Prevalence of Mutations in Mendelian Stroke Genes in Early Onset Stroke Patients.

OBJECTIVE: Heritability of stroke is assumed not to be low, especially in the young stroke population. However, most genetic studies have been performed in highly selected patients with typical clinical or neuroimaging characteristics. We investigated the prevalence of 15 Mendelian stroke genes and explored the relationships between variants and the clinical and neuroimaging characteristics in a large, unselected, young stroke population. METHODS: We enrolled patients aged ≤55 years with stroke or transient ischemic attack from a prospective, nationwide, multicenter stroke registry. We identified clinically relevant genetic variants (CRGVs) in 15 Mendelian stroke genes (GLA, NOTCH3, HTRA1, RNF213, ACVRL1, ENG, CBS, TREX1, ABCC6, COL4A1, FBN1, NF1, COL3A1, MT-TL1, and APP) using a customized, targeted next generation sequencing panel. RESULTS: Among 1,033 patients, 131 (12.7%) had 28 CRGVs, most frequently in RNF213 (n = 59), followed by ABCC6 (n = 53) and NOTCH3 (n = 15). The frequency of CRGVs differed by ischemic stroke subtypes (p < 0.01): the highest in other determined etiology (20.1%), followed by large artery atherosclerosis (13.6%). It also differed between patients aged ≤35 years and those aged 51 to 55 years (17.1% vs 9.3%, p = 0.02). Only 27.1% and 26.7% of patients with RNF213 and NOTCH3 variants had typical neuroimaging features of the corresponding disorders, respectively. Variants of uncertain significance (VUSs) were found in 15.4% patients. INTERPRETATION: CRGVs in 15 Mendelian stroke genes may not be uncommon in the young stroke population. The majority of patients with CRGVs did not have typical features of the corresponding monogenic disorders. Clinical implications of having CRGVs or VUSs should be explored. ANN NEUROL 2023;93:768-782.

Plasma osteoprotegerin level is associated with hemorrhagic transformation in stroke patients who underwent endovascular thrombectomy.

OBJECTIVE: Osteoprotegerin (OPG) is a component of the tumor necrosis factor receptor superfamily. Several studies have shown a relationship between OPG and cardiovascular disease. We investigated the association between plasma OPG levels and hemorrhagic transformation in stroke patients who received endovascular thrombectomy (EVT). METHODS: We prospectively enrolled 360 patients diagnosed with acute ischemic stroke and performed EVT from April 2014 to December 2020. Blood sampling for plasma OPG was performed after fasting for 12 h after EVT. Hemorrhagic transformation was defined using the definition and classification of the European Cooperative Acute Stroke Study-3 trial. RESULTS: Of all the included patients, 130 (36.1%) experienced hemorrhagic transformation. The mean ± standard deviation of the plasma OPG concentrations was 200.2 ± 74.4 pg/mL. In multivariable analysis, after adjusting for age, sex, body mass index (BMI), and variables with p < 0.1 in univariable analysis (diabetes mellitus, atrial fibrillation, coronary artery disease, alcohol intake, current smoking, NIHSS, ASPECT score, mass effect, hemoglobin, vitamin D 25(OH)D), increased plasma OPG concentration was independently related to any hemorrhagic transformation (highest tertile vs. lowest tertile of OPG; odds ratio [OR] 2.31, 95% confidence interval [CI] (1.29-4.14), p = 0.005) and severity of hemorrhagic transformation (OR 2.92, 95% CI (1.66-5.12), p = 0.001). CONCLUSIONS: Our results demonstrate that increased plasma OPG level is related to the occurrence and severity of hemorrhagic transformation in patients with cerebral infarction who receive EVT.

The association of plasma osteoprotegerin levels and functional outcomes post endovascular thrombectomy in acute ischemic stroke patients: a retrospective observational study.

Background: Osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor, is a tumor necrosis factor receptor superfamily component. There is an established relationship between OPG and cardiovascular disease. We hypothesized that plasma OPG levels are associated with functional outcomes in acute ischemic stroke patients who have undergone endovascular thrombectomy (EVT). Methods: From April 2014 through December 2020, a total of 360 acute ischemic stroke patients who underwent EVT were prospectively included in this retrospective observational study. Plasma OPG was measured after fasting for 12 postoperative hours after EVT. A modified Rankin Scale (mRS) was used to assess functional outcomes 3 months after index stroke occurrence. Univariate and multivariate binary logistic regression and ordinal logistic regression analyses were performed to investigate the association of plasma OPG levels with poor functional outcomes. Results: Overall, 145 (40.2%) patients had poor (mRS > 2) outcomes. The mean ± standard deviation plasma OPG level was 200.2 ± 74.4 pg/mL. Multivariate analysis after adjusting for sex, body mass index, and variables with p < 0.1 in the preceding univariate analysis revealed high plasma OPG levels were independently associated with poor functional outcomes (highest tertile vs. lowest tertile of OPG; odds ratios (OR) 2.121, 95% confidence interval (CI) [1.089-4.191], p = 0.037 in binary logistic regression, OR 2.102, 95% CI [1.301-3.412], p = 0.002 in ordinal logistic regression analysis). Conclusions: This study demonstrated that higher plasma OPG levels were associated with poor functional outcomes in acute ischemic stroke patients who underwent EVT.

Analysis of microRNA signatures in ischemic stroke thrombus.

BACKGROUND: We investigated the microRNA expression pattern from thrombus retrieved by mechanical thrombectomy in acute stroke patients to understand the stroke mechanism. METHODS: This study included acute ischemic stroke patients who had undergone intra-arterial thrombectomy at Chung-Ang University Hospital in Seoul, Korea between February 2016 and March 2019. The thrombus was retrieved and stored at -70℃ after obtaining informed consent. MicroRNA microarray analysis was performed for the patients with identified stroke mechanisms including (1) large artery atherosclerosis, (2) cardioembolism with atrial fibrillation, and (3) cardioembolism with valvular heart disease. The microRNAs derived from microarray analysis were validated by quantitative real-time polymerase chain reaction (qRT-PCR) from different patient populations. The correlation analysis was performed between microRNA levels and laboratory data to understand the functional relevance of the altered microRNA. RESULTS: In total, 55 thrombi were obtained from 74 patients, and the microRNAs were analyzed in 45 samples. Microarray analysis of 2578 microRNAs revealed that 50 microRNAs were significantly altered among the three groups. Validation using qRT-PCR showed that miR-378f and miR-450b-5p were significantly elevated among the cardioembolic thrombi; both microRNAs were inversely correlated with the ejection fraction from echocardiography. Thrombi from patients with early neurological deterioration exhibited higher levels of miR-93-5p and lower levels of miR-629-5p than those from neurologically stable patients. CONCLUSIONS: The microRNA expression pattern can provide information regarding the mechanism of stroke by reflecting the underlying pathological status of the organ from which the thrombus was derived.

Plasma osteoprotegerin levels are associated with the presence and burden of cerebral small vessel disease in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Osteoprotegerin (OPG) is a component of the tumor necrosis factor receptor superfamily. Several studies have shown a relationship between OPG and cardiovascular diseases. We hypothesized that there is a relationship between plasma OPG levels and cerebral small vessel disease (SVD). METHODS: Patients diagnosed with their first cerebral ischemic infarction between April 2014 and March 2017 were enrolled. All the enrolled patients were evaluated through the hospital stroke protocol, including routine blood tests, brain imaging, and measuring the plasma OPG levels. The presence and burden of cerebral SVD [cerebral microbleeds (CMBs), asymptomatic lacunar infarction (ALI), high-grade perivascular space (HPVS), high-grade white matter hyperintensity (HWMH)], and total SVD score were assessed through brain magnetic resonance imaging. RESULTS: Of the 270 patients included in our study, 158 (58.5%) were men. The mean age of the patients was 63.8 ± 11.6 years. In multivariable analysis, plasma OPG levels were positively associated with the presence and burden of each cerebral SVD. The odds ratios (OR) of CMBs, ALI, HPVS, and HWMH for the association of OPG per standard deviation (SD) increase were 1.58 [95% confidence interval (CI), 1.09-2.27], 1.40 (95% CI, 1.04-1.88), 1.88 (95% CI, 1.27-2.78), and 1.47 (95% CI, 1.04-2.08), respectively. Plasma OPG levels were positively correlated with total SVD score (beta = 0.211, standard error = 0.061, p-value = 0.009, R2 = 0.275). CONCLUSIONS: Plasma OPG levels correlate with the presence and burden of cerebral SVD in patients with acute ischemic stroke.

Executive Summary of Stroke Statistics in Korea 2018: A Report from the Epidemiology Research Council of the Korean Stroke Society.

Despite the great socioeconomic burden of stroke, there have been few reports of stroke statistics in Korea. In this scenario, the Epidemiologic Research Council of the Korean Stroke Society launched the "Stroke Statistics in Korea" project, aimed at writing a contemporary, comprehensive, and representative report on stroke epidemiology in Korea. This report contains general statistics of stroke, prevalence of behavioral and vascular risk factors, stroke characteristics, pre-hospital system of care, hospital management, quality of stroke care, and outcomes. In this report, we analyzed the most up-to-date and nationally representative databases, rather than performing a systematic review of existing evidence. In summary, one in 40 adults are patients with stroke and 232 subjects per 100,000 experience a stroke event every year. Among the 100 patients with stroke in 2014, 76 had ischemic stroke, 15 had intracerebral hemorrhage, and nine had subarachnoid hemorrhage. Stroke mortality is gradually declining, but it remains as high as 30 deaths per 100,000 individuals, with regional disparities. As for stroke risk factors, the prevalence of smoking is decreasing in men but not in women, and the prevalence of alcohol drinking is increasing in women but not in men. Population-attributable risk factors vary with age. Smoking plays a role in young-aged individuals, hypertension and diabetes in middle-aged individuals, and atrial fibrillation in the elderly. About four out of 10 hospitalized patients with stroke are visiting an emergency room within 3 hours of symptom onset, and only half use an ambulance. Regarding acute management, the proportion of patients with ischemic stroke receiving intravenous thrombolysis and endovascular treatment was 10.7% and 3.6%, respectively. Decompressive surgery was performed in 1.4% of patients with ischemic stroke and in 28.1% of those with intracerebral hemorrhage. The cumulative incidence of bleeding and fracture at 1 year after stroke was 8.9% and 4.7%, respectively. The direct costs of stroke were about ₩1.68 trillion (KRW), of which ₩1.11 trillion were for ischemic stroke and ₩540 billion for hemorrhagic stroke. The great burden of stroke in Korea can be reduced through more concentrated efforts to control major attributable risk factors for age and sex, reorganize emergency medical service systems to give patients with stroke more opportunities for reperfusion therapy, disseminate stroke unit care, and reduce regional disparities. We hope that this report can contribute to achieving these tasks.

Effect of Statins on Survival Following Stroke in Patients With Cancer.

The objective of this study was to investigate the potential benefits of statin therapy initiation in acute stroke in patients with active cancer. This study was conducted in two parts. First, data from patients who are presented with stroke and active cancer were obtained from prospectively collected multicenter hospital-based stroke registries. Patients were classified into statin user and non-user groups; the statin group was further divided into low-potency and high-potency statin subgroups. The primary outcome was time to mortality. Second, we obtained data from the Korean National Health Information Service-National Sample Cohort (NHIS-NSC) database for external validation and analyzed the effect of statins on mortality, taking compliance into consideration. For the stroke registry cohort, statin use was independently associated with reduced mortality in a multivariable model [hazard ratio (HR) = 0.675, 95% confidence interval (CI) = 0.457-0.996]. There was no interaction between statin use and cancer characteristics, vascular risk factors, or laboratory findings. A dose-dependent relationship between statin use and survival was also demonstrated. Analysis of the NHIS-NSC database found a similar association between statin therapy and reduced mortality (adjusted HR = 0.64, 95% CI = 0.45-0.90) and this effect persisted even after controlling for the adherence of statin use (HR = 0.60, 95% CI = 0.41-0.89). Statin therapy could be associated with reduced mortality in patients with acute stroke and active cancer.

Relation of serum homocysteine levels to cerebral artery calcification and atherosclerosis.

BACKGROUND AND AIMS: Elevated serum homocysteine level is known to be associated with increased risk of vascular event due to endothelial senescence. We investigated the association between serum homocysteine level and cerebral arteriosclerosis status including intracranial vascular calcification and atherosclerosis burden. METHODS: We identified 1193 consecutive patients (mean age = 68.6 ± 12.7, 537 female patients) who were admitted with acute cerebral infarction or transient ischemic attack from a single university medical center. The patients were categorized into three groups according to their serum homocysteine level. Cerebral artery calcification was assessed from the cavernous portion of both internal carotid arteries, and cerebral atherosclerosis burden was derived as the sum of stenosis degree of major intracranial arteries from brain computed tomography angiography. RESULTS: The mean homocysteine level was 14.1 ± 6.2 µmol/L, and intracranial cerebral artery calcification was present in 974 patients (81.6%), with 339 cases of advanced calcification (28.4%). The prevalence of cerebral artery calcification, advanced cerebral artery calcification and cerebral atherosclerosis burden showed increasing tendency throughout the homocysteine tertiles. Multivariable logistic regression analysis including age, sex, vascular risk factors, serum C-reactive protein, estimated glomerular filtration rate and homocysteine tertile disclosed that the highest serum homocysteine tertile was an independent predictor of advanced cerebral artery calcification (odds ratio = 1.45, confidence interval = 1.02-2.05) and advanced cerebral atherosclerosis (odds ratio = 1.42, confidence interval = 1.01-1.99) compared to the lowest group. CONCLUSIONS: An elevated serum homocysteine level was independently associated with intracranial arterial calcification and atherosclerosis burden. Future studies are warranted to test whether lowering serum homocysteine can delay cerebral arteriosclerotic changes.