in stroke patients with IADE. Methods Five hundred ten Caucasians patients with brain infarction were consecutively recruited at 12 centers. The diagnosis of IADE was made by consensus between 2 neurologists based on magnetic resonance imaging scans. Determination of MMP-2, -3, and -9 plasma levels was centralized in 1 laboratory. Because we found a threshold effect of MMP-3 plasma levels with the risk of IADE, determination of the MMP-3 5A/6A polymorphism was carried out. Results IADE was identified in 12% of stroke patients. There was no association of IADE with mean MMP-2, -3, and -9 plasma levels. After categorization of MMP plasma levels into tertiles, we found a higher risk of IADE with the lowest MMP-3 tertile (adjusted odds ratio [OR], 2.48; 95% confidence interval [CI], 1.17–5.23). In genotype analysis, there was a significant additive effect of the 5A allele on the risk of IADE, with an adjusted OR of 1.62 (95% CI, 1.03–2.55). Interpretation In this cohort of stroke patients of Caucasian ancestry, IADE was associated with low MMP-3 plasma levels and with the 5A/6A polymorphism of the promoter region of MMP-3. These results suggest that MMP-3 may play a role in IADE. ANN NEUROL 2010;67:508–515

Summary Background The efficacy of intravenous (IV) alteplase is restricted by the speed of recanalisation and the site of the occlusion. The aim of this study was to ascertain the effect of a combined IV–endovascular approach (intra-arterial alteplase and, if required, additional thrombectomy) in patients with stroke due to arterial occlusion. Methods We compared recanalisation rates, neurological improvement at 24 h, and functional outcome at 3 months between two periods (February, 2002, to March, 2007, vs April, 2007, to October, 2008) in patients in a prospective registry who were treated with different regimens of alteplase within 3 h of symptom onset. Patients with confirmed occlusion who were treated before April, 2007, were treated with IV alteplase; after April, 2007, patients were treated with a systematic IV–endovascular approach. Analysis was by intention to treat. Findings 46 (87%) of 53 patients treated with the IV–endovascular approach achieved recanalisation versus 56 (52%) of 107 patients in the IV group (adjusted relative risk [RR] 1·49, 95% CI 1·21–1·84; p=0·0002). Early neurological improvement (NIHSS score of 0 or 1 or an improvement of 4 points or more at 24 h) occurred in 32 (60%) patients in the IV–endovascular group and 42 (39%) patients in the IV group (adjusted RR 1·36, 0·97–1·91; p=0·07). Favourable outcome (mRS of 0–2 at 90 days) occurred in 30 (57%) patients in the IV–endovascular group and 47 (44%) patients in the IV group (adjusted RR 1·16, 0·85–1·58; p=0·35). The mortality rate at 90 days was 17% in both groups, and symptomatic intracranial haemorrhage was reported in five (9%) patients in the IV–endovascular group and in 12 (11%) patients in the IV group. Better clinical outcome was associated with recanalisation in both groups and with time to recanalisation in the IV–endovascular group. Interpretation An IV–endovascular approach is associated with higher recanalisation rates than is IV alteplase in patients with stroke and confirmed arterial occlusion. In patients treated with an IV–endovascular approach, a shorter time from symptom onset to recanalisation is associated with better clinical outcomes. Funding SOS-ATTAQUE CEREBRALE.

Background and Purpose— Uncontrolled studies have shown that statins can improve cerebral vasoreactivity (CVR) in patients with mild small vessel disease. We sought to determine whether high-dose atorvastatin increases CVR compared with placebo in patients with severe small vessel disease. Methods— Ninety-four adults with recent lacunar stroke were randomly allocated in a double-blind manner to 80 mg of atorvastatin daily or matching placebo after stratification for hypertensive and diabetic status. The primary end point was change in CVR after 3 months of treatment. Secondary outcomes were changes in brachial and carotid artery endothelial-dependent vasodilations. Results— At baseline, all patients had a severely impaired CVR (mean, 12.1%; 95% CI, 9.5–14.7) and carotid (mean, −0.25%; 95% CI, −1.17–0.67) and brachial artery (mean, 2.72%; 95% CI, 1.39–4.05) endothelial function. Despite reductions of 55% in low-density lipoprotein cholesterol and of 30% in high-sensitivity C-reactive protein in the active arm compared to placebo, atorvastatin 80 mg per day did not improve CVR or endothelial dysfunction of carotid and brachial arteries. Conclusion— We found no positive effect of 3-month treatment with atorvastatin on severe cerebral microvasculature endothelial dysfunction in patients with lacunar stroke.

Objective The contribution of lipids to stroke risk remains uncertain; little attention has been paid to the effect of triglyceride levels, an emerging risk factor. Methods We performed two independent systematic PubMed literature searches for epidemiological studies that examined the association of triglyceride levels with stroke and carotid intima-media thickness (CIMT). Results We identified 31 studies on the relationship between triglyceride levels and stroke risk and 38 on triglyceride levels and CIMT. Although study designs varied widely, nine of the 17 prospective cohort studies ( n =140,788) and six of the 14 case-control studies ( n =3458 cases, 4089 controls) supported a positive association between elevated triglyceride levels and increased risk of stroke. Combining all available data from prospective studies ( n =9) produced a pooled relative risk of main stroke outcome per 1 standard-deviation increase of 1.10 (95% confidence interval, 1.07–1.13) without evidence of heterogeneity. One prospective study and one case-control study reported a negative relationship with haemorrhagic stroke. Of the 38 studies on CIMT ( n =43,161), 11 reported a significant correlation between CIMT and triglyceride levels, of which three were unadjusted, and one reported an inverse relationship. All of the three studies with longitudinal analysis, two of which were restricted to women, reported a positive association between baseline triglyceride levels and progression of CIMT. Conclusions The weight of evidence in prospective cohort studies favours a positive association between triglyceride levels and stroke, and supports the evaluation of triglyceride-lowering therapy to prevent stroke. However, this review shows the need for additional large prospective studies, especially in stroke subtypes, to establish firmly the independent detrimental effect of triglyceride levels in stroke risk.

Aim: To define reference values for mean common carotid artery intima-media thickness (CCAIMTmean) from subjects without conventional cardiovascular risk factors. Methods: This nationwide study involved cardiologists at 246 centres in France. A total of 5,433 subjects with and without conventional cardiovascular risk factors participated. Results: In subjects without risk factors, CCAIMTmean was 0.712 ± 0.122 mm in men and 0.682 ± 0.105 mm in women (p < 0.0001). Age explained 27.7% (men) and 33.9% (women) of the variance in CCAIMTmean. Each 10-year increment in age was associated with a sex-adjusted increase in CCAIMTmean of 0.049 mm. In subjects with 1 risk factor, CCAIMTmean was 0.765 ± 0.121 (p < 0.0001 vs. subjects without risk factors). CCAIMTmean increased continuously with increasing number of risk factors, irrespective of age group. In multivariable analysis, age, sex and number of cardiovascular risk factors appeared independently associated with CCAIMTmean. Conclusion: CCAIMTmean may help to identify the population at intermediate cardiovascular risk. As an integrator of both conventional and genetic cardiovascular risk factors at the individual level, its additive value versus other risk scores must be evaluated, particularly in patients in their fourth and sixth decades.

Background and Purpose— The clinical usefulness of noninvasive measurement of carotid intima media thickness and plaque visualization in the general population is still uncertain. Methods— We evaluated the age-specific incidence rates of cerebrovascular events in a cohort of 1348 subjects randomly taken from the census list of San Daniele Township and followed for a mean period of 12.7 years. The association among common carotid intima media thickness, measured at baseline, arterial risk factors, and incidence of ischemic cerebrovascular events was modeled using Poisson regression. The predictive ability of common carotid intima media thickness over arterial risk factors (summarized in the Framingham Stroke Risk Score) was evaluated by receiver operating characteristic curve analysis. Results— During the follow-up, 115 subjects developed nonfatal ischemic stroke, transient ischemic attack, or vascular death, which were the predefined study end points. After adjustment for age and sex, hypertension, diabetes, common carotid intima media thickness above 1 mm, and carotid plaques were all independent risk factors for development of vascular events. Inclusion of carotid findings (presence of common carotid intima media thickness above 1 mm or carotid plaques) resulted in a predictive power higher than Framingham Stroke Risk Score alone only on for those subjects with a Framingham Stroke Risk Score over 20%. Conclusions— Although common carotid intima media thickness and presence of carotid plaques are known to be risk factors for the development of vascular events and to be independent from the conventional risk factors summarized in the Framingham Stroke Risk Score, their contribution to individual risk prediction is limited. Further studies will be required to address the role of carotid ultrasonography in the primary prevention of high-risk subjects.

Background and purpose Epidemiological studies have found no relationship between total cholesterol and stroke risk, but little attention has been paid to high-density lipoprotein-cholesterol (HDL-C). Methods We performed a systematic PubMed literature search for epidemiological studies that examined the association between HDL-C level and stroke or carotid intima-media thickness (IMT). Results We identified 18 studies on the relationship between HDL-C and stroke risk and 37 on HDL-C and carotid IMT. Eight of ten prospective cohort studies ( n =238739) and three of eight case–control studies ( n =3604 cases, 8220 controls) supported an association between elevated HDL-C level and decreased risk of stroke. Prospective cohort studies reporting on relative risk per unit increase in HDL-C showed an 11–15% decreased stroke risk per 10-mg/dl increase in HDL-C. Of 37 studies on carotid IMT, 31 reported cross-sectional, one longitudinal, and five both cross-sectional and longitudinal associations between HDL-C level and carotid IMT. Of 36 cross-sectional studies ( n =51288), 20 showed an inverse association between HDL-C level and carotid IMT. Of six longitudinal studies ( n =20065), three showed no association, one showed a weak association in a subgroup of white women and two showed a significant inverse relationship between HDL-C level and carotid IMT. Pooled estimates could not be calculated because of the variation in study designs and analysis. Conclusions The weight of evidence in the literature supports an inverse association between HDL-C level and stroke or carotid atherosclerosis, but more data are needed to firmly establish this protective effect.

Objective This cross-sectional, population-based observational study using stratified multistage sampling assessed the prevalence of cardiovascular risk factors and carotid plaques and measured carotid intima-media thickness in individuals living in major cities in 7 Latin American countries. Patients and Methods The study comprised individuals (n=11,550) aged 25 to 64 years, living in Barquisimeto, Bogota, Buenos Aires, Lima, Mexico City, Quito, and Santiago. Data on anthropometric parameters, blood pressure, fasting glucose, total and high-density lipoprotein cholesterol, triglycerides, carotid intima-media thickness, carotid plaque, and smoking status were collected through household interviews and clinical, biochemical, and sonographic measurements. Results The overall prevalence rates (ranges across cities) were as follows: hypertension (≥140/90 mm Hg or pharmacologic treatment), 18% (9%-29%); hypercholesterolemia (total cholesterol ≥240 mg/dL), 14% (6%-20%); diabetes (glycemia≥126 mg/dL or self-reported diabetes), 7% (4%-9%); metabolic syndrome, 20% (14%-27%); obesity (body mass index ≥30 kg/m 2 ), 23% (18%-27%); smoking, 30% (22%-45%); and plaque, 8% (5%-14%). The mean intima-media thickness was 0.65 mm (0.60-0.74 mm). Conclusion The prevalence of hypertension mirrored the world average in 3 cities but was lower in the rest. Hypercholesterolemia was highly prevalent even in countries of different socioeconomic levels. The prevalence of diabetes was similar to that in the developed countries. Tobacco use in women living in Santiago and Buenos Aires was among the world's highest. Intima-media thickness and carotid plaque prevalences varied widely.

The PARC-AALA (Paroi arterielle et Risque Cardiovasculaire in Asia Africa/ Middle East and Latin America) study was designed to evaluate the correlation between intima-media thickness of the common carotid artery (CCAIMT), carotid plaque and absolute cardiovascular risk in a multi-ethnic population. An international, cross-sectional, study including 79 centres from 21 countries in Asia, Africa, the Middle East and Latin America. Two thousand three hundred and twenty-eight subjects, meeting all inclusion criteria, were stratified by risk factors groups (no modifiable factor or at least both uncontrolled hypertension and hypercholesterolemia). CCAIMT, presence of plaque and cardiovascular risk factors were assessed for each individual. Some intergeographical characteristics in demographics, and risk factors were found accompanying early atherosclerosis marker differences. In Asia where the subjects were at lower risk, the mean CCAIMT was 4% lower than in Africa/Middle East and Latin America. On multiple linear regression analysis CCAIMT and carotid plaque were independently associated with increased Framingham cardiovascular score (FCS) without heterogeneity across geographic regions. CCAIMT and carotid plaque explained roughly 20% of the FCS in both genders. The PARC-AALA study confirms the correlation between CCAIMT and FCS in three different populations. Intima-media thickness (IMT) and plaque evaluation may represent a complementary predictive tool for detection of cardiovascular disease in individuals.

Intima-media thickness (IMT) is increasingly used as a surrogate end point of vascular outcomes in clinical trials aimed at determining the success of interventions that lower risk factors for atherosclerosis and associated diseases (stroke, myocardial infarction and peripheral artery diseases). The necessity to promote further criteria to distinguish early atherosclerotic plaque formation from thickening of IMT and to standardize IMT measurements is expressed through this updated consensus. Plaque is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. Standard use of IMT measurements is based on physics, technical and disease-related principles as well as agreements on how to perform, interpret and document study results. Harmonization of carotid image acquisition and analysis is needed for the comparison of the IMT results obtained from epidemiological and interventional studies around the world. The consensus concludes that there is no need to ‘treat IMT values’ nor to monitor IMT values in individual patients apart from exceptions named, which emphasize that inside randomized clinical trials should be performed. Although IMT has been suggested to represent an important risk marker, according to the current evidence it does not fulfill the characteristics of an accepted risk factor. Standardized methods recommended in this consensus statement will foster homogenous data collection and analysis. This will help to improve the power of randomized clinical trials incorporating IMT measurements and to facilitate the merging of large databases for meta-analyses.

Background and Purpose— Carotid intima-media thickness (IMT) reflects generalized atherosclerosis and is predictive of future vascular events. Evidence exists that carotid IMT is heritable, and genetic studies can provide clues in the pathogenesis of atherosclerosis. Methods— We recruited 470 white ischemic stroke patients, measured common carotid artery (CCA) IMT, and analyzed 54 polymorphisms with suspected roles in atherosclerosis. Results— Among the polymorphisms tested, the angiotensin-converting enzyme insertion/deletion, osteopontin (OPN) T-443C, monocyte chemoattractant protein-1 (MCP-1) G-927C, and MCP-1 A-2578G polymorphisms were associated with CCA–IMT in age-gender–adjusted analysis. In multivariate analysis, the association between the OPN and MCP-1 polymorphisms remained significant. The OPN-443C allele was associated with increased IMT in the dominant model (0.053 mm for the TC and CC genotypes; P =0.001). The MCP-1-927C allele was associated with increased IMT in the additive model (0.040 mm for each C allele; P =0.001), and the MCP-1-2578 G allele was associated with decreased IMT in the recessive model (0.088 mm for the GG genotype; P =0.002). Conclusions— The OPN and MCP-1 genes, coding for 2 cytokines with known roles in atherosclerosis, may contribute to increased carotid IMT and warrant further study.

Background: Cerebral infarction (CI), myocardial infarction, peripheral artery disease (PAD) and aortic atheroma are the main clinical manifestations of atherothrombosis. Long-term prevention after CI of atherothrombotic origin may require preventive measures at other sites, such as specific drug therapies, surgery, or angioplasty. Therefore the detection of other locations is potentially important. Objectives: The primary objective was to describe the other locations of atherothrombosis in patients hospitalized for a recent cerebral infarct of atherothrombotic origin. Secondary objectives were to describe their vascular risk factor profiles, and their management before and after the cerebral event. Method: This prospective, observational, multicenter survey was conducted in France between September 2003 and July 2004, mainly in neurological departments and stroke units. Results: 753 patients were included (74% men; mean age 69.3 years). Previous coronary events had occurred in 119 (16%). Previous stroke or transient ischemic attacks had occurred in 233 (31%). PAD was already known in 109 (15%). A search for other atherothrombotic locations was positive in 216 patients (29%). The minimum prevalence for any associated atherothrombotic location (either present before or identified during hospitalization) was 47.5% for any location, 33.7% for coronary artery disease, 16.6% for aortic atheroma, and 22.7% for PAD. Conclusion: Fifty percent of the patients with recent atherothrombotic CI have other locations of atherothrombosis. For this reason, a systematic search for these other locations is recommended because of the possible therapeutic consequences. However, the question of the most appropriate period for this search after the cerebral event remains unsettled.

The authors describe the design and the general, ultrasonographic, neuropsychological methodology of an observational epidemiological population survey, named REMEMBER (Registry Evaluation Memory in Buttrio e Remanzacco) conducted in the northeast of Italy in a randomized stratified sample of 1,026 subjects (554 F and 472 M) aged 55–98 years. The study was planned as cross-sectional and longitudinal survey of cognitive impairment, cardiovascular risk factors, carotid atherosclerosis in a midlife and older Italian population sample. The objectives of the first phase are to assess the prevalence of the different types of dementia, the cognitive impairment non-dementia, the cardiovascular risk factors, the carotid intima-media thickness and arterial distensibility, and of depression. The conclusions of this study will make it possible to organize preventive and interventional strategies for these epidemic conditions.

Background: Increased carotid intima media thickness (CIMT) is frequently associated with established modifiable and non-modifiable cardiovascular risk factors, and is thought to be an independent predictor of ischemic cerebrovascular and cardiac events. The presence of carotid plaque is considered an established feature of atherosclerosis. There exist few longitudinal data on the predictive role of CIMT in the occurrence of carotid plaque. Methods: We restudied the survivors of a cohort of the San Daniele Project, a large randomized general population study, investigated in 1990 regarding the prevalence and determinants of carotid atherosclerosis. Using ultrasonography, we determined in 1,193 subjects (548 men and 645 women), the common carotid IMT and the presence of non-stenotic and stenotic plaque. Results: In 795 subjects without plaques or previous ischemic events at baseline, we found in multivariate analysis that CIMT ≧1 mm, age, hypertension and history of smoking are significant predictive elements of the occurrence of a new carotid plaque. The incremental probability of plaque occurrence is greater in midlife. CIMT and age are the most predictive risk factors with ORs of 3.66 (95% CI 1.4–9.4) and 3.02 (95% CI 2.4–3.7), respectively. The ORs for hypertension and smoking account for 1.5 (95% CI 1.1–3.4) and 1.7 (95% CI 1.1–2.8), respectively. Conclusions: Age, hypertension, history of smoking and B-mode detection of CIMT increases in subjects without carotid atherosclerosis and free of previous vascular events predict the occurrence of carotid atherosclerotic plaque.

Background: Little is known about the relationship between hypercholesterolaemia and specific aetiological subtypes of brain infarction (BI). Methods: In a cross-sectional study of 492 pairs of patients with a BI proven by MRI and matched hospital controls, we determined the blood levels of triglycerides, total, HDL and LDL cholesterol, and apolipoprotein A1 and B, in the same centralized laboratory. We performed aetiological BI subtype classification. Results: Except for triglycerides, the risk of BI increased continuously with the lipid levels, without any heterogeneity between the main BI subtypes or the group on lipid-lowering therapy. The adjusted odds ratio per standard deviation in LDL cholesterol (0.93 mmol/l) was 1.74 (95% confidence interval, 1.02–2.98) in atherothrombotic strokes (n = 109) and 2.71 (95% confidence interval, 1.60–4.55) in lacunar strokes (n = 105). Eighty percent of patients were above the ATP-III guideline threshold LDL cholesterol of 2.59 mmol/l (100 mg/dl), with a major contribution of both atherothrombotic and lacunar stroke subtypes to this group. Conclusions: These findings suggest that blood lipids, particularly total and LDL cholesterol levels, are associated with all subtypes of BI, and that LDL above 2.59 mmol/l is highly prevalent.

Summary The risk of stroke increases with age, and hence the disease particularly affects the elderly, who are also at high risk for coronary heart disease. Epidemiological and observational studies have not shown a clear association between cholesterol concentrations and all causes of stroke. Large, long-term statin trials in patients with established or high risk for coronary heart disease have shown that statins decrease stroke incidence. These statin trials in a combined total of 70 020 patients indicate relative and absolute risk reductions for stroke of 21% and 0·9%, respectively. By comparison, the number of strokes prevented per 1000 patients treated for 5 years in patients with coronary heart disease is nine for statins versus 17·3 for antiplatelet drugs and 17 for antihypertensive drugs. Although the Heart Protection Study showed that statins lower the risk of major coronary events in patients with a previous stroke, statins may not lower stroke recurrence in these patients. In this review, we discuss the potential reasons for the effects of statins on stroke and the mechanisms of action. Treatment strategies on the basis of global cardiovascular risk may be most effective. Additional studies in patients representative of the typical stroke population are needed.

Background — In the last decades, interest has increased in the potential deleterious atherogenic effects of some cellular elastase activities. The results of experimental and clinical investigations were inconsistent. In this report, we assessed the associations of serum elastase activity and serum elastase inhibitors with carotid plaque occurrence during the 4-year follow-up in a population of 859 subjects free of coronary heart disease and stroke (age, 59 to 71 years). Methods and Results — Serum elastase activity and serum elastase inhibitors were measured at baseline examination. Carotid B-mode ultrasound examination was performed at baseline and 2 years and 4 years later. The occurrence of carotid plaques in subjects with the lowest serum elastase activity values (quartile 1), in those with the intermediate values (quartiles 2 to 3), and in those with the highest values (quartile 4) was, respectively, 24.6%, 18.9%, and 12.2% ( P P P P for trendP P Conclusions — Low values of serum elastase activity and high values of serum elastase inhibitors were strongly and independently associated with increased 4-year carotid plaque occurrence. Further studies are necessary to elucidate the nature of the associations between elastase parameters and atherosclerosis.

Hormone replacement therapy (HRT) may reduce atherosclerosis among postmenopausal women, partly by reducing vascular endothelium damage. We have tested this hypothesis by evaluating the association of HRT with firstly, carotid intima media thickness (IMT) and plaques, and secondly, with endothelial cell damage, indicated by soluble thrombomodulin (sTM). Then, we tested the association between the two markers of atherosclerosis and the levels of sTM. Among 747 postmenopausal women included into the EVA study, we compared 154 HRT users (including 80% transdermal treatment) with 593 never users. Carotid IMT and plaques were measured with B-mode ultrasonography and sTM with ELISA. At least one plaque was detected among 13.6% of HRT users and 27.3% of never users. After adjustment for confounding factors, the odds ratio for the presence of plaque was 0.45 (95% confidence interval, 0.25-0.78, P=0.005) in HRT users in comparison with nonusers. HRT users had a slightly lower crude mean IMT than nonusers, but the difference was not significant. sTM was positively associated with mean IMT (P for trend=0.001) but not with plaques. Finally, estrogen users had a lower sTM level than nonusers (difference 0.14 ng/ml, P=0.03). As HRT was associated with sTM and plaques, but not with IMT, while sTM was only associated with IMT, our hypothesis was not confirmed. This suggests that the possible beneficial effects of HRT on atherosclerosis may not go through the endothelial cell damage assessed by plasma thrombomodulin.

Carotid intima-media thickness (CIMT) is a validated predictive marker of increased plaque occurrence and the incidence of major cardiovascular events. However, due to technical issues associated with the measurement of CIMT, a well-trained and certified sonographer is needed to overcome causes of variability due to the patient, device, sonographer, and quantification tool. The recently updated Mannheim consensus defined and described how to differentiate CIMT from plaques. These definitions allow for the better analysis and quantification of early atherosclerosis. Indications for CIMT measurements largely include the detection of coronary heart disease risk among intermediate-risk patients. CIMT is frequently used in clinical trials, and recent technical recommendations have been provided to improve the quality of the procedures. The final choice of a CIMT protocol depends on the purpose of the measurement, the research question at hand, the cost effectiveness, the quality of the data and the added value provided by the additional information.

Carotid intima-media thickness (CIMT) is a validated predictive marker of increased plaque occurrence and the incidence of major cardiovascular events. However, due to technical issues associated with the measurement of CIMT, a well-trained and certified sonographer is needed to overcome causes of variability due to the patient, device, sonographer, and quantification tool. The recently updated Mannheim consensus defined and described how to differentiate CIMT from plaques. These definitions allow for the better analysis and quantification of early atherosclerosis. Indications for CIMT measurements largely include the detection of coronary heart disease risk among intermediate-risk patients. CIMT is frequently used in clinical trials, and recent technical recommendations have been provided to improve the quality of the procedures. The final choice of a CIMT protocol depends on the purpose of the measurement, the research question at hand, the cost effectiveness, the quality of the data and the added value provided by the additional information.

Background and Purpose —Patent foramen ovale (PFO) is a frequent finding in young patients with stroke. The aim of this study was to assess whether PFO is a family trait. Methods —Sixty-two consecutive patients younger than 60 years of age with ischemic stroke and 62 age and gender-matched control siblings were examined by means of contrast transcranial Doppler (TCD) of the middle cerebral artery, using a standardized protocol. The reliability of TCD examination in our laboratory was assessed against transesophageal echocardiography (TEE). All TCD recordings were reviewed by a blinded experienced observer from another center. Disagreements between readers were resolved by unblinded consensus review. Results —Siblings of patients with PFO had a significantly higher prevalence of PFO than had siblings of patients without PFO (61.5% versus 30.6%; OR 3.64 [1.3 to 10.5]; P =0.015). The κ statistics indicated that agreement of pairs (patients/control siblings) was not due to chance. The strength of the association was sex dependent. In women pairs, prevalence of a PFO was 76.5% in siblings of patients with PFO and 25% in siblings of patients without PFO, giving an OR of 9.8 (95% CI 2 to 47.9; P P =0.9). Conclusions —This study suggests that, in women, PFO is a family trait.

Cerebral blood flow velocity (CBF-V) measured by transcranial doppler was assessed in 628 elderly individuals who had cerebral magnetic resonance imaging performed as part of a population-based study on vascular aging. Cerebral white matter hyperintensities (WMHs) were associated with low CBF-V, such as the adjusted odds ratios of severe WMHs from highest (referent) to lowest quartile of mean CBF-V were 1.0, 1.7, 3.7, and 4.3 (p = 0.001). Further, CBF-V was found to be a stronger risk factor for WMHs than high blood pressure. These findings suggest that the assessment of CBF-V might be a powerful tool in future studies on WMHs.

Abstract —The role of the increase in the common carotid artery (CCA) intima-media wall thickness (IMT) in the atherosclerotic process is questionable. This longitudinal study examined the predictive value of CCA-IMT measured at baseline examination (at sites free of plaques) on the occurrence of atherosclerotic plaques in the extracranial carotid arteries during 4 years of follow-up study in a sample of 1010 subjects aged 59 to 71 years. Ultrasound examinations were performed at baseline and 2 years and 4 years later. The occurrence of carotid plaques during follow-up was defined as the appearance of ≥1 plaque in previously normal carotid segments and/or the appearance of new plaques in the carotid segments that previously had plaques. Carotid plaque occurrence was observed in 185 subjects (18.3%). Age- and sex- adjusted odds ratios of carotid plaque occurrence were 2.66 (95% CI 1.58 to 4.46, P P

Middle cerebral artery (MCA) atherosclerosis is currently diagnosed by indirect angiographic methods. The authors used high-resolution MRI (HR-MRI) to study MCA stenosis in six patients. At the level of stenosis, an MCA plaque was clearly delineated and significantly measured vs nonatherosclerotic MCA segments, showing that HR-MRI is an accurate direct imaging method.

There are few epidemiologic studies of the effects of lipid peroxidation and antioxidant status on atherosclerosis. The relation of lipid peroxidation evaluated by thiobarbituric acid-reactive substances (TBARS) and biological markers of antioxidant status to ultrasonographically assessed carotid atherosclerosis was examined from baseline data of a longitudinal study on cognitive and vascular aging (Etude sur le Vieillisement Artériel, the EVA Study). The study sample was composed of 1187 mean and women aged 59-71 y without any history of coronary artery disease or stroke. Ultrasound examination included measurements of intima-media thickness (IMT) on the common carotid arteries (CCAs) and at the site of plaques. After adjustment for conventional cardiovascular risk factors, erythrocyte vitamin E was significantly and negatively associated with CCA-IMT in both men and women whereas plasma selenium and carotenoids were not. No association was found between TBARS and CCA-IMT in either sex. However, TBARS were significantly higher in men with carotid plaques than in those without. This association was strengthened in men with concentrations of erythrocyte vitamin E, plasma selenium, and carotenoids below the lowest quartile. Our findings give some epidemiologic support to the hypothesis that lipid peroxidation and low antioxidant status are involved in the early phases of atherosclerosis.