Diastolic Dysfunction as a Positive Predictor of Recurrent Vascular Events in Patients With Noncardioembolic Stroke.

BACKGROUND: This study aimed to assess the effects of left ventricular diastolic dysfunction (LVDD) on vascular outcomes among patients with stroke of noncardioembolic origins. METHODS: This prospective observational study enrolled 563 patients with noncardioembolic stroke (mean age, 67.9 years; 66.7% men and 33.3% women individuals) registered in the Tokyo Women's Medical University Stroke Registry between 2013 and 2020. Then, patients were divided into the LVDD and non-LVDD groups. The primary outcome was a composite of major adverse cardiovascular events, including nonfatal stroke, nonfatal acute coronary syndrome, and vascular death 1 year after stroke onset. The effect of LVDD on vascular events was assessed using multivariable Cox regression analyses. RESULTS: A total of 130 (23.1%) patients had any grade of LVDD, and patients with LVDD had a higher risk of major adverse cardiovascular event at 1 year than those without LVDD (annual rate, 20.9% versus 10.8%; log-rank P=0.001). The multivariable Cox proportional hazards regression model demonstrated that the presence of LVDD was independently associated with the major adverse cardiovascular event risk (hazard ratio, 1.79 [95% CI, 1.02-3.12]; P=0.019). Furthermore, the LVDD grade was proportional to the risk of major adverse cardiovascular events and recurrent stroke. CONCLUSIONS: LVDD may be associated with further vascular events after a noncardioembolic stroke, suggesting the importance of LVDD evaluations in risk stratification and secondary prevention in patients with noncardioembolic stroke. REGISTRATION: URL: https://upload.umin.ac.jp; Unique identifier: UMIN000031913.

Long-Term Outcome in Patients With Acute Ischemic Stroke and Heart Failure.

BACKGROUND: This study aimed to identify the association between long term functional outcomes and acute ischemic stroke (AIS) in patients with heart failure (HF) in Japan and whether 1-year event risks can be related to these patients.Methods and Results: This was a prospective observational study, and 651 patients registered in the Tokyo Women's Medical University Stroke Registry were classified into the HF and non-HF groups. Functional outcome at 1 year after stroke onset was defined as either good (modified Rankin Scale [mRS] score of 0-2) or poor (mRS score of 3-6). The primary outcome was a composite of major adverse cardiovascular events (MACE), including non-fatal stroke, non-fatal acute coronary syndrome, and vascular death. Patients with HF had a higher poor functional outcome rate at 1 year than those without HF (54.7% vs. 28.2%, P<0.001). Multivariate logistic regression analysis also demonstrated the prevalence of HF was an independent predictor of an mRS score of ≥3 at 1 year after stroke onset (odds ratio, 1.05; 95% confidence interval, 1.00-1.10; P=0.036). Furthermore, patients with HF tended to have a higher risk of MACE and all-cause mortality than those without HF. CONCLUSIONS: AIS patients with HF were associated with poor functional outcome at the 1-year follow up. Further multicenter studies involving a larger number of patients are warranted to verify these results.

Atherogenic Dyslipidemia and Residual Vascular Risk After Stroke or Transient Ischemic Attack.

BACKGROUND AND PURPOSE: Notwithstanding the current guideline-based management, patients with stroke retain a substantial risk of further vascular events. We aimed to assess the contribution of atherogenic dyslipidemia (AD) to this residual risk. METHODS: This was a prospective observational study, in which 792 patients (mean age, 70.1 years; male, 60.2%) with acute ischemic stroke (n=710) or transient ischemic attack (n=82) within 1 week of onset were consecutively enrolled and followed for 1 year. AD was defined as having both elevated levels of triglycerides ≥150 mg/dL and low HDL-C (high-density lipoprotein cholesterol) <40 mg/dL in men or <50 mg/dL in women, under fasting conditions. The primary outcome was a composite of major adverse cardiovascular events, including nonfatal stroke, nonfatal acute coronary syndrome, and vascular death. RESULTS: The prevalence of AD was 12.2%. Patients with AD more often had intracranial artery stenosis than those without (42.3% versus 24.1%; P=0.004), whereas no differences were observed in the prevalence of extracranial artery stenosis (17.7% versus 12.9%; P=0.62) or aortic plaques (33.3% versus 27.0%; P=0.87). At 1 year, patients with AD were at a greater risk of major adverse cardiovascular events (annual rate, 24.5% versus 10.6%; hazard ratio [95% CI], 2.33 [1.44-3.80]) and ischemic stroke (annual rate, 16.8% versus 8.6%; hazard ratio [95% CI], 1.84 [1.04-3.26]) than those without AD. When patients were stratified according to baseline LDL-C (low-density lipoprotein cholesterol) level, AD was predictive of major adverse cardiovascular events among those with LDL-C ≥100 mg/dL (n=509; annual rate, 20.5% versus 9.6%; P=0.036) as well as those with LDL-C <100 mg/dL (n=283; annual rate, 38.6% versus 12.4%; P<0.001). CONCLUSIONS: AD is associated with intracranial artery atherosclerosis and a high residual vascular risk after a stroke or transient ischemic attack. AD should be a promising modifiable target for secondary stroke prevention. Registration: URL: https://upload.umin.ac.jp; Unique identifier: UMIN000031913.

Triglyceride-glucose index as a prognostic marker after ischemic stroke or transient ischemic attack: a prospective observational study.

BACKGROUND: Triglyceride-glucose (TyG) index has been proposed as a simple and credible surrogate for insulin resistance and an independent predictor of cardiovascular outcomes. Due to lack of data on TyG index in stroke, we aimed to evaluate the predictive value of the index for recurrent vascular event risk among stroke patients. METHODS: This was a prospective observational study, in which 866 patients (mean age, 70.1 years; male, 60.9%) with ischemic stroke (n = 781) or transient ischemic attack (n = 85) within 1 week of onset were consecutively enrolled and followed up for 1 year. The TyG index was calculated as ln (fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2). Patients were divided into 3 groups according to the tertile of TyG index levels: tertile 1, < 8.48; tertile 2, 8.48-9.01; and tertile 3, > 9.01. The primary outcome was a composite of major adverse cardiovascular events (MACE), including nonfatal stroke, nonfatal acute coronary syndrome, and vascular death. RESULTS: The median TyG index was 8.74 (interquartile range, 8.34-9.16). Higher levels of TyG index were significantly associated with increased prevalence of ipsilateral extracranial carotid (P = 0.032) and intracranial (P = 0.003) atherosclerotic stenosis. There were significant differences in the MACE risk between the three groups (annual rate, 8.6%, 11.6%, and 17.3% in the tertile 1, tertile 2, tertile 3 groups, respectively; log-rank P = 0.005). After multivariable adjustments, the TyG index remains to be a significant predictor of MACE, with an adjusted hazard ratio for tertile 3 versus tertile 1 groups (95% confidence interval) of 2.01 (1.16-3.47). Similar results were also found for the risk of recurrent stroke. CONCLUSIONS: TyG index is associated with cervicocerebral atherosclerosis and the MACE risk after a stroke, suggesting the potential value of TyG index to optimize the risk stratification of stroke patients. Trial registration URL:  https://upload.umin.ac.jp . Unique identifier: UMIN000031913.

Prevalence of Microembolic Signals in Embolic Stroke of Undetermined Source and Other Subtypes of Ischemic Stroke.

Background and Purpose- Embolic stroke of undetermined source (ESUS) has been proposed to cause thromboembolic infarction from unknown but potential embolic sources. However, an embolus remains undetected in ESUS. The goal of this study was to characterize the prevalence and risk factors of microembolic signals (MESs) in ESUS. Methods- We examined 108 patients with acute ischemic stroke in the internal carotid artery territory or transient ischemic attack within 14 days of symptom onset and who were admitted to our hospital between April 2017 and March 2019. MESs were monitored in the middle cerebral artery on transcranial Doppler for 60 minutes. We examined the prevalence and number of MES in ESUS and other stroke subtypes, such as cardioembolism, large artery atherosclerosis, cerebral small vessel disease, and transient ischemic attack. The present study was registered in University Hospital Medical Information Network Clinical Trials Registry (UMIN000031913). Results- MESs were detected in 33 (31%) of 108 patients. ESUS showed the highest proportion (12/24 [50%]), followed by large artery atherosclerosis (8/20 [40%]), cardioembolism (6/18 [33%]), transient ischemic attack (4/24 [17%]), and cerebral small vessel disease (3/21 [14%]). Univariate analysis showed that higher systolic blood pressure, body mass index, hemoglobin A1c, and ESUS were significantly associated with MES. In multiple logistic regression analysis, ESUS remained significantly associated with MES after adjustment for described covariates from univariate analysis (odds ratio, 2.86 [95% CI, 1.01-8.08]). Conclusions- This study demonstrated significant association of ESUS with MES, supporting the embolic nature of this stroke subtype. Registration- URL: https://upload.umin.ac.jp. Unique identifier: UMIN000031913.

Impaired Endothelial Function in Embolic Stroke of Undetermined Source.

BACKGROUND: Impairment of endothelial function is associated with atherosclerosis and atrial fibrillation, and could underlie several types of ischemic stroke. Embolic stroke of undetermined source (ESUS) recently attracted much attention as the major cause of cryptogenic stroke. This study aimed to clarify the endothelial function of patients with ESUS. METHODS AND RESULTS: Between 2015 September and July 2017 July, we used flow-mediated vasodilation (FMD) test to evaluate vascular endothelial function in 182 patients with any vascular risk factors or a history of cerebrovascular events. The subject group was classified into the No Stroke group and 5 stroke subtype groups, large artery atherosclerosis (LAA), cardiogenic embolism (CE), small vessel disease (SVD), ESUS, and others (Other). Endothelial function was expressed as percentage increase in brachial vessel diameter (%FMD) after the interruption of blood flow with mechanical compression for 5 minutes. Mean FMD in the No stroke, LAA, CE, SVD, ESUS and Other groups were 7.03 ± 2.14%, 5.02 ± 2.75%, 4.97 ± 1.62%, 5.19 ± 2.67%, 3.55 ± 1.42%, and 6.55 ± 3.50%, respectively. After the adjustment for confounding factors, FMD was significantly lower in the ESUS group than in the No stroke, SVD, and Other groups. FMD tended to be lower in the ESUS group than in the LAA and CE groups, but the difference was not significant. CONCLUSIONS: Endothelial function was impaired in patients with ESUS and may underlie its pathophysiology.

Association of IgG4-Related Arteritis With Recurrent Stroke.

Immunoglobulin G4-related disease (IgG4)-related disease is a newly recognized form of immune-mediated disease, which is characterized by IgG4+ lymphoplasmacytic infiltration and fibrosis in the systemic organs. Although aortitis/periaortitis is a phenotype of IgG4-related disease, the relationship between cerebrovascular disease and IgG4-related disease remains unclear. Herein, we report the case of a 49-year-old man with recurrent stroke induced by IgG4-related arteritis. Case reports or studies examining the association between IgG4-related arteritis and stroke are limited. Although a definitive link between IgG4-related arteritis and stroke has not been established, IgG4-related arteritis should be considered as an etiology in patients with recurrent idiopathic stroke.

Leptomeningeal anastomosis and early ischemic lesions on diffusion-weighted imaging in male murine focal cerebral ischemia.

Leptomeningeal anastomosis is a key factor for determining early ischemic lesions on diffusion-weighted imaging (DWI) in human stroke. However, few studies have validated this relationship in an experimental model. This study sought to clarify the involvement of leptomeningeal anastomosis in early ischemic lesions using a murine model. Adult male C57BL/6 mice were subjected to unilateral common carotid artery (CCA) occlusion or sham surgery. Seven or 14 days later, the middle cerebral artery (MCA) was occluded for 45 min. In the first experiment, the leptomeningeal collaterals were visualized using magnetic resonance imaging (MRI) DWI. In the second experiment, DWI was performed immediately after MCA occlusion, and the infarct sizes were determined 24 hr after recirculation. Unilateral CCA occlusion reduced the size of early ischemic lesions, enlarged the pial vessel diameter, and mitigated infarct size. The relationship between the DWI lesion size and pial vessel diameter was significant (r = 0.84, p < 0.01). The association between infarct size and DWI lesion size was also significant (r = 0.96, p < 0.01). In conclusion, involvement of the collateral circulation in early ischemic lesions was evident in the murine model. Both MRI and evaluation of leptomeningeal anastomosis could be used to develop a novel strategy targeting enhancement of the collateral circulation.

Association Between Cerebral Small Vessel Disease and Central Motor Conduction Time in Patients with Vascular Risk.

BACKGROUND AND PURPOSE: Cerebral small vessel disease (CSVD) is related to motor function disturbance. It includes several types: lacunar infarction, white matter hyperintensity, cerebral microbleeds (CMBs), and enlarged perivascular spaces (EPVS). Transcranial magnetic stimulation (TMS) has been successfully used to evaluate the function of the pyramidal tract. Central motor conduction time (CMCT) is one of the indicators of pyramidal tract dysfunction in motor evoked potential (MEP). The aim of this study was to investigate the association between each type of CSVD and CMCT. METHODS: We enrolled 350 patients with vascular risk factors or a history of cerebrovascular events, who showed signs of CSVD in magnetic resonance imaging in the prospective registry. Among them, 138 patients agreed to the evaluation of MEP. CMCT, resting motor threshold (RMT), and silent period are indicators of the function of motor pathways in MEP. A total of 276 hemispheres were divided into 45 symptomatic hemispheres with a history of pyramidal tract dysfunction and 231 without it. Correlation between each type of CSVD and CMCT were examined in total, symptomatic, and asymptomatic hemispheres. RESULTS: The mean age was 70.5 ± 10.3 (mean ± SD) years, and 89 (65%) were men. In the symptomatic hemisphere, CMCT and RMT were significantly higher than in the asymptomatic hemisphere. In the symptomatic hemisphere, significant association was observed between the number of EPVS in the white matter and CMCT (R2 = 0.201, p < .01). CONCLUSIONS: In the symptomatic hemispheres, CMCT was associated with the number of EPVS in the white matter. The EPVS in the white matter may be involved in the motor disturbance due to CSVD.

Recurrent Cerebral Infarction Due to Benign Uterine Myoma.

The hypercoagulable state in patients with cancer has been shown to be closely associated with ischemic stroke. However, it is unlikely that benign tumors are related to stroke. The development of benign uterine tumors is common in middle-aged women. Previous studies have shown cases of ischemic stroke with benign uterine tumor, but the causal relationship between these 2 remain unknown. We report a case of recurrent ischemic stroke in a middle-aged woman who had a benign uterine tumor. After excision, there was no recurrence for 2 years. Microemboli detection, clinical course and histological findings support a relationship between uterine tumor and ischemic stroke.

Ischemic Stroke due to Virologically-Confirmed Varicella Zoster Virus Vasculopathy: A Case Series.

BACKGROUND: Limited data are available regarding the characteristics and prognosis of patients with stroke due to varicella zoster virus (VZV) vasculopathy. METHODS: We studied 4 patients (2 men and 2 women; age, 38-63 years) from a single center who developed acute ischemic stroke due to VZV vasculopathy. The virological diagnosis was confirmed by detecting VZV DNA and/or the IgG antibody to VZV in the cerebrospinal fluid. RESULTS: Three patients were taking immunosuppressive agents, including prednisolone and/or methotrexate, at baseline. Each patient had a characteristic skin rash prior to stroke, with the interval from rash to stroke onset ranging from 13 to 122 days. Two patients experienced antecedent cranial nerve palsies; one had the third, seventh, ninth, and 10th nerve palsies and the other had the fourth nerve palsy before stroke. Cerebral infarctions were located in the anterior circulation lesion (n = 1), in the posterior circulation lesion (n = 2), and in both lesions (n = 1). Intracranial arterial stenosis was only identified in one patient on magnetic resonance angiography. A high plasma d-dimer level was detected in 1 patient, whereas high ß-thromboglobulin and platelet factor 4 levels were detected in 2 patients. As a result of combined therapies with acyclovir, steroid, and antithrombotic agents, neurological symptoms markedly improved in 3 patients, whereas 1 patient was left with moderate hemiplegia. CONCLUSIONS: Cranial nerve palsies may be prodromal symptoms of VZV-associated stroke. Increased levels of thrombotic markers may support the use of antithrombotic agents, although the benefit of combined treatment should be determined through larger studies.

Associations of Mitral and Aortic Valve Calcifications with Complex Aortic Atheroma in Patients with Embolic Stroke of Undetermined Source.

BACKGROUND: This study investigated the associations of mitral and aortic valve calcification with complex aortic atheroma among patients with embolic stroke of undetermined source. METHODS: We included 52 consecutive patients (mean age 58.1 years; 75.0% male) with embolic stroke of undetermined source. Mitral annular calcification, aortic annular calcification, and aortic valve sclerosis were assessed by transthoracic echocardiography. Complex aortic atheroma was assessed by transesophageal echocardiography and was defined as plaque protruding greater than or equal to 4 mm into the lumen or with ulcerated or mobile components. RESULTS: Ten patients (19.2%) had complex aortic atheroma. Patients with and without complex aortic atheroma showed significant differences in terms of hypertension (80.0% versus 38.1%, P = .017), dyslipidemia (90.0% versus 31.0%, P <.01), chronic kidney disease (60.0% versus 14.3%, P <.01), previous coronary artery disease (30.0% versus 4.8%, P = .013), prior stroke (40.0% versus 7.1%, P <.01), left atrial dimension (4.0 cm versus 3.6 cm, P = .023), aortic valve sclerosis (80.0% versus 26.2%, P <.01), aortic valve calcification (aortic annular calcification or aortic valve sclerosis) (80.0% versus 26.0%, P <.01), and left-sided valve calcification (mitral annular calcification or aortic annular calcification or aortic valve sclerosis) (80.0% versus 28.6%, P <.01). In multivariate analysis, left-sided valve calcification was independently associated with complex aortic atheroma (odds ratio 4.1, 95% confidence interval 1.3-26.1, P = .049). CONCLUSIONS: Mitral or aortic valve calcification detected by transthoracic echocardiography can be a useful marker for predicting complex aortic atheroma in patients with embolic stroke of undetermined source.

Prolonged QTc interval predicts poststroke paroxysmal atrial fibrillation.

BACKGROUND AND PURPOSE: Paroxysmal atrial fibrillation (PAF) is often difficult to detect in patients with acute ischemic stroke. We aimed to assess the predictive value of a prolonged QT interval corrected for heart rate (QTc) in PAF detection after acute ischemic stroke. METHODS: We enrolled 972 patients with acute ischemic stroke consecutively extracted from our observational stroke registry system. Exclusion criteria were as follows: (1) AF on the initial 12-lead ECG (n=171); (2) previously diagnosed PAF (n=47); and (3) the use of a cardiac pacemaker (n=10). Of the 972 patients, 744 (mean age, 67.6 years; men, 62.6%) were eligible for analysis. The clinical characteristics and 12-lead ECG findings of the patients with and without PAF were compared, and multiple logistic regression analysis was performed to identify predictors of poststroke PAF. RESULTS: The poststroke cardiac work-up yielded 69 (9.3%) de novo PAF cases among the 744 patients. The QTc interval was significantly longer in patients with PAF than in those without PAF (436 versus 417 ms; P<0.001). Each 10-ms increase in the QTc interval was associated with an increased risk of PAF after multivariate adjustments (odds ratio, 1.41; 95% confidence interval, 1.24-1.61; P<0.001). The optimal threshold value of QTc interval calculated by a receiver-operating characteristic curve was 438 ms, and the area under the curve was 0.73 in this data set. CONCLUSIONS: The QTc interval prolongation is potentially a strong and useful predictor for poststroke PAF.

Brain natriuretic peptide in acute ischemic stroke.

Elevated serum brain natriuretic peptide (BNP) levels are associated with cardioembolic stroke mainly because of atrial fibrillation (AF). However, the mechanisms of increased serum BNP levels are hitherto unclear. We aimed to identify the factors associated with increased BNP levels in patients with acute ischemic stroke. We measured serum BNP levels in consecutive patients aged 18 years or older. Stroke subtypes were classified using the Trial of ORG 10172 in Acute Stroke Treatment criteria. Categorical variables included age, sex, smoking status, alcohol consumption status, hypertension, diabetes mellitus, dyslipidemia, coronary artery disease (CAD), AF, antiplatelet therapy, and anticoagulant therapy. Continuous variables included hemoglobin, creatinine (Cr), ß-thromboglobulin, platelet factor 4, thrombin-antithrombin complex, and d-dimer levels. We further determined the relationship between serum BNP and intima-media thickness, left ventricular ejection fraction, size of infarction, National Institutes of Health Stroke Scale score on admission, and modified Rankin Scale (mRS) score at discharge. Of the 231 patients (mean age, 71 ± 12 years) with acute ischemic stroke (AIS), 36% were women. Serum BNP levels significantly correlated with CAD, AF, Cr, mRS, and cardioembolism (CE) (Dunnett method, P = .004). BNP levels were significantly higher in patients with larger infarcts, higher mRS scores, and higher CHADS2 scores. The levels were higher in patients with larger infarcts, higher mRS scores at discharge, and higher CHADS2 scores among AF patients.

Small-Vessel Disease and Intracranial Large Artery Disease in Brain MRI Predict Dementia and Acute Coronary Syndrome, Respectively: A Prospective, Observational Study in the Population at High Vascular Risk.

BACKGROUND: We aimed to clarify the predictive value of cerebral small-vessel disease and intracranial large artery disease (LAD) observed in magnetic resonance imaging of the brain and magnetic resonance angiography on future vascular events and cognitive impairment. METHODS AND RESULTS: Data were derived from a Japanese cohort with evidence of cerebral vessel disease on magnetic resonance imaging. This study included 862 participants who underwent magnetic resonance angiography after excluding patients with a modified Rankin Scale score >1 and Mini-Mental State Examination score <24. We evaluated small-vessel disease such as white matter hyperintensities and lacunes in magnetic resonance imaging and LAD with magnetic resonance angiography. Outcomes were incident stroke, dementia, acute coronary syndrome, and all-cause death. Over a median follow-up period of 4.5 years, 54 incident stroke, 39 cases of dementia, and 27 cases of acute coronary syndrome were documented. Both small-vessel disease (white matter hyperintensities and lacunes) and LAD were associated with stroke; however, only white matter hyperintensities were related to dementia. In contrast, only LAD was associated with acute coronary syndrome. Among the 357 patients with no prior history of stroke, coronary or peripheral artery disease, or atrial fibrillation, white matter hyperintensities emerged as the sole predictor of future stroke and dementia, while LAD was the sole predictor of acute coronary syndrome. CONCLUSIONS: Among cerebral vessels, small-vessel disease could underlie the cognitive impairment while LAD was associated with coronary artery disease as atherosclerotic vessel disease.

Brachial-Ankle Pulse Wave Velocity is Associated with Incident Dementia in Patients with Cerebral Small-Vessel Disease.

AIMS: Increased arterial stiffness is associated with the severity of cerebral small-vessel disease (SVD) and may predict incident dementia. This study investigated the predictive value of brachial-ankle pulse wave velocity (ba-PWV) for dementia and cognitive decline. METHODS: Data were obtained from a Japanese cohort of 478 patients who underwent ba-PWV measurement. Magnetic resonance imaging (MRI) was used to evaluate SVD severity. The Mini-Mental State Examination (MMSE) and the Japanese version of the Montreal Cognitive Assessment (MoCA-J) were used to assess the cognitive function. The primary outcome was the incidence of dementia. The secondary outcome was cognitive change during three years of follow-up. RESULTS: The median age was 71 years old, 61% were men, and the median ba-PWV was 1787 cm/s. Dementia was diagnosed in 23 patients during a mean follow-up of 4.8 years. A Cox proportional hazard regression analysis revealed that the highest quartile (ba-PWV ≥ 2102 cm/s) was associated with a significantly higher risk of dementia than the first to third quartiles (ba-PWV ≤ 2099 cm/s) after adjusting for risk factors, the mean blood pressure, the MoCA-J score, and SVD severity (adjusted HR, 3.40; 95% CI, 1.24-9.34; P=0.018). Longitudinal cognitive changes in 192 patients indicated that ba-PWV was negatively related to changes in the MoCA-J score (r=-0.184, P=0.011). The decline in the MoCA-J score in the highest quartile was greater than that in the first to third quartiles after adjusting for risk factors, SVD severity, and baseline MoCA-J score (P=0.017). CONCLUSIONS: ba-PWV was associated with incident dementia and cognitive decline, independent of age, risk factors, the baseline cognitive function, and the SVD severity.

Association of circulating CD34+ cells level and prognosis after ischemic stroke.

BACKGROUND: CD34 is a transmembrane phosphoglycoprotein and a marker of hematopoietic and nonhematopoietic stem/progenitor cells. In experimental studies, CD34+ cells are rich sources of endothelial progenitor cells and can promote neovascularization and endothelial repair. The potential role of CD34+ cells in stroke patients remains unclear. AIMS: We aimed to assess the prognostic effect of circulating CD34+ cell levels on the risk of vascular events and functional prognosis in stroke patients. PATIENTS AND METHODS: In this prospective observational study, patients with ischemic stroke were consecutively enrolled within 1 week of onset and followed up for 1 year. Patients were divided into three groups according to tertiles of the level of circulating CD34+ cells (Tertile 1, <0.51/µL; Tertile 2, 0.51-0.96/µL; and Tertile 3, >0.96/µL). The primary outcome was a composite of major adverse cardiovascular events (MACEs), including nonfatal stroke, nonfatal acute coronary syndrome, major peripheral artery disease, and vascular death. The secondary outcomes included the modified Rankin scale (mRS) scores. RESULTS: A total of 524 patients (mean age, 71.3 years; male, 60.1%) were included. High CD34+ cell levels were associated with younger age (p < 0.001) and low National Institutes of Health Stroke Scale scores at admission (p = 0.010). No significant differences were found in the risk of MACEs among the three groups (annual rates: 15.0%, 13.4%, and 12.6% in Tertiles 1, 2, and 3, respectively; log-rank p = 0.70). However, there were significant differences in the mRS scores at 3 months (median (interquartile range); 2 (1-4), 1 (1-3), and 1 (0-2) in Tertiles 1, 2, and 3, respectively; p = 0.010) and 1 year (3 (1-4), 2 (1-4), and 1 (0-3); p < 0.001) among these groups. After multivariable adjustments, a higher CD34+ cell level was independently associated with good functional outcomes (mRS score of 0-2) at 3 months (adjusted odds ratio (OR), 1.43; 95% confidence interval (CI), 1.01-2.05) and 1 year (adjusted OR, 1.53; 95% CI, 1.09-2.16). CONCLUSION: Although no correlations were found between circulating CD34+ cell levels and vascular event risk, elevated CD34+ cell levels were associated with favorable functional recovery in stroke patients. DATA ACCESS STATEMENT: Data supporting the findings of this study are available from the corresponding author on reasonable request. CLINICAL TRIAL REGISTRATION: The TWMU Stroke Registry is registered at https://upload.umin.ac.jp as UMIN000031913.

Small vessel disease burden predicts incident stroke and all-cause death, but not acute coronary event.

Total small vessel disease (SVD) score is used to measure the burden of SVD by incorporating four established neuroimaging markers; white matter hyperintensity, lacune, cerebral microbleed, and enlarged perivascular space, ranging from 0 to 4. Whether total SVD scores predict all vascular outcomes remains unclear. This study aimed to clarify the predictive value of the total SVD score for incident stroke, mortality, and acute coronary syndrome in independent outpatients with vascular risk factors. We derived data from The Tokyo Women's Medical University Cerebrovascular Disease registry, a prospective observational registry in which 1011 patients with evidence of cerebral vessel disease on magnetic resonance imaging were enrolled. They were followed up until March 2023. The primary outcomes were stroke, all-cause death, and acute coronary syndrome (ACS). After excluding those with a modified Rankin scale score >1, Mini-mental State Examination score <24, and missing T2* images, 692 patients were included. During a median follow-up period of 4.6 years, stroke, ACS, and all-cause death occurred in 52, 24, and 45 patients, respectively. In multivariate analysis, the total SVD score was independently associated with stroke, and all-cause death but not with acute coronary syndrome. Both cutoff values of the total SVD score for stroke, and all-cause death were 1. In conclusion, the total SVD score could predict stroke and mortality but not acute coronary syndrome. Our results suggest intensive management of patients with a total SVD score ≥1 to prevent stroke and all-cause death. Patients with higher total SVD scores were significantly more likely to have a stroke (A; P = 0.012) than those with lower total SVD scores. However, no association was observed between total SVD scores and acute coronary syndrome (B, P = 0.604). For incident stroke, total SVD scores of 1 and 2 were the cutoff levels.

Association of Transcranial Doppler Microembolic Signal With Short-Term Mortality in Acute Ischemic Stroke and Active Cancer.

BACKGROUND: This study aimed to clarify the characteristics and survival prediction value of transcranial Doppler microembolic signals (MES) in patients with acute cerebral infarction and active cancer. METHODS AND RESULTS: Between 2017 and 2022, 1089 cases of acute cerebral infarction were recorded within 7 days of disease onset. Among them, transcranial Doppler was successful in 33 patients who had active cancer, and these data were analyzed in this study. The primary outcomes were stroke recurrence and mortality at 3 months. The study population had the following characteristics [median (interquartile range)]: age, 70 years (63-78); body mass index, 21.6 (20-24), National Institutes of Health Stroke Scale 3 (1-6), and modified Rankin Scale score at discharge 1 (1-4). The most common cancer types were lung (24%), pancreatic (24%), and intestinal (18%). MES was present in 16 of 33 patients (48.5%). The presence and number of MES were significantly associated with the levels of D-dimer (P <0.001) and C-reactive protein (P=0.012). Moreover, the presence of MES was associated with multiple ischemic lesions and the 3-territory sign on magnetic resonance imaging. Of the 33 patients, 9 died at 3 months, and 1 had stroke recurrence. On Cox multivariate analysis, using the MES-negative group as a reference, the presence of MES was significantly associated with all-cause death (adjusted hazard ratio, 12.19 [95% CI, 1.45-216.85]; P=0.020). CONCLUSIONS: In patients with acute ischemic stroke and active cancer, the presence of MES was associated with D-dimer and C-reactive protein levels and multiple and 3-territory ischemic lesions, and was predictive of short-term survival.

Hyperhomocysteinemia Increases Vascular Risk in Stroke Patients with Chronic Kidney Disease.

AIMS: We aimed to assess the prognostic impact of hyperhomocysteinemia (HHcy) on the recurrent vascular event risk in stroke patients with or without chronic kidney disease (CKD). METHODS: In this prospective observational study, 621 patients (mean age, 69.5 years; male, 62.2%) with ischemic stroke or transient ischemic attack were consecutively enrolled within 1 week of onset and followed-up for 1 year. HHcy was defined as elevated levels of fasting total homocysteine ＞15 µmol/L. CKD was defined as an estimated glomerular filtration rate of ＜60 mL/min/1.73 m2 or a history of renal replacement therapy. The primary outcome was a composite of major adverse cardiovascular events (MACEs), including nonfatal stroke, nonfatal acute coronary syndrome, major peripheral artery disease, and vascular death. RESULTS: The prevalence of HHcy was 18.5%. Patients with HHcy were more likely to have intracranial (37.4% versus 24.8%; p=0.008) and extracranial (20.9% versus 13.0%; p=0.037) artery stenosis than were those without HHcy. At 1 year, patients with HHcy were at a greater risk of MACE than were those without HHcy (annual rate, 17.8% versus 10.4%; log-rank p=0.033). In the Cox proportional hazard regression models, HHcy was independently associated with an increased risk of MACE in patients with CKD (adjusted hazard ratio [HR], 2.06; 95% confidence interval [CI], 1.02-4.20), whereas HHcy was not predictive of MACE in those without CKD (adjusted HR, 1.00; 95% CI, 0.30-3.32). CONCLUSIONS: Elevated levels of serum homocysteine can be an important modifiable risk factor in stroke patients with CKD, but not in those without CKD.