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Background and Purpose— To test the hypothesis that covert brain infarcts (CBIs) are more likely to be located in noneloquent brain areas compared with clinical strokes and that CBI etiological subtypes carry a differential risk of vascular events compared with people without CBI. Methods— We used brain magnetic resonance imaging from 1290 stroke-free participants in the NOMAS (Northern Manhattan Study) to evaluate for CBI. We classified CBI as cardioembolic (ie, known atrial fibrillation), large artery atherosclerosis (extracranial and intracranial), penetrating artery disease, and cryptogenic (no apparent cause). CBI localized in the nonmotor areas of the right hemisphere were considered noneloquent. We then evaluated risk of events by CBI subtype with adjusted Cox proportional models. Results— At the time of magnetic resonance imaging, 236 participants (18%) had CBI (144 [61%] distal cryptogenic, 29 [12%] distal cardioembolic, 26 [11%] large artery atherosclerosis, and 37 [16%] penetrating artery disease). Smaller (per mm, odds ratio, 0.8 [0.8–0.9]) and nonbrain stem infarcts (odds ratio, 0.2 [0.1–0.6]) were more likely to be covert. During the follow-up period (10.4±3.1 years), 398 (31%) died (162 [13%] of vascular death) and 117 (9%) had a stroke (99 [85%]) were ischemic. Risks of events varied by CBI subtype, with the highest risk of stroke (hazard ratio, 2.2 [1.3–3.7]) and vascular death (hazard ratio, 2.24 [1.29–3.88]) noted in participants with intracranial large artery atherosclerosis-related CBI. Conclusions— CBI can be classified into subtypes that have differential outcomes. Certain CBI subtypes such as those related to intracranial large artery atherosclerosis have a high risk of adverse vascular outcomes and could warrant consideration of treatment trials.

Introduction: Prolonged cardiac monitoring after cryptogenic stroke reveals a cardiac cause in up to 30% of patients; however, practice patterns for monitoring vary widely. We sought to evaluate overall and race/ethnic trends in the rate of ECG monitoring and types of cardiac monitoring performed after ischemic stroke and transient ischemic attack (TIA) across a network of hospitals in Florida and Puerto Rico(PR). Methods: We identified 46,878 ischemic stroke and TIA cases with data on ECG monitoring in the Florida Stroke Registry from 2016-18. Univariate analysis was performed to determine the overall rate of ECG monitoring and the characteristics of patients who received cardiac surface monitoring ≤7days and >7days, and implantable cardiac monitoring. Multivariate logistic regression was performed to identify factors associated with the types of monitoring. Results: Overall, 39,333 (84%) patients admitted for stroke/TIA received ECG monitoring during hospital admission (mean age 71±14 years; 49% female; 63% white, 18% black, 15% FL-Hispanic, 4% PR-Hispanic). Compared to patients who received ECG monitoring, patients who did not were more likely to be younger (mean age 70±15 years), PR-Hispanic (24% vs 4.3%), and have TIA (13% vs 8%), Medicare (42% vs 35%), large vessel disease (14% vs 9%) and greater admission NIHSS (median score 5 vs 4). After adjustment, smokers and patients >80years were less likely to receive ECG monitoring overall (OR 0.95, 95% CI 0.9-0.99 for both). Black race was associated with receiving extended surface monitoring >7 days (OR 1.15, 95%CI 1.04-1.26), but negatively associated with implantable cardiac monitoring (OR 0.81, 95%CI 0.68-0.96). Patients with moderate/severe stroke had higher odds of extended surface monitoring >7days (OR 2.29, 95%CI 1.89-2.77), yet lower odds of implantable cardiac monitoring (OR 0.80, 95%CI 0.71-0.89). Conclusion: The majority of patients received ECG monitoring during hospital admission for stroke/TIA; however, significant differences were found with respect to age, race/ethnicity and stroke severity across the various types and duration of cardiac monitoring. Further research is needed to understand and address the underlying drivers of these differences.

Background and Purpose- To test the hypothesis that covert brain infarcts (CBIs) are more likely to be located in noneloquent brain areas compared with clinical strokes and that CBI etiological subtypes carry a differential risk of vascular events compared with people without CBI. Methods- We used brain magnetic resonance imaging from 1290 stroke-free participants in the NOMAS (Northern Manhattan Study) to evaluate for CBI. We classified CBI as cardioembolic (ie, known atrial fibrillation), large artery atherosclerosis (extracranial and intracranial), penetrating artery disease, and cryptogenic (no apparent cause). CBI localized in the nonmotor areas of the right hemisphere were considered noneloquent. We then evaluated risk of events by CBI subtype with adjusted Cox proportional models. Results- At the time of magnetic resonance imaging, 236 participants (18%) had CBI (144 [61%] distal cryptogenic, 29 [12%] distal cardioembolic, 26 [11%] large artery atherosclerosis, and 37 [16%] penetrating artery disease). Smaller (per mm, odds ratio, 0.8 [0.8-0.9]) and nonbrain stem infarcts (odds ratio, 0.2 [0.1-0.6]) were more likely to be covert. During the follow-up period (10.4±3.1 years), 398 (31%) died (162 [13%] of vascular death) and 117 (9%) had a stroke (99 [85%]) were ischemic. Risks of events varied by CBI subtype, with the highest risk of stroke (hazard ratio, 2.2 [1.3-3.7]) and vascular death (hazard ratio, 2.24 [1.29-3.88]) noted in participants with intracranial large artery atherosclerosis-related CBI. Conclusions- CBI can be classified into subtypes that have differential outcomes. Certain CBI subtypes such as those related to intracranial large artery atherosclerosis have a high risk of adverse vascular outcomes and could warrant consideration of treatment trials.

Background: Oral anticoagulants (OACs) for stroke prevention in atrial fibrillation (AF) are largely underutilized. We identified pre-admission OAC utilization patterns and factors predictive of OAC non-use in patients hospitalized for AF-related stroke. Methods: We included 22,220 patients with ischemic stroke due to previously diagnosed AF enrolled in the Florida Stroke Registry from 2010-2017. A multivariable-adjusted logistic regression model was used to identify factors associated with pre-stroke OAC use for patients with AF-related stroke. Results: A total of 16,246 (73%) patients with AF-related stroke were not on OAC pre-stroke. Compared to patients on OAC, non-OAC patients were more likely to be ≥80 years old, have Medicaid/no insurance, lower CHA 2 DS 2 -VASc scores and greater stroke severity at presentation. After adjustment for age, sex, race-ethnicity, insurance status and vascular risk factors, baseline OAC non-use was higher for patients with Medicaid/no insurance (vs. private insurance, (OR 1.34 [95% CI 1.08-1.67]), smokers (OR 1.29 [1.09-1.52] and patients with NIHSS ≥6 (vs. NIHSS≤5, OR 1.18 [1.11-1.26]). A trend towards greater odds of OAC non-use was seen in women (vs. men, OR 1.07 [0.99-1.14, P=0.07]). Conclusion: The majority of AF-related stroke patients with known AF were not anticoagulated prior to hospitalization for stroke in our study. Insurance status and smoking status had the greatest influence on pre-stroke OAC use. Anticoagulated patients had lower stroke severity on admission. Further efforts are needed to increase OAC use to reduce the burden of stroke for patients with AF, especially for vulnerable populations.

Background: Individuals with stroke due to high-degree intracranial stenosis (i.e. > 70% by WASID criteria have a high 1-year risk of stroke recurrence. Whether high-degree intracranial stenosis in stroke-free individuals increases the risk of vascular events is less certain. We hypothesized that high-degree intracranial stenosis in stroke-free individuals is associated with risk of death and vascular events. Methods: Participants in the population-based Northern Manhattan Study (NOMAS) with available time-of-flight MRA were included in this study. We rated intracranial stenosis using WASID criteria and defined high-degree intracranial stenosis if the lumen was reduced by > 70% in the anterior, middle, or posterior cerebral arteries or in the basilar, vertebral or intracranial carotid arteries. Death and vascular events were prospectively ascertained, blinded to stenosis status. Stroke outcomes were subtypes according to the Trial of Organon in Acute Stroke Trial (TOAST) criteria. Results: We included 1,206 NOMAS participants (mean age 70.6±9 years, 60.5% women, 65.7% Hispanic). The participants were followed for an average of 10.4 years (IQR 9.5-12.6). The prevalence of high-degree intracranial stenosis was 3.5% (74% isolated anterior circulation, 21% isolated posterior circulation, and 5% anterior and posterior circulation). In univariate analysis, high-degree intracranial stenosis was associated with older age (P=0.003), hypertension (P=0.02) and diabetes (0.02). The risk of vascular death and stroke was higher among stroke-free individuals with high-degree intracranial stenosis (table), and in particular with strokes due to large artery atherosclerosis. Conclusions: Evidence of high-degree intracranial stenosis among stroke-free individuals identifies those at risk of vascular events and may be used to select individuals for testing aggressive measures to reduce vascular risks.

Background and Purpose— Electrocardiographic left atrial abnormality has been associated with stroke independently of atrial fibrillation (AF), suggesting that atrial thromboembolism may occur in the absence of AF. If true, we would expect an association with cryptogenic or cardioembolic stroke rather than noncardioembolic stroke. Methods— We conducted a case-cohort analysis in the Northern Manhattan Study, a prospective cohort study of stroke risk factors. P-wave terminal force in lead V 1 was manually measured from baseline ECGs of participants in sinus rhythm who subsequently had ischemic stroke (n=241) and a randomly selected subcohort without stroke (n=798). Weighted Cox proportional hazard models were used to examine the association between P-wave terminal force in lead V 1 and stroke etiologic subtypes while adjusting for baseline demographic characteristics, history of AF, heart failure, diabetes mellitus, hypertension, tobacco use, and lipid levels. Results— Mean P-wave terminal force in lead V 1 was 4452 (±3368) μV*ms among stroke cases and 3934 (±2541) μV*ms in the subcohort. P-wave terminal force in lead V 1 was associated with ischemic stroke (adjusted hazard ratio per SD, 1.20; 95% confidence interval, 1.03–1.39) and the composite of cryptogenic or cardioembolic stroke (adjusted hazard ratio per SD, 1.31; 95% confidence interval, 1.08–1.58). There was no definite association with noncardioembolic stroke subtypes (adjusted hazard ratio per SD, 1.14; 95% confidence interval, 0.92–1.40). Results were similar after excluding participants with a history of AF at baseline or new AF during follow-up. Conclusions— ECG-defined left atrial abnormality was associated with incident cryptogenic or cardioembolic stroke independently of the presence of AF, suggesting atrial thromboembolism may occur without recognized AF.

Background and Purpose— Interventional Management of Stroke (IMS) III is a randomized, parallel arm trial comparing the approach of intravenous tissue-type plasminogen activator followed by endovascular treatment with intravenous tissue-type plasminogen activator alone in patients with acute ischemic stroke presenting Methods— Conditional power was defined as the likelihood of finding statistical significance at the end of the study, given the accumulated data to date and with the assumption that a minimum hypothesized difference of 10% truly exists between the 2 groups. The evolution of study data leading to futility determination is described, including the interaction between the unblinded study statisticians and the Data and Safety Monitoring Board in the complex deliberation of analysis results. Results— The futility boundary was crossed at the trial’s fourth interim analysis. At this point, based on the conditional power criteria, the Data and Safety Monitoring Board recommended termination of the trial. Conclusions— Even in spite of prespecified interim analysis boundaries, interim looks at data pose challenges in interpretation and decision making, underscoring the importance of objective stopping criteria. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00359424.

In their interesting letter, Chen et al point out that there was no placebo arm in the WARCEF trial (Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction), preventing an estimation of stroke incidence without antithrombotic treatment and, therefore, of the benefit, if any, of such treatment for stroke prevention. Although this is true, it should be noted that some antithrombotic treatment is usually prescribed to patients with systolic heart failure, whether because of a previous myocardial infarction, and therefore the need of antiplatelet treatment for secondary prevention, or of past episodes of atrial fibrillation, which are frequent in heart failure and mandate systemic anticoagulation. Also, heart failure is associated with blood hypercoagulability,1,2 and an ischemic, possibly embolic, mechanism is involved in the majority of strokes observed in patients with systolic heart failure,2 …

Background and Purpose— Patent foramen ovale (PFO) and cryptogenic stroke are commonly associated but some PFOs are incidental. Specific radiological findings associated with PFO may be more likely to indicate a PFO-related cause. We examined whether specific radiological findings are associated with PFO among subjects with cryptogenic stroke and known PFO status. Methods— We analyzed the Risk of Paradoxical Embolism(RoPE) Study database of subjects with cryptogenic stroke and known PFO status, for associations between PFO and: (1) index stroke seen on imaging, (2) index stroke size, (3) index stroke location, (4) multiple index strokes, and (5) prior stroke on baseline imaging. We also compared imaging with purported high-risk echocardiographic features. Results— Subjects (N=2680) were significantly more likely to have a PFO if their index stroke was large (odds ratio [OR], 1.36; P =0.0025), seen on index imaging (OR, 1.53; P =0.003), and superficially located (OR, 1.54; P P P =0.161). No echocardiographic variables were related to PFO status. Conclusions— This is the largest study to report the radiological characteristics of patients with cryptogenic stroke and known PFO status. Strokes that were large, radiologically apparent, superficially located, or unassociated with prior radiological infarcts were more likely to be PFO-associated than were unapparent, smaller, or deep strokes, and those accompanied by chronic infarcts. There was no association between PFO and multiple acute strokes nor between specific echocardiographic PFO features with neuroimaging findings.

Background and Purpose— In heart failure (HF), left ventricular ejection fraction (LVEF) is inversely associated with mortality and cardiovascular outcomes. Its relationship with stroke is controversial, as is the effect of antithrombotic treatment. We studied the relationship of LVEF with stroke and cardiovascular events in patients with HF and the effect of different antithrombotic treatments. Methods— In the Warfarin Versus Aspirin in Reduced Ejection Fraction (WARCEF) trial, 2305 patients with systolic HF (LVEF≤35%) and sinus rhythm were randomized to warfarin or aspirin and followed for 3.5±1.8 years. Although no differences between treatments were observed on primary outcome (death, stroke, or intracerebral hemorrhage), warfarin decreased the stroke risk. The present report compares the incidence of stroke and cardiovascular events across different LVEF and treatment subgroups. Results— Baseline LVEF was inversely and linearly associated with primary outcome, mortality and its components (sudden and cardiovascular death), and HF hospitalization, but not myocardial infarction. A relationship with stroke was only observed for LVEF of P =0.009), which more than doubled the adjusted stroke risk (adjusted hazard ratio, 2.125; 95% CI, 1.182–3.818; P =0.012). In warfarin-treated patients, each 5% LVEF decrement significantly increased the stroke risk (adjusted hazard ratio, 1.346; 95% CI, 1.044–1.737; P =0.022; P value for interaction=0.04). Conclusions— In patients with systolic HF and sinus rhythm, LVEF is inversely associated with death and its components, whereas an association with stroke exists for very low LVEF values. An interaction with warfarin treatment on stroke risk may exist. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00041938.

Background: Increased P-wave terminal force in lead V1 (PTFV1) of a standard 12-lead electrocardiogram (EKG), a marker of left atrial dilatation and possibly fibrosis, has been associated with stroke risk in the absence of atrial fibrillation (AF), and with subclinical infarcts in some cohorts. We hypothesized that PTFV1 would be associated with an increased prevalence of subclinical infarcts, especially cortical ones, and leukoaraiosis in a population-based, multi-ethnic cohort. Methods: PTFV1 was collected manually from baseline EKGs of participants in the population-based, prospective Northern Manhattan Study (NOMAS) who had remained clinically stroke-free and undergone brain MRI (n=1,290). MRIs were read for superficial and deep infarcts and white matter hyperintensity volume adjusted for head size (WMHV). Logistic regression models were used for the association of PTFV1 with all subclinical infarcts and with cortical infarcts, and linear regression models with logWMHV. Models were adjusted for demographics and risk factors. Results: Among the 1174 participants with PTFV1, mean age was 70 + 9 SD years at the time of MRI, 40.3% were male, and 14.4% were white, 17.6% black, and 65.8% Hispanic. Hypertension was present in 68.0%. Mean PTFV1 was 3587.35 ± 2315.62 μV-ms. MRIs were performed a mean of 6.0 + 3.4 years after EKG. Subclinical infarcts were present in 170 (15.1%) participants, and were cortical in 40 (3.6%). PTFV1 >5000 μV-ms was associated with greater WMHV even after adjusting for demographics and risk factors, including baseline AF (mean difference in logWMHV 0.14, 95% CL 0.01-0.28). There was a trend toward an association of PTFV1 with cortical (unadjusted OR per SD change logPTFV1 1.30, 95% CI 0.94-1.81) but not with all subclinical infarcts (unadjusted OR 1.00, 95% CI 0.85-1.18). Conclusion: EKG evidence of left atrial abnormality was associated with leukoaraiosis, and possibly with subclinical cortical infarcts, though the limited number of outcomes did not permit us to confirm this finding. Left atrial cardiopathy may be a source of emboli, but may also cause cerebral hypoperfusion-related injury. Further studies in large cohorts are needed to determine the relationship of PTFV1 to risk of subclinical cerebrovascular disease.

Background: While left atrial (LA) enlargement increases incident stroke risk, the association with recurrent stroke is unclear. Our aim was to determine the association of LA enlargement (LAE) with stroke recurrence risk and recurrent stroke subtypes likely related to embolism (cryptogenic or cardioembolic). Methods: We enrolled 655 first ischemic stroke patients in the Northern Manhattan Stroke Study. LA size was measured by two-dimensional echocardiogram as part of the clinical evaluation and patients were followed annually for up to 5 years. LA size adjusted for sex and body surface area was categorized into three groups: normal (52.7%), mild LAE (31.6%), and moderate to severe LAE (15.7%). The outcomes were total recurrent stroke, and recurrent combined cryptogenic or cardioembolic stroke. Cox proportional hazard models assessed the association between LA size and risk of stroke recurrence. Results: Of 655 patients, LA size data was present in 529 (81%). Mean age was 69 ± 13 years; 46% were male and 18% had atrial fibrillation. Over a median of 4 years, recurrent stroke occurred in 83 patients (16%), 29 were cardioembolic or cryptogenic stroke. After adjusting for baseline demographics and risk factors including atrial fibrillation and congestive heart failure, compared to normal LA size, moderate to severe LAE was associated with greater risk of recurrent combined cardioembolic or cryptogenic stroke (adjusted HR 2. 99, 95% CI 1. 10 to 8.13), but not with risk of total stroke recurrence (adjusted HR 1.18, 95% CI 0.60 to 2.32). Mild LAE was not associated with either total stroke recurrence or the combined recurrent cryptogenic or cardioembolic stroke subtypes. Conclusion: Moderate to severe LAE is an independent marker of recurrent cardioembolic or cryptogenic stroke in a multiethnic cohort of ischemic stroke patients. Future research is needed to determine if anticoagulant use reduces the risk of recurrence in ischemic stroke patients with moderate to severe LAE.

Background and Purpose— Although left atrial enlargement (LAE) increases incident stroke risk, the association with recurrent stroke is less clear. Our aim was to determine the association of LAE with recurrent stroke most likely related to embolism (cryptogenic and cardioembolic) and all ischemic stroke recurrences. Methods— We followed 655 first ischemic stroke patients in the Northern Manhattan Stroke Study for ≤5 years. LA size from 2D echocardiography was categorized as normal LAE (52.7%), mild LAE (31.6%), and moderate–severe LAE (15.7%). We used Cox proportional hazard models to calculate the hazard ratios and 95% confidence intervals for the association of LA size and LAE with recurrent cryptogenic/cardioembolic and total recurrent ischemic stroke. Results— LA size was available in 529 (81%) patients. Mean age at enrollment was 69±13 years; 45.8% were male, 54.0% Hispanic, and 18.5% had atrial fibrillation. Over a median of 4 years, there were 65 recurrent ischemic strokes (29 were cardioembolic or cryptogenic). In multivariable models adjusted for confounders, including atrial fibrillation and heart failure, moderate–severe LAE compared with normal LA size was associated with greater risk of recurrent cardioembolic/cryptogenic stroke (adjusted hazard ratio 2.83, 95% confidence interval 1.03–7.81), but not total ischemic stroke (adjusted hazard ratio 1.06, 95% confidence interval, 0.48–2.30). Mild LAE was not associated with recurrent stroke. Conclusion— Moderate to severe LAE was an independent marker of recurrent cardioembolic or cryptogenic stroke in a multiethnic cohort of ischemic stroke patients. Further research is needed to determine whether anticoagulant use may reduce risk of recurrence in ischemic stroke patients with moderate to severe LAE.

Background and Purpose— Stroke remains a substantial cause of mortality and morbidity in the United States. Racial differences in stroke incidence and mortality persist with well-known excesses among blacks. Information on stroke among Hispanics is limited. In particular, little is known about whether patent foramen ovale (PFO), atrial septal aneurysm (ASA), and other atrial anomalies associated with cryptogenic stroke differ among minority populations. Methods— As a part of the PFO in Cryptogenic Stroke Study, transesophageal echocardiography was performed in a cohort of 630 ischemic stroke patients (mean age, 59±12 years; 44% women; 45% whites, 35% blacks, 17% Hispanics, 3% other). The prevalences of PFO, ASA, and right atrial (RA) anatomy favoring paradoxical embolization were compared among race-ethnic groups. Statistical analyses used analysis of variance for continuous variables and logistic regression for dichotomous variables with adjustments for age and sex. Results— Age- and sex-adjusted prevalences of PFO and ASA were similar across race-ethnic subgroups. However, large PFO was significantly less prevalent among blacks than among whites (odds ratio, 0.47; 95% confidence interval, 0.24 to 0.91; P =0.02). RA anatomy favoring paradoxical embolization was also significantly less prevalent among blacks compared with whites (odds ratio, 0.62; 95% confidence interval, 0.43 to 0.91; P =0.01). There were no significant differences in prevalence between whites and Hispanics. Conclusions— Although the frequency of PFO did not vary among race-ethnic groups, a large PFO and RA anatomy favoring paradoxical embolization were significantly more prevalent among whites and Hispanics compared with blacks. These may be relatively more important risk factors for stroke among whites and Hispanics than among blacks.

Background and Purpose— Leukocyte count has been associated with cardiovascular and cerebrovascular disease, including carotid plaque thickness, in several studies. We hypothesized that white blood cell count is associated with aortic arch plaque thickness (AAPT). Methods— Leukocyte count was measured in randomly selected stroke-free community participants undergoing transesophageal echocardiography. AAPT was measured for each subject and dichotomized into Results— Mean leukocyte count was 5.88±1.76×10 9 /L. Each unit increase in leukocyte count was associated with a mean 0.28-mm increase in AAPT ( P =0.0036). After adjustment for other atherosclerosis risk factors, including age, sex, hypertension, diabetes, hyperlipidemia, and smoking, the relationship persisted (mean increase in AAPT, 0.24 mm; P =0.0064). Thirty-five participants (24.1%) had AAPT ≥4 mm. Mean leukocyte count among those with thick plaque was significantly higher than among those with plaque 9 /L, respectively; P =0.009). Each unit increase in leukocyte count was associated with an increased risk of thick plaque (adjusted odds ratio, 1.38; 95% CI, 1.05 to 1.79). The relationships were similar for men and women and for those Conclusions— Leukocyte count is associated with AAPT and is specifically correlated with AAPT ≥4 mm, a degree of thickening associated with increased stroke risk. These findings are consistent with current hypotheses regarding the inflammatory or infectious etiology of risk of atherosclerosis and stroke.

Background and Purpose —Aortic arch atheromas (AAs) have been shown to be a risk factor for ischemic stroke (IS) in the elderly because of their potential for cerebral embolization. However, the association between AAs and the presence of cerebral microemboli has not been clearly established. The aim of this study was to determine whether large AAs are associated with an increased frequency of high-intensity transient signals (HITS) in elderly patients with IS. Methods —We performed bitemporal simultaneous HITS monitoring of both middle cerebral arteries in 62 consecutive elderly patients with acute IS (mean age 72.5±8.8 years, 65% men). In 16 patients, one or both temporal windows were inadequate; therefore, the analysis of HITS was performed in the remaining 46 patients. All patients underwent omniplane transesophageal echocardiography (TEE), and they had no significant extracranial or intracranial artery disease and no cardiac prosthetic valves. Large AA was defined as ≥4 mm in thickness. Complex AA was defined as ulcerated or mobile, regardless of plaque thickness. HITS monitoring was performed within 24 hours of TEE and analyzed by an experienced neurologist-sonographer blinded to TEE findings. A 9-dB threshold was chosen to discriminate HITS from background Doppler signal. The HITS counts in the left and in the right middle cerebral arteries were added and reported as a total number of HITS in 30 minutes. Results —HITS were detected in 14 (78%) of 18 patients with large AAs versus 8 (29%) of 28 patients with no or small AAs (odds ratio [OR] 8.8, 95% CI 2.2 to 34.8; P =0.001). The association was also present in 27 patients with no other cardiac embolic sources, such as atrial fibrillation, patent foramen ovale, spontaneous echo contrast, and thrombus (7 of 10 patients with large AAs versus 3 of 17 patients with small or no AA; OR 10.9, 95% CI 1.7 to 68.5; P =0.013). Complex AAs were associated with a higher frequency of HITS than were noncomplex AAs (6 of 6 patients with complex AAs versus 15 of 39 patients with noncomplex AAs; OR 2.6, 95% CI 1.7 to 3.9; P =0.005). Conclusions —HITS are significantly associated with large AAs in elderly stroke patients. This observation may support the causal role of large AAs in IS.

Background and Purpose —The association between left atrial size and ischemic stroke is controversial and has been suggested to exist only in men and to be mediated by left ventricular mass. Data are available almost exclusively for white patients. The purpose of this study was to evaluate the association between left atrial size and ischemic stroke in a multiethnic population. Methods —A population-based case-control study was conducted in 352 patients aged >39 years with first ischemic stroke and in 369 age-, gender-, and race-ethnicity–matched community controls. Left atrial diameter was measured by 2-dimensional transthoracic echocardiography and indexed by body surface area. Conditional logistic regression analysis was performed to assess the risk of stroke associated with left atrial index in the overall group and in the age, gender, and race-ethnic strata after adjustment for the presence of other stroke risk factors. Results —Left atrial index was associated with ischemic stroke in the overall group (adjusted OR 1.47 per 10 mm/1.7 m 2 of body surface area; 95% CI 1.03 to 2.11). The association was present in men (adjusted OR 2.81, 95% CI 1.42 to 5.57) but not in women (adjusted OR 1.08, 95% CI 0.70 to 1.66), and in patients aged 60 years (adjusted OR 1.23, 95% CI 0.84 to 1.81). Subgroup analyses showed the risk to be present in men across all age subgroups. In women, the lack of association between left atrial index and stroke was most strongly influenced by left ventricular hypertrophy. A trend toward an association between left atrial index and stroke was observed in whites (adjusted OR 1.81, 95% CI 0.81 to 4.09) and Hispanics (adjusted OR 1.61, 95% CI 0.98 to 2.65) but was less evident in blacks (adjusted OR 1.25, 95% CI 0.74 to 2.14). Conclusions —Left atrial enlargement is associated with an increased risk of ischemic stroke after adjustment for other stroke risk factors, including left ventricular hypertrophy. The association is observed in men of all ages, whereas in women it is attenuated by other factors, especially left ventricular hypertrophy. Interracial differences in the stroke risk may exist that need further investigation.

Background and Purpose Patent foramen ovale (PFO) is associated with stroke of unknown etiology or cryptogenic stroke. However, optimal treatment to prevent recurrence in cryptogenic stroke patients with PFO is not clearly defined. Since PFO represents a surgically repairable lesion, interest in closing it is high. This report reviews our experience with cryptogenic stroke patients with PFO who underwent surgical PFO closure and were followed for recurrence of neurological events. Methods We followed 28 cryptogenic stroke patients (17 men, 11 women; mean age, 41±13 years) with transesophageal echocardiograpy–defined PFO who had undergone PFO closure by open thoracatomy. All patients selected for surgery refused, could not take, or failed warfarin therapy. They were followed by physician visits and telephone interviews. Results There were no surgical complications. With a mean follow-up of 19 months, four patients experienced neurological event recurrence, one stroke, and three transient ischemic attacks. Kaplan-Meier survival analysis demonstrated that the actuarial rate of recurrence was 19.5% (95% confidence limit 2.2-36.8%) at 13 months of follow-up. None of the 17 patients (0%) younger than 45 years suffered a recurrence, whereas four of 11 patients (35%) aged 45 or older experienced a recurrence of neurological event ( P Conclusions Although PFO is easily repairable in patients with cryptogenic stroke, its closure does not consistently prevent recurrence of ischemic events. The recurrence appears to occur more frequently in older cryptogenic stroke patients.

Background and Purpose Valvular strands, thin filamentous material attached to the mitral or aortic valve, are seen during transesophageal echocardiography and have been associated with stroke. Little is known about this association in different age, sex, and race-ethnic subgroups and the effect of various strand characteristics on this association. Methods From patients referred for transesophageal echocardiography, 73 patients with recent ischemic stroke (68) or transient ischemic attack (5) were age matched to 73 stroke- and transient ischemic attack–free control subjects. The association between valvular strands and cerebral ischemia was evaluated for the overall group and demographic subgroups. The effect of strand location, length, number, and valve thickness was also determined. Results An association between cerebral ischemia and valvular strands was observed (odds ratio [OR]=4.4; 95% confidence interval [CI]=2.0 to 9.6). The association was found for both men and women and among all three race-ethnic groups. The OR was greater in those who were younger (12.5 [95% CI=2.4 to 64.5] for age Conclusions Valvular strands, whether mitral or aortic, are associated with ischemic stroke, especially among younger persons.

Background and Purpose— We evaluated the association between electrocardiographic left atrial abnormality (ECG-LAA) and ischemic stroke, especially whether ECG-LAA provides additional prognostic information to that provided by echocardiography. Methods— A population-based, case-control study included 146 patients with first ischemic stroke and 195 age-, gender-, and race/ethnicity-matched community control subjects. ECG-LAA was defined as either P-wave duration >120 ms or P-terminal force in precordial lead V 1 (PTFV 1 ) >40 ms·mm. Results— PTFV 1 >40 ms·mm was associated with ischemic stroke after adjustment for other stroke risk factors (odds ratio [OR], 2.32; 95% CI, 1.29 to 4.18). The association remained significant after adding echocardiographic left atrial diameter to the model (OR, 2.31; 95% CI, 1.28 to 4.17). PTFV 1 was independently associated with stroke in patients in the upper half of echocardiographically determined left ventricular mass (adjusted OR, 4.5; 95% CI, 2.20 to 9.15) but not in those in the lower half (OR, 0.58; 95% CI, 0.20 to 1.65; P =0.0008). Conclusions— ECG-LAA can supplement 2D echocardiography in assessing the risk of ischemic stroke, especially in subjects with increased left ventricular mass.

Background The “RoPE Score” is a predictive model created to stratify patients by the likelihood that a patent foramen ovale (PFO) is incidental or pathogenic using clinical variables. We hypothesized that the predictors of recurrent stroke differ between patients with pathogenic and incidental PFOs. Methods Patients in the Risk of Paradoxical Embolism (RoPE) database with cryptogenic stroke (CS) and PFO were classified as having a probable pathogenic PFO (RoPE Score of >6, estimated PFO attributable fraction 72-99%, n=646) and others (RoPE Score of Results Follow-up was available for 91%, 80%, and 58% at 1, 2, and 3 years. Overall, a higher recurrence risk was associated with an index TIA, not being on a statin at baseline, and having a prior radiological stroke. For the low RoPE score group, older age, male sex, high cholesterol and antiplatelet (vs warfarin) treatment predicted recurrence. For those with high RoPE scores, predictors were prior (clinical) stroke/TIA and 2 echo features: septal hypermobility and a small shunt ( Conclusions Predictors of recurrence differ when PFO relatedness is classified by the RoPE Score. The hypothesis that patients with CS and PFO form a heterogenous group with different stroke mechanisms is supported. Conventional stroke risk factors were strong predictors among patients with lower RoPE scores. Echocardiographic features - including a counterintuitive association between smaller shunts and increased recurrence risk - were uniquely predictive in the high RoPE score group (likely pathogenic PFO).

Introduction: A patent foramen ovale (PFO) discovered in the setting of a cryptogenic stroke (CS) may be stroke-related or incidental. We have developed a score to stratify CS patients according to the probability that the event is attributable to a PFO (the Risk of Paradoxical Embolism (RoPE) Score), based on easily obtainable clinical and neuroradiological (but not transesophageal echocardiographic (TEE) variables. In this study, we examined whether putative “high risk” TEE features - shunt size, presence of a hypermobile septum, and presence of a right-to-left shunt at rest - vary across RoPE Score strata. Methods and Results: The RoPE Study combined existing cohort studies to create a pooled database of patients with CS and PFO. We dichotomized patients into groups and examined whether putative high risk TEE features are seen more frequently in those with “probable stroke-related” PFOs (RoPE Score of >6, estimated PFO attributable fraction 72-99%, n=637) than in those with lower RoPE Scores ( Conclusion: We found no evidence that proposed TEE markers for “high risk” PFOs correlate with the estimated likelihood that a PFO is related to an index CS. Additional imaging tools or better standardization of imaging techniques are needed to determine whether specific anatomic features are associated with whether a discovered PFO is likely to be related to CS.

Background Stroke databanks have consistently found a high ratio of anterior circulation (AC) to posterior circulation (PC) strokes without significant differences when compared for vascular risk factors, stroke etiology, treatments and outcome. One study suggested that there was a deviation from this consistent observation when comparing men and women with cryptogenic stroke (CS) and patent foramen ovale (PFO). We tested these associations using the RoPE database. Methods The Risk of Paradoxical Embolism (RoPE) Study is an international collaboration of 12 merged cohort studies of patients with CS and known PFO status (n=3674). This analysis was restricted to those subjects in the RoPE database with index strokes in the AC or PC (excluding both or unknown) from the 7 databases that had data for CS with, and without, PFO. We compared the effect of sex on infarct location among patients with versus without PFO. We used generalized linear mixed models to examine whether PFO status modified the gender effect on infarct location adjusting for study cohort as a random effect. Results Among cryptogenic stroke patients both with and without PFO, AC strokes were more common (61%) than PC overall (n=1535). Among patients with PFO, PC stroke was higher in men than in women (50% vs. 33%, OR 2.23, 95% CI: 1.58-3.13). This gender effect was attenuated in those without PFO (38% vs. 31%; OR 1.32, 95% CI: 0.98-1.77). The gender-by-PFO-status interaction was significant (p= 0.0224) and was highly consistent across study cohorts. Conclusions These data confirm that males with CS and PFO contravene the otherwise consistent pattern that AC strokes are more commonly observed than PC strokes in stroke populations. The potential mechanisms underlying this interaction between gender and PFO-status remain to be elucidated.

Background and Purpose— Cardiac mortality after stroke is common, and small studies have suggested an association of short-term cardiac mortality with insular location of cerebral infarction. Few population-based studies with long-term follow-up have evaluated the effect of stroke location on the long-term risk of cardiac death or myocardial infarction (MI) after first ischemic stroke. We sought to determine the association between stroke location and cardiac death or MI in a multiethnic community-based cohort. Methods— The Northern Manhattan Study is a population-based study designed to determine stroke incidence, risk factors, and prognosis in a multiethnic urban population. First ischemic stroke patients age 40 or older were prospectively followed up for cardiac death defined as fatal MI, fatal congestive heart failure, or sudden death/arrhythmia and for nonfatal MI. Primary brain anatomic site was determined by consensus of research neurologists. Hazard ratios (HRs) and 95% CIs were calculated by Cox proportional-hazards models and adjusted for vascular risk factors (age, sex, history of coronary disease, hypertension, diabetes, cholesterol, and smoking), stroke severity, infarct size, and stroke etiology. Results— The study population consisted of 655 patients whose mean age was 69.7±12.7 years; 44.6% were men and 51.3% were Hispanic. During a median follow-up of 4.0 years, 44 patients (6.7%) had fatal cardiac events. Of these, fatal MI occurred in 38.6%, fatal congestive heart failure in 18.2%, and sudden death in 43.2%. In multivariate models, clinical diagnosis of left parietal lobe infarction was associated with cardiac death (adjusted HR=4.45; 95% CI, 1.83 to 10.83) and cardiac death or MI (adjusted HR=3.30; 95% CI, 1.45 to 7.51). When analysis of anatomic location was restricted to neuroimaging (computed tomography, magnetic resonance imaging, or both [n=447]), left parietal lobe infarction was associated with cardiac death (adjusted HR=3.37; 95% CI, 1.26 to 8.97), and both left (adjusted HR=3.49; 95% CI, 1.38 to 8.80) and right (adjusted HR=3.13; 95% CI, 1.04 to 9.45) parietal lobe infarctions were associated with cardiac death or MI. We did not find an association between frontal, temporal, or insular stroke and fatal cardiac events, although the number of purely insular strokes was small. Conclusions— Parietal lobe infarction is an independent predictor of long-term cardiac death or MI in this population. Further studies are needed to confirm whether parietal lobe infarction is an independent predictor of cardiac events and death. Surveillance for cardiac disease and implementation of cardioprotective therapies may reduce cardiac mortality in patients with parietal stroke.

Background and Purpose— Left ventricular dysfunction (LVD) is associated with cardiovascular mortality. Its association with ischemic stroke has been mainly documented after myocardial infarction. The stroke risk associated with LVD, especially of mild degree, in the general population is unclear. The purpose of this study was to evaluate the relationship between LVD and ischemic stroke in a multiethnic cohort. Methods— LV systolic function was assessed by transthoracic 2-dimensional echocardiography in a subset of subjects from the Northern Manhattan Study (NOMAS), 270 patients with first ischemic stroke and 288 age-, gender- and race-matched community controls. LV ejection fraction was measured by a simplified cylinder-hemiellipsoid formula, and categorized as normal (>50%), mildly (41% to 50%), moderately (31% to 40%) or severely (≤30%) decreased. The association between impaired ejection fraction and ischemic stroke was evaluated by logistic regression analysis after adjustment for established stroke risk factors. Results— LVD of any degree was more frequent in stroke patients (24.1%) than in controls (4.9%; P P Conclusions— LVD, even of mild degree, is independently associated with an increased risk of ischemic stroke. The assessment of LV function should be considered in the assessment of the stroke risk.

Background and Purpose— Serologic evidence of infection with Chlamydia pneumoniae has been associated with cardiovascular disease, but its relationship with stroke risk remains uncertain. The objective of this study is to determine whether serological evidence of C pneumoniae infection is associated with risk of ischemic stroke. Methods— A population-based case-control study was performed in an urban, multiethnic population. Cases (n=246) had first ischemic stroke, and controls (n=474) matched for age, sex, and race–ethnicity were derived through random-digit dialing. Titers of C pneumoniae –specific IgG and IgA antibodies were measured using microimmunofluorescence, and positive titers were prospectively defined. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% CIs adjusting for medical, behavioral, and socioeconomic factors. Results— Mean age among cases was 72.3±9.7 years; 50.8% were women. Elevated C pneumoniae IgA titers were associated with increased risk of ischemic stroke after adjusting for hypertension, diabetes mellitus, current cigarette use, atrial fibrillation, and levels of high-density lipoprotein and low-density lipoprotein (adjusted OR, 1.5; 95% CI, 1.0 to 2.2). Elevated IgG titers were not associated with stroke risk (adjusted OR, 1.2; 95% CI, 0.8 to 1.8). There was a trend toward an association of elevated IgA titers with atherosclerotic and lacunar stroke but less so cardioembolic or cryptogenic subtypes. Conclusions— Serologic evidence of C pneumoniae infection is associated with ischemic stroke risk. IgA titers may be a better marker of risk than IgG. This association is independent of other stroke risk factors and is present for atherosclerotic, lacunar, and cardioembolic subypes. Further studies of the effect of C pneumoniae on stroke risk are warranted.

Background— Valvular strands are associated with ischemic stroke. The recurrent rate of adverse events in stroke patients with valvular strands has not been defined and, importantly, there are no randomized studies to evaluate efficacy of antithrombotic therapies in these patients. Methods— Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS) enrolled 630 stroke patients, of whom 312 (49.5%) were randomized to warfarin and 318 (50.5%) were randomized to aspirin; 265 patients experienced cryptogenic stroke and 365 experienced stroke with known subtypes. Endpoints were recurrent ischemic stroke or death from any cause. All transesophageal echocardiography studies were blindly, centrally analyzed and all endpoints were blindly adjudicated. Results— Overall, of 619 studies analyzed, valvular strands were present in 39.4% of the patients (244/619), 5.8% (36/619) on the aortic valve and 27.8% (172/619) on the mitral valve, and 5.8% (36/619) on both valves. In an intention-to-treat analysis, there was no significant difference in the time to primary endpoints between patients with and without strands in the overall population ( P =0.82; hazard ratio: 1.05; 95% CI: 0.70 to 1.57; 2-year event rates: 16.4% versus 15.5%). Among the patients with strands, there was no significant difference in the time to primary endpoints between those treated with warfarin or aspirin ( P =0.21; hazard ratio: 0.67; 95% CI: 0.36 to 1.26; 2-year event rates: 13.5% versus 19.6%). Conclusions— While on medical therapy, valvular strands do not significantly increase recurrent adverse event rates in patients with ischemic stroke. Furthermore, the study does not provide evidence to support an advantage of warfarin or aspirin for this purpose.

Background and Purpose—Large atherosclerotic plaques in the aortic arch detected by transesophageal echocardiography (TEE) are associated with increased risk of ischemic stroke in the elderly. The atherosclerotic process also affects aortic distensibility, which can also be assessed by TEE. The purpose of this study was to evaluate the possible association of aortic stiffness by TEE with ischemic stroke in elderly patients.Methods—We performed TEE in 40 consecutive elderly patients aged ≥55 years with acute ischemic stroke and in 42 consecutive control subjects aged ≥55 years. Aortic stiffness index β, which has been used in the literature to express the stiffness of the aortic wall, was calculated as follows: β=ln (systolic blood pressure/diastolic blood pressure)/([Dmax−Dmin]/Dmin), where ln is natural logarithm, Dmaxis maximum aortic lumen diameter, and Dminis minimum aortic lumen diameter by TEE. The association of index β with ischemic stroke was evaluated by logistic regression analysis after adjustment for potential confounders, including thickness of aortic arch plaques.Results—Index β was significantly greater in stroke patients than in controls (9.7±5.0 versus 5.3±3.5;PConclusions—Aortic stiffness by TEE is associated with ischemic stroke, independent of thickness of aortic arch plaques and other stroke risk factors. This suggests that aortic stiffness by TEE may add prognostic information when assessing the risk of ischemic stroke in the elderly.

Background and Purpose —Atherosclerotic plaque of the proximal portion of the aorta is associated with an increased risk of ischemic stroke in the elderly. Different cutoffs of plaque thickness have been used in the literature for risk stratification and have been applied to both men and women. However, the assumption that the relationship between plaque thickness and stroke risk is the same in the 2 genders has not been proven. The aim of this study was to evaluate whether the prevalence of different degrees of aortic plaque thickness differed in men and women with ischemic stroke. Methods —We performed transesophageal echocardiography in 152 patients aged >59 years with acute ischemic stroke (76 men and 76 women) and in 152 control subjects of similar age (70 men and 82 women). Odds ratios (ORs) for ischemic stroke with 95% CIs for different plaque thickness definitions were calculated for the overall group and separately for men and women by logistic regression analysis after adjusting for age, arterial hypertension, and hypercholesterolemia. Results —Aortic plaques ≥4 mm were significantly more frequent in men than in women (31.5% versus 20.3%, respectively; P =0.025) and were associated with ischemic stroke in both men (adjusted OR 6.0, CI 2.1 to 16.8) and women (adjusted OR 3.2, CI 1.2 to 8.8). However, plaques 3 to 3.9 mm in thickness had a significant association with stroke in women (adjusted OR 4.8, CI 1.7 to 15.0) but not in men (adjusted OR 0.8, CI 0.2 to 3.0). Plaques Conclusions —Smaller aortic plaques are significantly associated with ischemic stroke in women but not in men. If the increased prevalence of smaller plaques in women is confirmed to be associated with increased risk for embolic stroke, different cutoff points may have to be adopted in men and women for risk stratification and for decisions regarding medical intervention.

Background and Purpose —Although the cause of stroke among patients with patent foramen ovale (PFO) may be due to paradoxical cerebral embolism (PCE), this mechanism is often difficult to prove. The aim of our study was to evaluate the association between brain imaging findings suggestive of embolism and PFO among ischemic stroke patients. Methods —As part of the Northern Manhattan Stroke Study, 95 patients with first ischemic stroke over age 39 underwent transesophageal echocardiography (TEE) for evaluation of a cardiac source of embolism. The stroke subtype was determined by modified NINDS Stroke Data Bank criteria. Stroke subtype and MRI/CT imaging data were evaluated blind to the presence of a PFO. These findings were compared between two groups: patients with medium to large PFO (≥2 mm) and small ( Results —Of the 95 patients who underwent TEE, 31 (33%) had a PFO. The frequency of PFO was significantly greater among patients with cryptogenic infarcts (19 of 42; 45%) compared with patients with determined cause of stroke (12 of 53, 23%; P =0.02). Medium to large PFOs were found more often among cryptogenic strokes than among infarcts of determined cause (26% versus 6%; P =0.04). Superficial infarcts occurred more often in the group with larger PFOs than in the group with small or no PFOs (50% versus 21%; P =0.02). Patients with medium or large PFOs more frequently had occipital and infratentorial strokes (57% versus 27%; P =0.02). Conclusions —Stroke patients with larger PFOs show more brain imaging features of embolic infarcts than those with small PFOs. Larger PFOs may be more likely to cause paradoxical embolization and may help explain the stroke mechanism among patients with no other definite cause.