Relationship Between Lipoprotein (a) [Lp(a)] and Cognition in Different Ischemic Stroke Subtypes

Background and Purpose: Although elevated serum lipoprotein (a) [Lp(a)] is considered to be a risk factor of ischemic stroke, the relationship between Lp(a) and cognitive impairment after stroke remains unclear. This study investigated the association between serum Lp(a) and cognitive function after acute ischemic stroke (AIS) or transient ischemic attack (TIA).Methods: The study included 1,017 patients diagnosed with AIS or TIA from the cognition subgroup of the Third China National Stroke Registry (CNSR3). Montreal Cognitive Assessment (MoCA) at 2 weeks or discharge, 3 months, and 1 year was evaluated. The primary outcome was cognitive impairment at 1 year, defined as MoCA ≤ 22. The secondary outcome was cognition improvement at 1 year compared with 2 weeks. The association between Lp(a) levels and cognitive function was analyzed.Results: Among the 1,017 patients included, 326 (32.1%) had cognitive impairment at 1 year. Patients with MoCA ≤ 22 at 1 year were older, received less education, and had higher baseline NIHSS, higher proportion of ischemic stroke history, large artery atherosclerosis (LAA) subtype, and multiple infarctions (P < 0.05 for all). Patients with highest Lp(a) quartile had slightly higher percentage of cognitive impairment at 1 year but without statistical difference. In subgroup analysis of LAA subtype, the patients with highest Lp(a) quartile had higher percentage of cognitive impairment at 1 year (adjusted OR:2.63; 95% CI: 1.05–6.61, P < 0.05). What is more, the patients with highest Lp(a) quartile in LAA subtype had lower percentage of cognition improvement at 1 year. However, similar results were not found in small artery occlusion (SAO) subtype.Conclusion: Higher Lp(a) level was associated with cognitive impairment and less improvement of cognition in patients after AIS or TIA with large-artery atherosclerosis subtype.

Night-time diastolic blood pressure variability relates to stroke recurrence in patients who had ischaemic stroke with small artery occlusion

Background and purposeThe association between blood pressure variability (BPV) and stroke recurrence among patients who had ischaemic stroke (IS) remains unclear. This study aimed to investigate the association between BPV and stroke recurrence in patients who had IS of large artery atherosclerosis (LAA) subtype and small artery occlusion (SAO) subtype.MethodsData from the BOSS (Blood Pressure and Clinical Outcome in Transient Ischemic Attack or Ischemic Stroke) study were examined. IS subtypes were diagnosed according to the Trial of Org 10172 in Acute Stroke Treatment criteria. BPV was performed by 24-hour ambulatory blood pressure monitoring and defined through SD of blood pressure. The primary outcome was stroke recurrence within 90 days after discharge. Multivariable Cox regression model was used to assess the association between BPV and stroke recurrence in patients who had IS of LAA subtype and SAO subtype.ResultsA total of 1390 patients who had IS from the BOSS study were included in the present study. Multivariable analysis suggests that 24-hour systolic BPV (SBPV) and night-time diastolic BPV (DBPV) were significantly associated with stroke recurrence among all patients who had IS (HR, 2.50, 95% CI 1.07 to 5.84; HR, 1.85, 95% CI 1.07 to 3.21, respectively). Night-time SBPV and night-time DBPV were significantly associated with stroke recurrence in patients with SAO subtype (HR, 2.77, 95% CI 1.07 to 7.15; HR, 3.60, 95% CI 1.39 to 9.29, respectively). However, in the adjusted model, only night-time DBPV remained significant in patients with SAO subtype (HR, 3.87, 95% CI 1.40 to 10.71). Similar results were not found in patients who had IS of LAA subtype.ConclusionsHigh night-time DBPV was associated with increased risk of stroke recurrence among patients who had IS of SAO subtype. The results of this study have implications for the secondary prevention management and future research of patients who had IS of SAO subtype. The association between BPV and stroke recurrence in patients who had IS of LAA subtype and SAO subtype should be investigated in larger, population-based studies.

Heart Failure and Ischemic Stroke: A Bidirectional and Multivariable Mendelian Randomization Study

Background: Heart failure (HF) is a potential cause of ischemic stroke (IS), and previous studies have reported an association between HF and IS. This study aimed to analyze the causal link between HF and IS using bidirectional and multivariable Mendelian randomization (MR) studies.Methods: Genetic variants significantly associated with HF and IS were selected in the MR analysis from two large genome-wide association studies. Bidirectional and multivariable MR analyses were performed to evaluate the effect of HF on IS or the effect of IS on HF.Results: Two-sample MR analysis showed causal effects of HF on IS of all causes [odds ratio (OR) = 1.555, 95% confidence interval (CI): 1.343–1.799, p = 3.35 × 10−9] and large artery atherosclerosis stroke (LAS) (OR = 1.678, 95% CI: 1.044–2.696, p = 3.03 × 10−5), while there was a suggestive effect of HF on cardioembolic stroke (CES) (OR = 3.355, 95% CI: 1.031–10.919, p = 0.044). Genetically predicted HF was not associated with small artery occlusion stroke. Bidirectional MR analysis showed causal effects of IS of all causes (OR = 1.211, 95% CI: 1.040–1.410, p = 0.014) and CES (OR = 1.277, 95% CI: 1.213–1.344, p = 6.73 × 10−21) on HF, while there were no causal effects of LAS on HF.Conclusion: This MR analysis provided evidence of the causal links between genetically predicted HF and IS. Subgroup analysis highlighted the causal or suggestive relationship between genetically predicted HF and LAS or CES. The potential causal links need further investigation with genetic information about other ancestries or etiologies of HF.

Circulating Exosomal miRNAs as Novel Biomarkers Perform Superior Diagnostic Efficiency Compared With Plasma miRNAs for Large-Artery Atherosclerosis Stroke

Recently, exosomal miRNAs have been reported to be associated with some diseases, and these miRNAs can be used for diagnosis and treatment. However, diagnostic biomarkers of exosomal miRNAs for ischemic stroke have rarely been studied. In the present study, we aimed to identify exosomal miRNAs that are associated with large-artery atherosclerosis (LAA) stroke, the most common subtype of ischemic stroke; to further verify their diagnostic efficiency; and to obtain promising biomarkers. High-throughput sequencing was performed on samples from 10 subjects. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed on exosomes and plasma in the discovery phase (66 subjects in total) and the validation phase (520 subjects in total). We identified 5 candidate differentially expressed miRNAs (miR-369-3p, miR-493-3p, miR-379-5p, miR-1296-5p, and miR-1277-5p) in the discovery phase according to their biological functions, 4 of which (miR-369-3p, miR-493-3p, miR-379-5p, and miR-1296-5p) were confirmed in the validation phase. These four exosomal miRNAs could be used to distinguish LAA samples from small artery occlusion (SAO) samples, LAA samples from atherosclerosis (AS) samples, and LAA samples from control samples and were superior to plasma miRNAs. In addition, composite biomarkers achieved higher area under the curve (AUC) values than single biomarkers. According to our analysis, the expression levels of exosomal miR-493-3p and miR-1296-5p were negatively correlated with the National Institutes of Health Stroke Scale (NIHSS) score. The four identified exosomal miRNAs are promising biomarkers for the diagnosis of LAA stroke, and their diagnostic efficiency is superior to that of their counterparts in plasma.

Trimethylamine N-Oxide and Stroke Recurrence Depends on Ischemic Stroke Subtypes

Background and Purpose: Trimethylamine N-oxide (TMAO) has been recognized as a risk factor for cardiovascular disease. However, the role of TMAO in ischemic stroke remains unclear. As we know, ischemic stroke is a heterogeneous disease with variable pathogenesis. Hence, we aimed to investigate the association between TMAO and stroke recurrence according to etiology subtypes. Methods: A total of 10 756 ischemic stroke/transient ischemic attack patients from the Third China National Stroke Registry were enrolled, and 1-year follow-up data for stroke recurrence were analyzed. TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria was used to classify the etiology subtypes. Plasma TMAO levels were quantified by liquid chromatography–mass spectrometry. The association between TMAO and stroke outcomes was analyzed using Cox regression models. We also conducted a meta-analysis on the association of TMAO levels and stroke risk. Results: Elevated TMAO level was independently associated with the risk of stroke recurrence (Q4 versus Q1: adjusted hazard ratio, 1.37 [95% CI, 1.15–1.64]) in multivariate Cox regression model. After stratification by TOAST subtypes, there was a significant association between TMAO and stroke recurrence in small artery occlusion subtype (adjusted hazard ratio, 1.43 [95% CI, 1.03–2.00]) but not in the others subtype (large-artery atherosclerosis, 1.19 [0.95–1.48]; cardioembolism, 1.54 [0.95–2.48]; others, 1.19 [0.98–1.44]). The meta-analysis reported on stroke recurrence for the highest versus lowest TMAO levels with a pooled hazard ratio of 1.66 (95% CI, 0.91–3.01) and similarly found an increased risk of stroke recurrence. Conclusions: Elevated TMAO level is associated with increased risk of stroke recurrence in patients with small artery occlusion subtype, but this association seems to be attenuated in large-artery atherosclerosis, cardioembolism, and others subtypes.

Platelet Endothelial Aggregation Receptor 1 Polymorphism Is Associated With Functional Outcome in Small-Artery Occlusion Stroke Patients Treated With Aspirin

Background: The role of genetic polymorphisms is important in defining the patient's prognosis and outcomes in coronary artery disease. The present study aimed to explore the association between platelet endothelial aggregation receptor 1 (PEAR1) rs12041331 polymorphism and the outcomes in patients with acute ischemic stroke treated with aspirin or dual antiplatelet therapy (DAPT) with clopidogrel.Methods: A total of 868 ischemic stroke patients admitted to our hospital from January 1, 2016 to December 30, 2018 were retrospectively studied. The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification defined stroke subtypes. These patients were treated with aspirin alone or DAPT. The genotype distribution of PEAR1 rs12041331 single-nucleotide polymorphism (AA, AC, and CC) between different TOAST subtypes and treatment groups was assessed, and the clinical impact of genetic variants on functional outcomes defined by the National Institutes of Health Stroke Scale, modified Rankin Scale, and Barthel Index was analyzed using univariate and multivariate logistic regression models.Results: Among the 868 stroke patients, the PEAR1 AA genotype was 16%, GA was 47%, and GG was 36%. Forty-four percent had aspirin alone, and 56% had DAPT. Overall, the distribution of PEAR single-nucleotide polymorphism was not significant among the two treatment groups or subtypes of TOAST. In contrast, in patients treated with aspirin alone, PEAR1 AA tended to be higher in the small-artery occlusion (SAO) subtype when compared with the no-lacunar subtype, including cardioembolism and large-artery atherosclerosis. PEAR1 AA genotype was significantly associated with favorable functional outcomes at day 7 and discharge only in SAO patients treated with aspirin alone compared with the GG genotype. Multivariate regression models further suggested that AA genotype was independently associated with favorable outcomes in this group after being adjusted for three common stroke risk factors such as age, hypertension history, and C-reactive protein level [odds ratio (OR) 0.23, 95% confidence interval (CI), 0.07–0.64, P = 0.02 for 7-day National Institutes of Health Stroke Scale; OR 0.2, 95% CI, 0.06–0.66, P = 0.03 for 7-day modified Rankin Scale, and OR 0.25, 95% CI, 0.08–0.72, P = 0.03 for 7-day Barthel Index, respectively].Conclusion: The impact of PEAR1 rs12041331 polymorphism on aspirin depends on the TOAST subtype. PEAR1 AA carrier with SAO stroke is most sensitive to aspirin therapy. PEAR1 AA is an independent factor for the short-term functional outcomes in SAO patients treated with aspirin alone.Clinical Registration Number: 1800019911.

Delayed Stroke Treatment during COVID-19 Pandemic in China

<b><i>Background:</i></b> Social distance, quarantine, pathogen testing, and other preventive strategies implemented during CO­VID-19 pandemic may negatively influence the management of acute ischemic stroke (AIS). <b><i>Objective:</i></b> The current study aimed to evaluate the impacts of COVID-19 pandemic on treatment delay of AIS in China. <b><i>Methods:</i></b> This study included patients with AIS admitted in 2 hospitals in Jiangsu, China. Patients admitted before and after the COVID-19 pandemic outbreak (January 31, 2020, as officially announced by the Chinese government) were screened to collect sociodemographic data, medical history information, and symptom onset status from clinical medical records and compared for pre- (measured as onset-to-door time [ODT]) and posthospital delay (measured as door-to-needle time [DNT]). The influencing factors for delayed treatment (indicated as onset-to-needle time &#x3e;4.5 h) were analyzed with multivariate logistic regression analysis. <b><i>Results:</i></b> A total of 252 patients were included, of which 153 (60.7%) were enrolled before and 99 (39.3%) after the COVID-19 pandemic. ODT increased from 202 min (interquartile range [IQR] 65–492) before to 317 min (IQR 75–790) after the COVID-19 pandemic (<i>p =</i> 0.001). DNT increased from 50 min (IQR 40–75) before to 65 min (IQR 48–84) after the COVID-19 pandemic (<i>p =</i> 0.048). The proportion of patients with intravenous thrombolysis in those with AIS was decreased significantly after the pandemic (15.4% vs. 20.1%; <i>p</i> = 0.030). Multivariate logistic regression analysis indicated that patients after COVID-19 pandemic, lower educational level, rural residency, mild symptoms, small artery occlusion, and transported by other means than ambulance were associated with delayed treatment. <b><i>Conclusions:</i></b> COVID-19 pandemic has remarkable impacts on the management of AIS. Both pre- and posthospital delays were prolonged significantly, and proportion of patients arrived within the 4.5-h time window for intravenous thrombolysis treatment was decreased. Given that anti-COVID-19 measures are becoming medical routines, efforts are warranted to shorten the delay so that the outcomes of stroke could be improved.

Prevalence and Clinical Correlates of Intracranial Dolichoectasia in Individuals With Ischemic Stroke

Background and Purpose: Acute ischemic stroke is a known complication of intracranial dolichoectasia (IDE). However, the frequency of IDE causing brain infarction is unknown. We aim to determine the prevalence and clinical correlates of IDE in acute ischemic stroke by employing an objective IDE definition for major intracranial arteries of the anterior and posterior circulation. Methods: Consecutive patients with acute ischemic stroke admitted to a tertiary-care hospital during a 4-month period were analyzed. Intracranial arterial diameter, length, and tortuosity were determined by semiautomatic vessel segmentation and considered abnormal if ≥2 SDs from the study population mean. Either ectasia (increased diameter) or dolichosis (increased length or tortuosity) of at least one proximal intracranial artery defined IDE. Symptomatic IDE was considered when the infarct was located in the territory supplied by an affected artery in the absence of any alternative pathogenic explanation. Multivariate models were fitted to determine IDE clinical correlates. Results: Among 211 cases screened, 200 patients (mean age 67±14 years, 47.5% men) with available intracranial vessel imaging were included. IDE was identified in 24% cases (5% with isolated ectasia, 9.5% with isolated dolichosis, and 9.5% with both ectasia and dolichosis). IDE was considered the most likely pathogenic mechanism in 12 cases (6% of the entire cohort), which represented 23.5% of strokes initially categorized as undetermined cause. In addition, 21% of small-artery occlusion strokes had the infarct territory supplied by a dolichoectatic vessel (3% of the entire cohort). IDE was independently associated with male sex (odds ratio, 4.2 [95% CI, 1.7–10.6]) and its component of ectasia was associated with advanced age (odds ratio, 3.5 [95% CI, 1.3–9.5]). Vascular risk profile was similar across patients with stroke with and without IDE. Conclusions: Our findings suggest that IDE is an arteriopathy frequently found in patients with acute ischemic stroke and is likely responsible for a sizable fraction of strokes initially categorized as of undetermined cause and perhaps also in those with small-artery occlusion.

Effect of Intensive Versus Standard Blood Pressure Control on Stroke Subtypes

In the SPRINT (Systolic Blood Pressure Intervention Trial), the number of strokes did not differ significantly by treatment group. However, stroke subtypes have heterogeneous causes that could respond differently to intensive blood pressure control. SPRINT participants (N=9361) were randomized to target systolic blood pressures of <120 mm Hg (intensive treatment) compared with <140 mm Hg (standard treatment). We compared incident hemorrhage, cardiac embolism, large- and small-vessel infarctions across treatment arms. Participants randomized to the intensive arm had mean systolic blood pressures of 121.4 mm Hg in the intensive arm (N=4678) and 136.2 mm Hg in the standard arm (N=4683) at one year. Sixty-nine strokes occurred in the intensive arm and 78 in the standard arm when SPRINT was stopped. The breakdown of stroke subtypes across treatment arms included hemorrhagic (intensive treatment, n=6, standard treatment, n=7) and ischemic stroke subtypes (large artery atherosclerosis: intensive treatment n=11, standard treatment, n=13; cardiac embolism: intensive treatment n=11, standard treatment n=15; small artery occlusion: intensive treatment n=8, standard treatment n=8; other ischemic stroke: intensive treatment n=3, standard treatment n=1). Fewer strokes occurred among participants without prior cardiovascular disease in the intensive (n=43) than the standard arm (n=61), but the difference did not reach predefined statistical significance level of 0.05 ( P =0.09). The interaction between baseline cardiovascular risk factor status and treatment arm on stroke risk did not reach significance ( P =0.05). Similar numbers of stroke subtypes occurred in the intensive BP control and standard control arms of SPRINT.