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Background and Purpose: It is unknown when to start anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF). Early anticoagulation may prevent recurrent infarctions but may provoke hemorrhagic transformation as AF strokes are typically larger and hemorrhagic transformation-prone. Later anticoagulation may prevent hemorrhagic transformation but increases risk of secondary stroke in this time frame. Our aim was to compare early anticoagulation with apixaban in AF patients with stroke or transient ischemic attack (TIA) versus warfarin administration at later intervals. Methods: AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation) was an open-label, randomized controlled trial comparing the safety of early use of apixaban at day 0 to 3 for TIA, day 3 to 5 for small-sized AIS ( Results: Although AREST ended prematurely after a national guideline focused update recommended direct oral anticoagulants over warfarin for AF, it revealed that apixaban had statistically similar yet generally numerically lower rates of recurrent strokes/TIA (14.6% versus 19.2%, P =0.78), death (4.9% versus 8.5%, P =0.68), fatal strokes (2.4% versus 8.5%, P =0.37), symptomatic hemorrhages (0% versus 2.1%), and the primary composite outcome of fatal stroke, recurrent ischemic stroke, or TIA (17.1% versus 25.5%, P =0.44). One symptomatic intracerebral hemorrhage occurred on warfarin, none on apixaban. Five asymptomatic hemorrhagic transformation occurred in each arm. Conclusions: Early initiation of anticoagulation after TIA, small-, or medium-sized AIS from AF does not appear to compromise patient safety. Potential efficacy of early initiation of anticoagulation remains to be determined from larger pivotal trials. Registration: URL: https://www.clinicaltrials.gov/ ; Unique identifier: NCT02283294.

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 and Purpose— We sought to estimate risk of recurrent stroke/TIA/death in the subgroup of the Patent Foramen Ovale in the Cryptogenic Stroke Study (PICSS) cohort with patent foramen ovale (PFO) and antiphospholipid antibodies (aPL) and to estimate risk of recurrent stroke/TIA/death in aPL-positive patients who have thickened left-side heart valves (VaT). PFO is associated with cryptogenic ischemic stroke. Also, the presence of aPL is associated with ischemic cerebrovascular disease. Methods— Combined data from 2 major substudies of the Warfarin Aspirin Recurrent Stroke Trial (WARSS) were evaluated. PICSS subjects were included if they were enrolled in the Antiphospholipid Antibodies and Stroke Study (APASS) and underwent a baseline aPL test (lupus anticoagulant, anticardiolipin antibodies, or both) within 1 month of the stroke. All patients in PICSS underwent transesophageal echocardiography for PFO as well as VaT, which was performed blinded to aPL status and treatment arm (325 mg/day aspirin or adjusted dose warfarin; target international normalized ratio, 1.4–2.8). The primary outcome event was the 2-year risk of recurrent stroke/TIA/death and was evaluated using Cox proportional hazards model. Because there was no treatment effect, warfarin and aspirin groups were combined to increase power. For the combined end point, power to detect HR of 2 was 47.8% for the PFO and aPL-positive group, and 75.3% for the valve thickening and aPL-positive group, assuming 2-sided type I error of 0.05. Results— Five hundred twenty-five subjects were tested for the combined presence of PFO and aPL and were available for evaluation. The primary outcome event rate was 23.9% (HR, 1.39; 95% CI, 0.75–2.59) in the PFO-positive/aPL-positive group, compared to 13.9% (HR, 0.83; 95% CI, 0.44–1.56) in the PFO-positive/aPL-negative group, and 19.9% (HR, 1.16; 95% CI, 0.68–1.90) in the PFO-negative/aPL-positive group. Five hundred forty-five subjects tested for combined presence of aPL and left-side cardiac VaT were available for evaluation. The primary event rate was 22.6% (HR, 1.65; 95% CI, 0.88–3.09) in the VaT-positive/aPL-positive group, compared to 19.4% (HR, 1.50; 95% CI, 0.82–2.75) in the VaT-positive/aPL-negative group, and 20.2% (HR, 1.63; 95% CI, 0.81–3.25) in the VaT-negative/aPL-positive group. Conclusions— The combined presence of aPL either with a PFO or with left-side cardiac VaT did not significantly increase risk of subsequent cerebrovascular events in this PICCS/APASS cohort of patients.

Background and Purpose— More than 47 million individuals in the United States meet the criteria for the metabolic syndrome. The relation between the metabolic syndrome and stroke risk in multiethnic populations has not been well characterized. Methods— As part of the Northern Manhattan Study, 3298 stroke-free community residents were prospectively followed up for a mean of 6.4 years. The metabolic syndrome was defined according to guidelines established by the National Cholesterol Education Program Adult Treatment Panel III. Cox proportional-hazards models were used to calculate hazard ratios (HRs) and 95% CIs for ischemic stroke and vascular events (ischemic stroke, myocardial infarction, or vascular death). The etiologic fraction estimates the proportion of events attributable to the metabolic syndrome. Results— More than 44% of the cohort had the metabolic syndrome (48% of women vs 38% of men, P Conclusions— The metabolic syndrome is an important risk factor for ischemic stroke, with differential effects by sex and race/ethnicity.

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).

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: A patent foramen ovale (PFO) discovered in the setting of a cryptogenic stroke (CS) may be incidental or pathogenic. Based on Bayes theorem, the proportion of CS that is PFO-attributable among patients found to have a PFO has been shown to be related to PFO prevalence in CS versus control patients. However, the prevalence of PFO in CS patients is itself dependent on the presence or absence of other risk factors. We exploited this relationship to create an index to stratify CS patients with PFO by their likelihood that the CS is PFO-attributable. Methods This project is part of the Risk of Paradoxical Embolism (RoPE) Study, an international, multicenter collaboration that has combined data for patients with CS and cryptogenic TIA who have known PFO status from 12 component studies (n=3665). For this study, we included those subjects within the 7 databases enrolling subjects both with and without PFO (n=3023). We used generalized linear mixed models to identify variables associated with the presence of a PFO, accounting for clustering within study. Based on this model, we created a simple index. Bayes theorem was used to estimate the PFO-attributable fraction in each stratum assuming a PFO prevalence in the general population of ∼25%. Results: Variables negatively associated with the presence of a PFO included: age (odds ratio [OR] = 0.97 per 1 year increase, p absence of each stroke risk factor was assigned a point, with age dichotomized at 50 years. PFO prevalence in each stratum is shown in the table for patients < age 60, i.e. the subset of patients likely to be considered for PFO closure trials. Conclusion: Even among CS patients in the younger age range considered eligible for closure trials, there is considerable heterogeneity in the distribution of risk factors for stroke and other characteristics that identify subgroups of CS patients with variation in PFO prevalence. This reflects substantial and clinically important variation in the probability that a discovered PFO is likely to be pathogenic rather than incidental. This score may be useful in selecting patients for closure trials, or for stratification within trials, particularly if combined with a recurrence risk model.

Introduction We aim to determine whether radiological findings are associated with patent foramen ovale (PFO) among patients with cryptogenic stroke (CS). Radiological findings associated with the presence of a PFO may represent stroke patterns typical of paradoxical embolism which may be distinct from other mechanisms of CS. Methods This project is part of the Risk of Paradoxical Embolism (RoPE) Study, an international collaboration that has combined individual-level data for subjects with CS and TIA who have known PFO status from 12 component studies (n=3665). For this study 7 databases (n=3023) were used that included subjects with and without PFO, and with radiologic data. Five variables were tested for their relationship with PFO status: 1) protocol-defined large vs. small infarct , 2) Index stroke seen on imaging, 3) superficial vs. deep infarct, 4) multiple index lesions, 5) Prior stroke, i.e. chronic infarct on index imaging. Results are presented in the table . Odds ratios and p-values are adjusted for age, database, sex, diabetes, hypertension, smoking, and history of stroke/TIA. This is the largest study to report the radiological characteristics of patients with CS who are known to have, or not to have, a PFO. Some prior studies had null findings but were limited by small sample size and low statistical power. Because CS unrelated to PFO may also be embolic, the radiological pattern of paradoxical embolism may not be expected to be different from other cryptogenic emboli. Despite this, PFOs were significantly more common in CS patients with large and with superficial infarcts. Conversely, infarcts that were small and deep were associated with PFO absence. This suggests that lacunar disease may account for some non-PFO related CS. Conclusion Participants were significantly more likely to have a PFO if they had 1) an index stroke seen on neuroimaging, 2) a large stroke, 3) a superficial stroke; there was no effect of the variables prior ( i.e. chronic) infarct or multiple vs. single infarcts. Further analyses may help to clarify the ability of neuroimaging to predict the finding of a PFO.

Patent foramen ovale is associated with ischemic stroke in patients without a clearly identifiable etiology for stroke (cryptogenic stroke). Paradoxical embolization is thought to be a potential mechanism. However, patent foramen ovale is also found in patients with known cause of stroke. Therefore, using contrast transesophageal echocardiography, we characterized the patent foramen ovale in cryptogenic stroke patients to assess morphological factors that may contribute to paradoxical embolization. Contrast transesophageal echocardiographic studies of 74 consecutive patients referred for ischemic stroke were reviewed. Twenty-three patients with patent foramen ovale were identified. These patients were classified as having strokes of determined origin or cryptogenic strokes according to criteria developed for the Stroke Data Bank of the National Institute of Neurological Disorders and Stroke. Separation of septum primum from secundum and the number of microbubbles appearing in left atrium were then quantitated. These parameters were compared between patients with cryptogenic stroke and those with known cause of stroke. The patent foramen ovale dimension was significantly larger in patients with cryptogenic stroke compared with patients with an identifiable cause of stroke (2.1 +/- 1.7 mm versus 0.57 +/- 0.78 mm [mean +/- SD]; P < .01). The number of microbubbles was also greater in patients with cryptogenic stroke compared with patients with an identifiable cause of stroke (13.9 +/- 10.7 versus 1.6 +/- 0.8 [mean +/- SD]; P < .0005). Patients with cryptogenic stroke have larger patent foramen ovale with more extensive right-to-left interatrial shunting than patients with stroke of determined cause. Transesophageal echocardiographically identifiable characteristics of patent foramen ovale may be important in defining the clinical significance of individual patent foramina.

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 and Purpose— Patent foramen ovale (PFO) is associated with cryptogenic stroke. There is no study that assessed the effect of age on adverse event rates in cryptogenic stroke patients with PFO. The purpose of this retrospective analysis from PFO in Cryptogenic Stroke Study (PICSS) database was to assess the effect of age on the risk of adverse events in medically treated cryptogenic stroke patients with PFO. Methods— 250 cryptogenic stroke patients from PICSS were followed-up for 24 months, with death and recurrent ischemic stroke as primary endpoints. Hazard ratios were calculated for determination of relative risk in cryptogenic stroke patients with and without PFO in 3 age groups (younger than 55, 55 to 64, and 65 years or older). Results— Among the 2 younger age groups, the presence of PFO did not significantly affect the risk of adverse events ( P =0.15; hazard ratio=0.21; 95% CI, 0.02 to 1.78; 2-year event rates, 2.0% versus 9.3%; and P =0.70; hazard ratio=0.72; 95% CI, 0.14 to 3.73; 2-year event rates, 10.0% versus 13.9%). However, in those aged 65 years or older, the risk of adverse events was significantly higher in the patients with PFO ( P =0.01; hazard ratio=3.21; 95% CI, 1.33 to 7.75; 2-year event rates 37.9% versus 14.5%). Conclusions— In this exploratory analysis, the presence of PFO in the younger cryptogenic stroke patients did not increase the risk of adverse events. However, in the older patients, PFO significantly increased the risk of adverse events.

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 —Electrocardiographic abnormalities and elevations of the creatine kinase myocardial isoenzyme (CK-MB) occur frequently after subarachnoid hemorrhage. In some patients, a reversible and presumably neurogenic form of left ventricular dysfunction is demonstrated by echocardiography. It is not known whether cardiac injury of this type adversely affects cardiovascular hemodynamic performance. Methods —We retrospectively studied 72 patients admitted to our neuro-ICU for aneurysmal subarachnoid hemorrhage over a 2.5-year period. We selected patients who met the following criteria: (1) CK-MB levels measured within 3 days of onset, (2) pulmonary artery catheter placed, (3) echocardiogram performed, and (4) no history of preexisting cardiac disease. Hemodynamic profiles were recorded on the day after surgery (n=67) or on the day of echocardiography (n=5) if surgery was not performed (mean, 3.3±1.7 days after onset). The severity of cardiac injury was classified as none (peak CK-MB 2%, n=6), or severe (abnormal left ventricular wall motion, n=9). Results —Abnormal left ventricular wall motion occurred exclusively in patients with peak CK-MB levels >2% ( P P =0.002), and female sex ( P =0.02). Left ventricular stroke volume index and stroke work index were elevated above the normal range in patients with peak CK-MB levels P P P =0.04) and depressed cardiac index (odds ratio, 2.1; 95% CI, 1.0 to 4.1; P =0.04) were independent predictors of symptomatic vasospasm. Conclusions —Myocardial enzyme release and echocardiographic wall motion abnormalities are associated with impaired left ventricular performance after subarachnoid hemorrhage. In severely affected patients, reduction of cardiac output from normally elevated levels may increase the risk of cerebral ischemia related to vasospasm.

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.

Cardiac effects of intracranial hemorrhage were initially described in 1903 by Cushing, who noted alterations in blood pressure and cardiac rhythm in such patients.1 However, since ECG was not available at that time, it was not until 1947 that Byer et al described ECG changes in a patient with subarachnoid hemorrhage (SAH).2 Later, a series of experiments described the effect of hypothalamic stimulation on ECG morphology and rhythm indicating that myocardial damage need not be present for ECG changes to occur.3,4 Indeed, some form of ECG changes are noted in almost all patients with SAH.5 Up to 10% of the patients with SAH are noted to have a potentially lethal arrhythmia such as ventricular tachycardia and fibrillation, and it has been suggested that this may account for some of the mortality in patients not reaching medical care with SAH. A series of autopsy studies in patients with SAH demonstrated petechial subendocardial hemorrhage, and histologically, myocardial cell cytoplasm with dense …

The prevalence of a patent foramen ovale has been shown to be increased in patients with ischemic stroke. Transesophageal echocardiography, transthoracic echocardiography, and transcranial Doppler examination with contrast injection can all be used to search for a patent foramen ovale. We compared the accuracy of these techniques for identifying a patent foramen ovale in 49 patients with acute ischemic stroke or transient ischemic attack. Transcranial Doppler examination of the right middle cerebral artery was performed during simultaneous transthoracic echocardiography with aerated saline injection, and again during transesophageal echocardiography; the latter was adopted as the "gold standard" for assessing the sensitivity of the other two tests. Contrast transesophageal echocardiography detected a patent foramen ovale in 19 of 49 patients (39%), during normal respiration in 15 of them and during Valsalva maneuver in 4. Transcranial Doppler correctly identified 13 patients with a patent foramen ovale and all 30 patients without it. Therefore, the sensitivity of transcranial Doppler was 68% (13/19), and its specificity 100% (30/30). The 6 patients misclassified by transcranial Doppler (false negatives) had a very small right-to-left shunt detected by transesophageal echocardiography. Contrast transthoracic echocardiography was found to be the least sensitive test, detecting a patent foramen ovale in only 9 of 19 patients (47%). The specificity of transthoracic echocardiography was 100% (30/30 patients). The low sensitivity of transthoracic echocardiography was principally due to the suboptimal image quality obtained in false-negative patients. Both transcranial Doppler and transthoracic echocardiography were more sensitive in patients with cryptogenic stroke than in patients with stroke of determined origin. This may indicate the presence of larger, more easily detectable shunts in patients with cryptogenic stroke. Transesophageal echocardiography is more sensitive than transcranial Doppler examination in detecting a patent foramen ovale, but only in cases of minimal right-to-left shunts, the clinical relevance of which remains to be established. The sensitivity of transthoracic echocardiography is heavily hampered by the frequency of inadequate heart visualization.