Higher Frequency of Premature Atrial Contractions Correlates With Atrial Fibrillation Detection after Cryptogenic Stroke.

BACKGROUND: Covert atrial fibrillation (AF) is a major cause of cryptogenic stroke. This study investigated whether a dose-dependent relationship exists between the frequency of premature atrial contractions (PACs) and AF detection in patients with cryptogenic stroke using an insertable cardiac monitor (ICM). METHODS: We enrolled consecutive patients with cryptogenic stroke who underwent ICM implantation between October 2016 and September 2020 at 8 stroke centers in Japan. Patients were divided into 3 groups according to the PAC count on 24-hour Holter ECG: ≤200 (group L), >200 to ≤500 (group M), and >500 (group H). We defined a high AF burden as above the median of the cumulative duration of AF episodes during the entire monitoring period. We evaluated the association of the frequency of PACs with AF detection using log-rank trend test and Cox proportional hazard model and with high AF burden using logistic regression model, adjusting for age, sex, CHADS2 score. RESULTS: Of 417 patients, we analyzed 381 patients with Holter ECG and ICM data. The median age was 70 (interquartile range, 59.5-76.5), 246 patients (65%) were males, and the median duration of ICM recording was 605 days (interquartile range, 397-827 days). The rate of new AF detected by ICM was higher in groups with more frequent PAC (15.5%/y in group L [n=277] versus 44.0%/y in group M [n=42] versus 71.4%/y in group H [n=62]; log-rank trend P<0.01). Compared with group L, the adjusted hazard ratios for AF detection in groups M and H were 2.11 (95% CI, 1.24-3.58) and 3.23 (95% CI, 2.07-5.04), respectively, and the adjusted odds ratio for high AF burden in groups M and H were 2.57 (95% CI, 1.14-5.74) and 4.25 (2.14-8.47), respectively. CONCLUSIONS: The frequency of PACs was dose-dependently associated with AF detection in patients with cryptogenic stroke.

One-year morbidity and mortality in patients treated with standard-dose and low-dose apixaban after acute large vessel occlusion stroke.

Although low-dose direct oral anticoagulants (DOACs) are recommended for patients at high risk of bleeding complications, it remains unclear whether the dose reduction in real-world setting is also appropriate in patients after large-vessel occlusion (LVO) stroke. This study hypothesized that patients with atrial fibrillation (AF) and LVO receiving low-dose DOACs have an increased risk of ischemic and hemorrhagic events. The study aimed to assess 1 year morbidity and mortality in patients treated with standard-dose and low-dose apixaban after LVO stroke. A post hoc analysis was performed using the acute LVO registry data, which enrolled patients with AF and LVO who received apixaban within 14 days of stroke onset. The incidences of ischemic events (ischemic stroke, acute coronary syndrome, acute myocardial infarction, and systemic embolism), major bleeding events, and death from any cause were compared between patients receiving standard- and low-dose apixaban. Of 643 patients diagnosed with LVO, 307 (47.7%) received low-dose apixaban. After adjustment for clinically relevant variables, no significant differences were observed in the incidence of ischemic events (adjusted hazard ratio [aHR]: 2.12, 95% confidence interval [CI] 0.75-6.02), major bleeding events (aHR: 1.17, 95% CI 0.50-2.73), and death from any cause (aHR: 1.95, 95% CI 0.78-4.89) between patients receiving standard- and low-dose apixaban. No significant differences were observed in the incidence of ischemic events, major bleeding events, or death from any cause between patients with AF and LVO receiving standard- and low-dose apixaban.

Adult-onset botulism in a Japanese woman with prolonged spore excretion.

We report a case of an 80-year-old woman with botulism from 2020 in Osaka, Japan. The patient complained of dysarthria and dizziness. On the same day, the patient developed respiratory failure, and was intubated and placed on mechanical ventilation. Subsequently, ophthalmoparesis and quadriparesis progressed rapidly. Ten days after onset, the patient failed to respond to any external stimulation. Blood tests showed anemia, and computed tomography revealed undiagnosed cervical cancer. Initially, diagnosis of neuromuscular junction disorder and acute motor neuropathy, including paraneoplastic syndrome, were considered. However, intravenous immunoglobulin therapy and plasma exchange were ineffective. A fecal sample on day 30 showed a large number of C. botulinum spores. On day 34, a mouse bioassay revealed botulinum toxin type A in the patient's serum; therefore, a botulinum antitoxin was administered. Later, the patient's muscle strength was gradually improved. However, severe muscle paralysis persisted, and the patient died of cachexia owing to cervical cancer on day 196. The etiology of this case was unknown because no contaminated food was identified during an inspection of the patient's home. Fecal 16S rRNA gene sequencing revealed dysbiosis of the intestinal microbiota with abundant Enterococcus species. Long-lasting excretion of substantial botulinum spores even on day 30 indicated colonization of C. botulinum in the intestinal tract. This case suggests that C. botulinum colonization with co-existing intestinal dysbiosis may be associated with severe and prolonged symptoms of botulism.

CREB Coactivator CRTC2 Plays a Crucial Role in Endothelial Function.

The cAMP pathway is known to stabilize endothelial barrier function and maintain vascular physiology. The family of cAMP-response element binding (CREB)-regulated transcription coactivators (CRTC)1-3 activate transcription by targeting the basic leucine zipper domain of CREB. CRTC2 is a master regulator of glucose metabolism in liver and adipose tissue. However, the role of CRTC2 in endothelium remains unknown. The aim of this study was to evaluate the effect of CRTC2 on endothelial function. We focused the effect of CRTC2 in endothelial cells and its relationship with p190RhoGAP-A. We examined the effect of CRTC2 on endothelial function using a mouse aorta ring assay ex vivo and with photothrombotic stroke in endothelial cell-specific CRTC2-knock-out male mice in vivo CRTC2 was highly expressed in endothelial cells and related to angiogenesis. Among CRTC1-3, only CRTC2 was activated under ischemic conditions at endothelial cells, and CRTC2 maintained endothelial barrier function through p190RhoGAP-A expression. Ser171 was a pivotal regulatory site for CRTC2 intracellular localization, and Ser307 functioned as a crucial phosphorylation site. Endothelial cell-specific CRTC2-knock-out mice showed reduced angiogenesis ex vivo, exacerbated stroke via endothelial dysfunction, and impaired neurologic recovery via reduced vascular beds in vivo These findings suggest that CRTC2 plays a crucial protective role in vascular integrity of the endothelium via p190RhoGAP-A under ischemic conditions.SIGNIFICANCE STATEMENT Previously, the role of CRTC2 in endothelial cells was unknown. In this study, we firstly clarified that CRTC2 was expressed in endothelial cells and among CRTC1-3, only CRTC2 was related to endothelial function. Most importantly, only CRTC2 was activated under ischemic conditions at endothelial cells and maintained endothelial barrier function through p190RhoGAP-A expression. Ser307 in CRTC2 functioned as a crucial phosphorylation site. Endothelial cell-specific CRTC2-knock-out mice showed reduced angiogenesis ex vivo, exacerbated stroke via endothelial dysfunction, and impaired neurologic recovery via reduced vascular beds in vivo These results suggested that CRTC2 maybe a potential therapeutic target for reducing blood-brain barrier (BBB) damage and improving recovery.

Sex Differences in Blood Pressure-Lowering Therapy and Outcomes Following Intracerebral Hemorrhage: Results From ATACH-2.

BACKGROUND AND PURPOSE: Evidence regarding sex differences in clinical outcomes and treatment effect following intracerebral hemorrhage is limited. Using the ATACH-2 trial (Antihypertensive Treatment in Intracerebral Hemorrhage-2) data, we explored whether sex disparities exist in outcomes and response to intensive blood pressure (BP)-lowering therapy. METHODS: Eligible intracerebral hemorrhage subjects were randomly assigned to intensive (target systolic BP, 110-139 mm Hg) or standard (140-179 mm Hg) BP-lowering therapy within 4.5 hours after onset. Relative risk of death or disability corresponding to the modified Rankin Scale score of 4 to 6 was calculated, and interaction between sex and treatment was explored. RESULTS: In total, 380 women and 620 men were included. Women were older, more prescribed antihypertensive drugs before onset, and had more lobar intracerebral hemorrhage than men. Hematoma expansion was observed less in women. After multivariable adjustment, the relative risk of death or disability in women was 1.19 (95% CI, 1.02-1.37, P=0.023). The relative risk of death or disability between intensive versus standard BP-lowering therapy was 0.91 (95% CI, 0.74-1.13) in women versus 1.13 (95% CI, 0.92-1.39) in men (P for interaction=0.11), with inconclusive Gail-Simmon test (P=0.16). CONCLUSIONS: Women had a higher risk of death or disability following intracerebral hemorrhage. The benefit of intensive BP-lowering therapy in women is inconclusive, consistent with the overall results of ATACH-2. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01176565.

Frequent Premature Atrial Contractions in Cryptogenic Stroke Predict Atrial Fibrillation Detection with Insertable Cardiac Monitoring.

OBJECTIVE: To determine whether frequent premature atrial contractions (PAC) predict atrial fibrillation (AF) in cryptogenic stroke patients, we analyzed the association between frequent PACs in 24-h Holter electrocardiogram recording and AF detected by insertable cardiac monitoring (ICM). METHODS: We retrospectively analyzed a database of 66 consecutive patients with cryptogenic stroke who received ICM implantation between October 2016 and March 2018 at 5 stroke centers. We included the follow-up data until June 2018 in this analysis. We defined frequent PACs as the upper quartile of the 66 patients. We analyzed the association of frequent PACs with AF detected by ICM. RESULTS: Frequent PACs were defined as >222 PACs per a 24-h period. The proportion of patients with newly detected AF by ICM was higher in patients with frequent PACs than those without (50% [8/16] vs. 22% [11/50], p < 0.05). Frequent PACs were associated with AF detection and time to the first AF after adjustment for CHADS2 score after index stroke, high plasma -B-type natriuretic peptide (BNP; >100 pg/mL) or serum -N-terminal pro-BNP levels (>300 pg/mL), and large left atrial diameter (≥45 mm). CONCLUSION: High frequency of PACs in cryptogenic stroke may be a strong predictor of AF detected by ICM.

Late Neurological Deterioration after Acute Intracerebral Hemorrhage: A post hoc Analysis of the ATACH-2 Trial.

BACKGROUND: Neurological deterioration (ND) has a major influence on the prognosis of intracerebral hemorrhage (ICH); however, factors associated with ND occurring after 24 h of ICH onset are unknown. METHODS: We performed exploratory analyses of data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 trial, which compared intensive and standard blood pressure lowering treatment in ICH. NDs were captured on the adverse event case report form. Logistic regression analysis was performed to examine the independent predictors of late ND. RESULTS: Among 1,000 participants with acute ICH, 82 patients (8.2%) developed early ND (≤24 h), and 64 (6.4%) had late ND. Baseline hematoma volume (adjusted OR [aOR] per 1-cm3 increase 1.04, 95% CI 1.02-1.06, p < 0.0001), hematoma volume increase in 24 h (aOR 2.24, 95% CI 1.23-4.07, p = 0.008), and the presence of intraventricular hemorrhage (IVH; aOR 2.38, 95% CI 1.32-4.29, p = 0.004) were independent predictors of late ND (vs. no late ND). Late ND was a significant risk factor for poor 90-day outcome (OR 3.46, 95% CI 1.82-6.56). No statistically significant difference in the incidence of late ND was noted between the 2 treatment groups. CONCLUSIONS: Initial hematoma volume, early hematoma volume expansion, and IVH are independent predictors of late ND after ICH. Intensive reduction in the systolic blood pressure level does not prevent the development of late ND.

The Prospective Studies of Atherosclerosis (Proof-ATHERO) Consortium: Design and Rationale.

Atherosclerosis - the pathophysiological mechanism shared by most cardiovascular diseases - can be directly or indirectly assessed by a variety of clinical tests including measurement of carotid intima-media thickness, carotid plaque, -ankle-brachial index, pulse wave velocity, and coronary -artery calcium. The Prospective Studies of Atherosclerosis -(Proof-ATHERO) consortium (https://clinicalepi.i-med.ac.at/research/proof-athero/) collates de-identified individual-participant data of studies with information on atherosclerosis measures, risk factors for cardiovascular disease, and incidence of cardiovascular diseases. It currently comprises 74 studies that involve 106,846 participants from 25 countries and over 40 cities. In summary, 21 studies recruited participants from the general population (n = 67,784), 16 from high-risk populations (n = 22,677), and 37 as part of clinical trials (n = 16,385). Baseline years of contributing studies range from April 1980 to July 2014; the latest follow-up was until June 2019. Mean age at baseline was 59 years (standard deviation: 10) and 50% were female. Over a total of 830,619 person-years of follow-up, 17,270 incident cardiovascular events (including coronary heart disease and stroke) and 13,270 deaths were recorded, corresponding to cumulative incidences of 2.1% and 1.6% per annum, respectively. The consortium is coordinated by the Clinical Epidemiology Team at the Medical University of Innsbruck, Austria. Contributing studies undergo a detailed data cleaning and harmonisation procedure before being incorporated in the Proof-ATHERO central database. Statistical analyses are being conducted according to pre-defined analysis plans and use established methods for individual-participant data meta-analysis. Capitalising on its large sample size, the multi-institutional collaborative Proof-ATHERO consortium aims to better characterise, understand, and predict the development of atherosclerosis and its clinical consequences.

Cortical Cerebral Microinfarcts on 3T Magnetic Resonance Imaging in Patients With Carotid Artery Stenosis.

Background and Purpose- Carotid artery stenosis is common in the elderly and contributes to cognitive impairment and dementia. Cortical cerebral microinfarcts (CMIs) play an important role in vascular cognitive impairment and dementia. We aimed to investigate the association between CMIs on 3T magnetic resonance imaging and clinical and radiological features, including plaque morphology, and cognitive function in patients with carotid stenosis. Methods- Eighty-nine patients with >30% carotid stenosis on ultrasound were prospectively enrolled, and underwent brain and carotid artery magnetic resonance imaging. CMIs were rated according to predetermined criteria based on 3D-double inversion recovery and fluid-attenuated inversion recovery images. Results- CMIs were identified in 26 patients (29%; median number 0, range 0-9). Poisson regression models adjusted for age and sex revealed that CMIs were associated with intraplaque hemorrhage (rate ratio, 1.95; 95% CI, 1.26-3.18), lacunar infarcts (rate ratio, 1.54; 95% CI, 1.00-2.44), and cortical infarcts (rate ratio, 3.22; 95% CI, 2.20-5.00). These associations were also observed in asymptomatic patients (n=64). Of 81 patients with unilateral carotid stenosis, the prevalence and number of CMIs were significantly higher in the hemisphere ipsilateral to the carotid stenosis than in the contralateral hemisphere ( P=0.005 and P<0.001, respectively). The presence of CMIs was associated with poor cognitive function. Conclusions- Our results indicate that vulnerable carotid plaque increases the risk of CMIs and subsequent cognitive impairment. Carotid atherosclerosis could be a potential therapeutic target for cognitive impairment.

Prevalence of RNF213 p.R4810K Variant in Early-Onset Stroke With Intracranial Arterial Stenosis.

Background and Purpose- The ring finger protein 213 gene ( RNF213) is a susceptibility gene for moyamoya disease and large-artery ischemic stroke in East Asia. We examined the prevalence and correlates of the RNF213 p.R4810K variant in patients with early-onset ischemic stroke in a Japanese single-center cohort. Methods- We analyzed 70 early-onset stroke patients with intracranial arterial stenosis who developed a noncardioembolic stroke or transient ischemic attack from 20 to 60 years of age. Patients with moyamoya disease were excluded. Results- The RNF213 p.R4810K variant was found in 17 patients (24%), and more often in women than men (38% versus 16%, odds ratio 3.3; 95% CI, 1.1-10.2, P=0.04). The variant was identified in 35% of patients with stenosis in the M1 segment of the middle cerebral artery or the A1 segment of the anterior cerebral artery (odds ratio, 25.0; 95% CI, 1.4-438; P<0.01) but in only one patient (9%) with intracranial posterior circulation stenosis. Conventional atherosclerotic risk factors did not differ between variant carriers and noncarriers. Conclusions- The RNF213 p.R4810K variant is common in early-onset ischemic stroke with anterior circulation stenosis in Japan. Further investigation of the RNF213 gene will provide new insights into pathogenetic mechanisms of early-onset stroke.

Relationship Between Bacteremia and Hemorrhagic Stroke in Patients With Continuous-Flow Left Ventricular Assist Device.

BACKGROUND: Blood stream infection is thought to increase the risk of hemorrhagic stroke, a major adverse event with devastating outcome, in patients with continuous-flow left ventricular assist devices (LVADs). We analyzed the risk factors of hemorrhagic stroke in LVAD patients, as well as the time relationship between systemic bacteremia and hemorrhagic stroke.Methods and Results:We evaluated the incidence of systemic bacteremia and stroke in 164 patients who underwent continuous-flow LVAD implantation between 2005 and 2016. At 1 and 2 years after implantation, the incidence of bacteremia was 29% and 36%, and the incidence of hemorrhagic stroke was 22% and 22% in patients without bacteremia, and 32% and 44% in those with bacteremia, respectively (P=0.035). This higher prevalence of hemorrhagic stroke in patients with bacteremia was notable particularly in the chronic phase (>90 days after implantation). Multivariate analysis revealed that bacteremia was an independent risk factor of hemorrhagic stroke in the chronic phase [hazard ratio, 2.36 (1.02-5.62); P=0.044]. The hazard rate was the highest immediately after the onset of bacteremia, and the risk steadily declined by 90 days after the last episode of bacteremia and flattened thereafter. CONCLUSIONS: Bacteremia was an independent risk factor of hemorrhagic stroke in patients in the chronic phase, with the highest risk seen in the early phase following an episode of bacteremia.

Arterial Spin Labeling Cerebral Perfusion Magnetic Resonance Imaging in Migraine Aura: An Observational Study.

BACKGROUND: Changes in cerebral perfusion during migraine with aura (MA) have been assessed mainly using dynamic susceptibility contrast (DSC) magnetic resonance perfusion imaging. A contrast agent-free method to assess these changes would be desirable. We assessed changes in cerebral perfusion during MA using arterial spin labeling (ASL) perfusion magnetic resonance imaging. METHODS: We investigated 4 patients with a standardized protocol including ASL perfusion imaging during MA (n = 2) or early headache phase (n = 2) and asymptomatic follow-up. Semiquantitative evaluation was done using a region of interest (ROI) within hypoperfused or hyperperfused areas and corresponding ROIs in the contralateral hemisphere. Relative ratios of mean perfusion in the corresponding ROIs were calculated. DSC imaging was done at initial time points and compared visually with ASL findings. RESULTS: In all patients, regional perfusion changes were detected in the acute phase. These abnormalities did not respect the boundaries of major cerebral vascular territories but overlapped onto adjoining regions. During MA, adjacent hypoperfused and hyperperfused areas were found, whereas during headache, regional hyperperfusion only was observed. Perfusion abnormalities normalized on follow-up. CONCLUSIONS: ASL perfusion imaging is a contrast agent-free method suitable for assessment of reversible perfusion changes during or immediately after MA.

Relationship Between Infarct Volume and Prothrombin Time-International Normalized Ratio in Ischemic Stroke Patients With Nonvalvular Atrial Fibrillation.

BACKGROUND: In Japan, warfarin treatment at prothrombin time-international normalized ratio (PT-INR) of 1.60-2.60 is recommended for elderly patients with nonvalvular atrial fibrillation (NVAF). But it remains unknown whether PT-INR 1.60-1.99 has a similar effect on stroke severity as a value >2.0. The purpose of this study was to clarify the association between infarct volume and PT-INR levels.Methods and Results:The 180 patients (mean age, 76 years [SD, 10 years], 53% male) selected from 429 consecutive ischemic stroke patients admitted within 48 h of onset between 2004 and 2014 with NVAF were included. We classified them into 4 groups according to their PT-INR values on admission: no warfarin (NW), 129 patients; PT-INR <1.60 (poor control: PC), 29 patients; PT-INR 1.60-1.99 (low-intensity control: LC), 14 patients; and PT-INR ≥2.00 (high-intensity control: HC), 8 patients. Median (interquartile range: IQR) of infarct volume was 55 mL (IQR 14-175) in the NW, 42 mL (IQR 27-170) in the PC, 36 mL (IQR 6-130) in the LC, and 11 mL (IQR 0-39) in the HC groups. The infarct volume of the HC group was significantly smaller than in the other 3 groups, but no difference existed between the LC and PC groups or the LC and NW groups. CONCLUSIONS: Warfarin control at PT-INR of 1.60-1.99 is not effective for reducing the severity of ischemic stroke in NVAF patients.

Prediction of Early Reperfusion From Repeated Arterial Spin Labeling Perfusion Magnetic Resonance Imaging During Intravenous Thrombolysis.

BACKGROUND AND PURPOSE: There are few in vivo data on the pathophysiology of reperfusion during systemic thrombolysis. We monitored the time course of cerebral perfusion changes in patients during thrombolysis with repeated arterial spin labeling perfusion magnetic resonance imaging. METHODS: Ten patients with proximal arterial occlusion within 4.5 hours after symptom onset were prospectively enrolled. All patients received intravenous thrombolysis during the magnetic resonance imaging examination. Repeated arterial spin labeling perfusion images were acquired during the 60-minute therapy and at follow-up after 24 to 72 hours. Clinical data, magnetic resonance imaging features, and cerebral perfusion changes were analyzed. RESULTS: Before thrombolysis, arterial spin labeling hypoperfusion and fluid-attenuation inversion recovery vascular hyperintensity in the territory of the occluded arteries were observed in all patients. In 5 patients, extensive arterial transit artifacts (ATA) developed in the hypoperfused area. The ATA corresponded with fluid-attenuation inversion recovery vascular hyperintensities. All 5 patients who developed extensive ATA in the hypoperfused area had complete reperfusion after thrombolysis, whereas the 5 without extensive ATA showed no or only partial reperfusion (P<0.01). The development of ATA preceded the normalization of tissue perfusion. CONCLUSIONS: The development of ATA during thrombolysis is associated with early reperfusion after thrombolysis. arterial spin labeling assessment during intravenous thrombolysis has the potential to guide subsequent therapeutic strategies in patients with acute stroke.

Prevalence of positive diffusion-weighted imaging findings and ischemic stroke recurrence in transient ischemic attack.

BACKGROUND: The relationship between transient ischemic attack (TIA) clinical etiology, positive diffusion-weighted imaging (DWI) findings, and stroke recurrence is controversial. This study aimed to clarify the prevalence of positive DWI findings and TIA recurrence in relation to TIA patient characteristics. METHODS: The subjects were patients admitted to our stroke unit within 7 days after symptom onset between January 2006 and July 2013. We examined DWI findings and TIA recurrence according to etiologic subtypes. RESULTS: We enrolled 139 patients with lacunar TIA (n = 17), atherothrombotic TIA (n = 35), cardioembolic TIA (n = 25), TIA due to other causes (n = 32), or TIA with undetermined etiology (n = 30). The prevalence of positive DWI findings was highest among the cardioembolic TIA patients (56.0%). No association was found between the prevalence of positive DWI findings and symptom duration, motor presence, or ABCD(2) score. Plasma d-dimer level was significantly higher in the DWI-positive group than that in the DWI-negative group (P = .01). The prevalence of TIA recurrence was highest (5 of 35, 14.3%) among the atherothrombotic TIA patients, regardless of positive DWI findings. None of the patients treated with the anticoagulant and antiplatelet combination therapy experienced a recurrence. In contrast, almost all patients with cardioembolic TIA received anticoagulant treatment and none experienced recurrence. CONCLUSIONS: The prevalence of positive DWI findings was high among the cardiogenic TIA patients. TIA recurrence was often observed among the atherothrombotic TIA patients treated with antiplatelets. Management of patients with atherothrombotic TIA requires further aggressive antithrombotic strategy.

Association of interleukin-6 with the progression of carotid atherosclerosis: a 9-year follow-up study.

BACKGROUND AND PURPOSE: Limited information is available on the long-term effects of interleukin-6 (IL-6) on systemic atherosclerosis. The purpose of the present study was to clarify the relationship between chronic elevation of IL-6 and the long-term progression of carotid atherosclerosis. METHODS: We prospectively evaluated 210 patients with ≥1 vascular risk factors for 9.0±1.0 years. Carotid mean-maximal intima-media thickness (mmIMT), the serum high-sensitivity C-reactive protein (hs-CRP) level, and the serum IL-6 level were measured at baseline and every 3 years. The associations between the progression of mmIMT and the long-term average levels of hs-CRP and IL-6 were analyzed. RESULTS: Carotid mmIMT increased throughout the study period (0.031±0.026 mm/y). Baseline mmIMT was significantly associated with baseline hs-CRP (P=0.002) and baseline IL-6 (P<0.001) levels. Progression of mmIMT was positively correlated with average hs-CRP (P=0.001) and average IL-6 (P<0.001) levels. When adjusted for age, sex, traditional risk factors, and baseline mmIMT, mmIMT progression remained significantly associated only with the average IL-6 level (standardized ß=0.17; P=0.02), but not with the average hs-CRP level (standardized ß=0.10; P=0.18). CONCLUSIONS: Chronic elevation of serum IL-6 was associated with the progression of atherosclerosis in patients with vascular risk factors. IL-6 could be used as a quantitative marker and a potential therapeutic target for accelerated atherosclerosis.

Echogenicity of medium-to-large carotid plaques predicts future vascular events.

BACKGROUND: Although the echolucent plaque in carotid stenosis is associated with future ischemic stroke, the predictive value of echogenicity in small and medium size carotid plaques on vascular events has not been thoroughly examined. Thus, we prospectively tested the hypothesis that plaque echogenicity of carotid atheroma can predict the future total cardiovascular events in patients with vascular risk factors. METHODS: Ultrasound assessment of carotid intima-media complex thickness (IMT) and plaque echogenicity using integrated backscatter (IBS) analysis was performed in 596 patients aged 40 or more, with any history of vascular events or with at least 1 risk factor, who were enrolled between 2001 and 2006 in the Osaka Follow-up Study for Carotid Atherosclerosis, part 2 (OSACA2). We followed the incidence of total cardiovascular events including cerebrovascular events, coronary heart disease (CHD), and peripheral artery disease (PAD) for 6.4 years. We divided the patients into two groups according to the IBS index above (echorich plaques) and under (echolucent plaque) the median value, and calculated the hazard ratios (HR) of the echolucent group compared with the echogenic group in the risk of cardiovascular events. RESULTS: Among 596 patients, carotid stenosis was found only in 87 patients. During the follow-up period, we observed 121 cardiovascular events including 63 cerebrovascular events, 45 CHD cases, and 13 PAD cases. The patients with incident cardiovascular events had larger plaque thickness and lower IBS index than those without incident vascular events. The relative risk of vascular events for echolucent versus echorich plaques was 1.45 (95% confidence interval [CI] 0.99-2.13, p = 0.058) after adjustment for risk factors and plaque thickness. In patients with plaque size above the median value (>2.1 mm), the relative risk of vascular events for echolucent plaques was 1.72 (95% CI 1.06-2.85, p = 0.029), but this association was not observed in patients with plaque size <2.0 mm. CONCLUSIONS: The association between echogenicity of carotid plaque and incident vascular events is dependent on the plaque size. Echolucent medium-to-large plaques, but not small plaques, are associated with the risk of future total cardiovascular events. This finding suggests that measurement of echolucency in medium-to-large carotid plaques may improve selection of patients at high risk for total vascular events.

Association between interleukin-6 levels and first-ever cerebrovascular events in patients with vascular risk factors.

OBJECTIVE: The objective of this study was to examine the association of inflammatory markers with risk of first-ever cerebrovascular events (CVEs), while simultaneously evaluating subclinical vascular disease. METHODS AND RESULTS: We enrolled 464 outpatients who had vascular risk factors without any preexisting cardiovascular disease. We examined the presence of silent lacunar infarction (SLI) by magnetic resonance imaging; carotid intima-media thickness by ultrasound; and measured high-sensitivity C-reactive protein, interleukin (IL)-6, and IL-18 at baseline, and assessed their associations with CVEs using Cox proportional hazards models of 4.8±2.6 years follow-up. We further calculated measures of reclassification and discrimination. In age- and sex-adjusted analysis, IL-6, but neither high-sensitivity C-reactive protein nor IL-18, was associated with CVEs. The association remained significant after adjustment for conventional risk factors, intima-media thickness, and SLI (hazard ratios: 1.80, per 1-SD increase in log IL-6, P=0.03). Compared with the patients with below median IL-6 without SLI, those with above median IL-6 and SLI had a higher risk of CVEs (hazard ratios: 4.14, P=0.0014). The combination of IL-6 and SLI resulted in the net reclassification improvement of 14.3% (P=0.04), and the integrated discrimination improvement gain of 2.1% (P=0.05). CONCLUSIONS: IL-6 levels were independently associated with CVEs and could improve reclassification in those with SLI.