METTL3 Regulates Osteoclast Biological Behaviors via iNOS/NO-Mediated Mitochondrial Dysfunction in Inflammatory Conditions.

Excessive differentiation of osteoclasts contributes to the disruption of bone homeostasis in inflammatory bone diseases. Methyltransferase-like 3 (METTL3), the core methyltransferase that installs an N6-methyladenosine (m6A) modification on RNA, has been reported to participate in bone pathophysiology. However, whether METTL3-mediated m6A affects osteoclast differentiation in inflammatory conditions remains unelucidated. In this study, we observed that the total m6A content and METTL3 expression decreased during LPS-induced osteoclastogenesis. After knocking down METTL3, we found reduced levels of the number of osteoclasts, osteoclast-related gene expression and bone resorption area. A METTL3 deficiency increased osteoclast apoptosis and pro-apoptotic protein expression. RNA sequencing analysis showed that differentially expressed genes in METTL3-deficient cells were mainly associated with the mitochondrial function. The expression of the mitochondrial function-related genes, ATP production and mitochondrial membrane potential decreased after METTL3 knockdown. Moreover, the most obviously upregulated gene in RNA-Seq was Nos2, which encoded the iNOS protein to induce nitric oxide (NO) synthesis. METTL3 knockdown increased the levels of Nos2 mRNA, iNOS protein and NO content. NOS inhibitor L-NAME rescued the inhibited mitochondrial function and osteoclast formation while suppressing osteoclast apoptosis in METTL3-silenced cells. Mechanistically, a METTL3 deficiency promoted the stability and expression of Nos2 mRNA, and similar results were observed after m6A-binding protein YTHDF1 knockdown. Further in vivo evidence revealed that METTL3 knockdown attenuated the inflammatory osteolysis of the murine calvaria and suppressed osteoclast formation. In conclusion, these data suggested that METTL3 knockdown exacerbated iNOS/NO-mediated mitochondrial dysfunction by promoting a Nos2 mRNA stability in a YTHDF1-dependent manner and further inhibited osteoclast differentiation and increased osteoclast apoptosis in inflammatory conditions.

YTHDF1 regulates endoplasmic reticulum stress, NF-κB, MAPK and PI3K-AKT signaling pathways in inflammatory osteoclastogenesis.

Abnormal increases in osteoclast differentiation and activity contribute to excessive bone resorption in inflammatory bone diseases. The specific m6A-binding protein YT521-B homology domain family 1 (YTHDF1) participates in many physiopathological processes by regulating mRNA stability or translation. However, whether YTHDF1 is involved in the regulation of inflammatory osteoclastogenesis remains a mystery. This study revealed that YTHDF1 expression was upregulated during lipopolysaccharide (LPS)-stimulated osteoclast differentiation. Knockdown of Ythdf1 inhibited osteoclast formation, bone resorption and the expression of osteoclast-related genes (Tnfrsf11a, Traf6, Mmp9 and Acp5). Analysis of RNA sequencing data showed that the genes downregulated by Ythdf1 knockdown were closely associated with endoplasmic reticulum (ER) stress and osteoclast differentiation. Western blotting confirmed that Ythdf1 depletion suppressed activation of the ER stress-related PERK, IRE1α and ATF6 signaling pathways. The ER stress activator tunicamycin (Tm) partially rescued the decreased expression of Mmp9 and Acp5 caused by Ythdf1 deficiency. Meanwhile, Ythdf1 depletion inhibited the phosphorylation levels of key proteins in the NF-κB, MAPK and PI3K-AKT signaling pathways and decreased the mRNA stability of Tnfrsf11a, which is the major upstream signaling molecule that mediates the activation of these pathways during osteoclast differentiation. In conclusion, our findings suggest that Ythdf1 knockdown inhibits inflammatory osteoclast differentiation and function by suppressing ER stress signaling pathways. Ythdf1 knockdown also inactivates the signaling pathways involved in osteoclast differentiation by inhibiting Tnfrsf11a mRNA stability. These findings will help shed light on the molecular mechanisms of m6A-mediated epigenetic regulation in inflammatory osteoclastogenesis.

Blood Pressure Rhythm and Blood Pressure Variability as Risk Factors for White Matter Lesions: A Cross-Sectional Study.

BACKGROUND White matter lesions are common in the elderly. The aim of this study was to explore the correlation between blood pressure rhythm and blood pressure variability with white matter lesions. MATERIAL AND METHODS A total of 144 subjects aged 40 to 80 years underwent MRI scanning to assess the degree of white matter lesions using the Fazekas scale. The regional cerebral blood flow was detected by brain perfusion imaging, and an ambulatory blood pressure monitor was used to measure the circadian blood pressure rhythm. Odds ratio and the 95% confidence interval was computed using logistics regression analysis. The relationship between various factors and blood pressure was calculated by curve simulation. RESULTS With the increase of white matter lesions, the regional cerebral blood flow at the lesion decreased gradually. Systolic blood pressure day/night difference ratio (OR=0.815, 95% CI 0.729-0.910), diastolic blood pressure day/night difference ratio (OR=0.895, 95% CI 0.831-0.964), systolic blood pressure coefficient of variation (OR=1.589, 95% CI 1.273-1.983), and diastolic blood pressure coefficient of variation (OR=1.363, 95% CI 1.150-1.616) were significantly associated with Fazekas score (P<0.05 for all). CONCLUSIONS Greater blood pressure variability and blood pressure rhythm disorders were associated with lower regional cerebral blood flow in patients with white matter lesions.

Higher uric acid is associated with better discharge recovery and short-term outcome in stroke patients treated with thrombolysis.

BACKGROUND: Uric acid (UA) possesses antioxidant features and potential neuroprotective effects. However, conflicting results regarding the association between serum uric acid (SUA) levels and the prognosis of stroke have been obtained. We aimed to assess whether SUA is related to discharge recovery and short-term outcomes in patients who underwent thrombolysis therapy. METHODS: We recruited 393 consecutive patients who were diagnosed with acute ischaemic stroke (AIS) and treated with thrombolysis. The demographic information, including sex and age, was collected. Haematology tests, including SUA, fasting plasma glucose (FPG), and blood lipid parameters, were performed under fasting conditions the morning after admission. The modified Rankin Scale (mRS) was used to assess the functional outcome of patients at discharge and 3 months after onset. RESULTS: A negative correlation was observed between the levels of SUA and the National Institute of Health Stroke Scale (NIHSS) score at discharge (r = - 0.171, P = 0.003). Additionally, a positive correlation was observed between the levels of SUA and the difference between the baseline NIHSS and discharge NIHSS (r = 0.118, P = 0.032). The levels of SUA in the patients with good outcomes (353.76 ± 93.05) were higher than those in the patients with poor outcomes (301.99 ± 92.24; P = 0.015) at 3 months. The multivariate logistic regression analysis demonstrated that a higher SUA level (odds ratio 0.988, 95% confidence interval 0.985-0.991, P = 0.002) was an independent predictor of a good outcome at 3 months. CONCLUSION: Higher SUA levels were associated with better discharge recovery and 3-month outcomes in patients with ischaemic stroke who received thrombolysis.

Association of Blood Pressure, White Matter Lesions, and Regional Cerebral Blood Flow.

BACKGROUND At present, the association between blood pressure, regional cerebral blood flow, and white matter lesions is not well understood. MATERIAL AND METHODS A total of 147 subjects aged from 40 to 80 years were assessed by the Fazekas score for white matter lesions, CT perfusion imaging for regional cerebral blood flow, and 24-h ambulatory blood pressure monitoring for blood pressure level and rhythm. Logistic regression analysis was used to obtain the odds ratio and 95% confidence interval between Fazekas scores and relevant factors. The relationship between blood pressure index and regional cerebral blood flow was analyzed through cubic curve estimation. RESULTS Fazekas score was negatively correlated with regional cerebral blood flow (r=-0.801; r=-0.831, P<0.001). For subcortical lesion, the regional cerebral blood flow of Fazekas grade 0 was 1.976 times that of Fazekas grade 3 (OR=1.976, 95% CI=1.576-2.477), and for periventricular lesion, the regional cerebral blood flow of Fazekas grade 0 was 2.034 times that of Fazekas grade 3 (OR=2.034, 95% CI=1.602-2.583). Increased nighttime systolic blood pressure may be more dangerous (OR=1.112, 95% CI=1.059-1.169). The day-night systolic blood pressure ratio (OR=0.801, 95% CI 0.711-0.902) and the day-night diastolic blood pressure ratio (OR=0.876, 95% CI 0.807-0.950) were significantly correlated with Fazekas score. CONCLUSIONS The decrease of white matter regional cerebral blood flow caused by hypertension is probably one of the important causes of white matter lesions. Patients with white matter lesions should also pay attention to the rhythm of blood pressure when controlling hypertension, especially if their blood pressure is too high or too low at night.

Circ_0062166 aggravates cerebral ischemia-reperfusion injury through targeting miR-526b-5p/BCL2L13 axis.

BACKGROUND: Cerebral ischemia-reperfusion (CIR) injury is a severe disease, which may cause serious dysfunction of the brain. Most circular RNAs (circRNAs) have been demonstrated to play a significant role in CIR injury. However, a novel circRNA, circ_0062166 (circ_BCL2L13) has not been investigated for CIR injury. Hence, we aim to disclose the role of circ_0062166 in CIR injury in this study. METHODS: Firstly, RT-qPCR was applied to examine the expression of circ_0062166 in oxygen-glucose deprivation and reoxygenation (OGD/R) cell model. Functional assays were conducted to detect the role of circ_0062166 in CIR injury. RNA pull down, RIP and luciferase reporter assays were implemented to probe into the regulatory mechanism of circ_0062166. RESULTS: Circ_0062166 was significantly up-regulated in neuro-2A (N2A) neuroblastoma cells following OGD/R. Functionally, the silencing of circ_0062166 inhibited cell proliferation and promoted cell apoptosis under OGD/R condition. From the perspective of mechanism, circ_0062166 functioned as a competing endogenous RNA (ceRNA) for microRNA-526b-5p (miR-526b-5p) and regulated BCL2 like 13 (BCL2L13). Eventually, the promoting role of the circ_0062166/miR-526b-5p/BCL2L13 axis in the CIR injury was verified. CONCLUSION: To sum up, the present study has demonstrated that circ_0062166/miR-526b-5p/BCL2L13 axis accelerated the progression of CIR injury, which might provide effective strategies for CIR injury therapy.

The role of carotid stenosis ultrasound scale in the prediction of ischemic stroke.

INTRODUCTION: To improve the accuracy of ultrasound techniques for the assessment of carotid stenosis, we designed a novel carotid artery stenosis ultrasound scale (CASUS), and evaluated its accuracy, reliability, and its value in predicting the occurrence of cardiovascular and cerebrovascular diseases in a prospective study. METHODS: A total of 750 patients with first-time ischemic stroke and hospitalized within 24 h were enrolled in the study. Using color Doppler ultrasound (CDUS), the degree of stenosis and blood flow (BF) in bilateral internal carotid arteries (ICA) and the V1-V3 segment of vertebral arteries (VA) was assessed. Cubic simulation curves for BF and global blood flow (GBF) over the stenosis score (SS), total stenosis score (TSS), and radiological imaging- total stenosis score (RI-TSS) were fitted and compared. The receiver operating characteristic (ROC) curves using TSS, RI-TSS, or GBF to predict various ischemic stroke endpoints were also analyzed and compared. RESULTS: There was a linear relationship between SS and BF both ICA and VA (R2 were 0.734 and 0.783, respectively, both P < 0.05). Both TSS and RI-TSS with GBF showed an inverse "S" curve relationship (R2 was 0.839 and 0.843, all P < 0.05). The AUC values of TSS-based and RI-TSS-based predictions of each endpoint were all greater than 0.7 (all P < 0.05), but the differences of the AUC values between TSS, RI-TSS, and GBF were not statistically significant (all P > 0.05). CONCLUSIONS: The novel CASUS can better reflect the level of cerebral reperfusion in patients with ischemic stroke and can better predict the occurrence of cardiovascular and cerebrovascular diseases.

Age and Diastolic Blood Pressure Play an Important Role in the Progression of White Matter Lesions: A Meta-Analysis.

INTRODUCTION: White matter lesions (WMLs) are currently considered as a cerebral microvascular disease, and hypertension is considered as its most important risk factor. This study analysis systematically evaluated the effects of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on the progression of WMLs. METHODS: We searched the MeSH terms: "white matter," "blood pressure," "hypertension," "Leukoencephalopathy," and "leukoaraiosis" on PubMed and Cochrane from January 2000 to August 2019. A total of 12 closely related literature were included for research. RESULTS: The results of the meta-analysis showed that the increase of both SBP and DBP can promote the progression of WMLs (respectively, odds ratio [OR] = 2.90, 95% confidence interval [CI] 2.86-2.94; OR = 3.13, 95% CI 3.03-3.23). Subgroup analysis found that patients with hypertension aged younger than 70 years are at a greater risk of WML progression when their DBP increased (OR = 4.69, 95% CI 3.31-6.65). CONCLUSION: The relationship between DBP and WMLs is closer than that of SBP. Also, the risk of WML progression in patients aged under 70 years was higher than that in patients aged over 70 years. Furthermore, when DBP is elevated in patients younger than 70 years of age, the risk of WML progression may be higher. Therefore, it is expected that more researchers will attach importance to the change in DBP and identify the range of blood pressure and strategies that control DBP, thus contributing to delay the progression of WMLs.

MTHFR Gene and Serum Folate Interaction on Serum Homocysteine Lowering: Prospect for Precision Folic Acid Treatment.

OBJECTIVE: This post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial) assessed the individual variation in total homocysteine (tHcy)-lowering response after an average 4.5 years of 0.8 mg daily folic acid therapy in Chinese hypertensive adults and evaluated effect modification by methylenetetrahydrofolate reductase (MTHFR) C677T genotypes and serum folate levels. APPROACH AND RESULTS: This analysis included 16 413 participants from the CSPPT, who were randomly assigned to 2 double-blind treatment groups: either 10-mg enalapril+0.8-mg folic acid or 10-mg enalapril, daily and had individual measurements of serum folate and tHcy levels at baseline and exit visits and MTHFR C677T genotypes. Mean baseline tHcy levels were comparable between the 2 treatment groups (14.5±8.5 versus 14.4±8.1 µmol/L; P=0.561). After 4.5 years of treatment, mean tHcy levels were reduced to 12.7±6.1 µmol/L in the enalapril+folic acid group, but almost stayed the same in the enalapril group (14.4±7.9 µmol/L, group difference: 1.61 µmol/L; 11% reduction). More importantly, tHcy lowering varied by MTHFR genotypes and serum folate levels. Compared with CC and CT genotypes, participants with the TT genotype had a more prominent L-shaped curve between tHcy and serum folate levels and required higher folate levels (at least 15 ng/mL) to eliminate the differences in tHcy by genotypes. CONCLUSIONS: Compared with CC or CT, tHcy in the TT group manifested a heightened L-shaped curve from low to high folate levels, but this difference in tHcy by genotype was eliminated when plasma folate levels reach ≈15 ng/mL or higher. Our data raised the prospect to tailor folic acid therapy according to individual MTHFR C677T genotype and folate status. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.

Effect of Smoking and Folate Levels on the Efficacy of Folic Acid Therapy in Prevention of Stroke in Hypertensive Men.

BACKGROUND AND PURPOSE: We aimed to examine whether the efficacy of folic acid therapy in the primary prevention of stroke is jointly affected by smoking status and baseline folate levels in a male population in a post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial). METHODS: Eligible participants of the CSPPT were randomly assigned to a double-blind daily treatment of a combined enalapril 10-mg and folic acid 0.8-mg tablet or an enalapril 10-mg tablet alone. In total, 8384 male participants of the CSPPT were included in the current analyses. The primary outcome was first stroke. RESULTS: The median treatment duration was 4.5 years. In the enalapril-alone group, the first stroke risk varied by baseline folate levels and smoking status (never versus ever). Specifically, there was an inverse association between folate levels and first stroke in never smokers (P for linear trend=0.043). However, no such association was found in ever smokers. A test for interaction between baseline folate levels and smoking status on first stroke was significant (P=0.045). In the total sample, folic acid therapy significantly reduced the risk of first stroke in never smokers with folate deficiency (hazard risk, 0.36; 95% confidence interval, 0.16-0.83) and in ever smokers with normal folate levels (hazard risk, 0.69; 95% confidence interval, 0.48-0.99). CONCLUSIONS: Baseline folate levels and smoking status can interactively affect the risk of first stroke. Our data suggest that compared with never smokers, ever smokers may require a higher dosage of folic acid to achieve a greater beneficial effect on stroke. Our findings need to be confirmed by future randomized trials. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00794885.

Effects of Blood Pressure in the Early Phase of Ischemic Stroke and Stroke Subtype on Poststroke Cognitive Impairment.

BACKGROUND AND PURPOSE: Blood pressure (BP) control in the early phase of stroke is controversial to reduce the risk of poststroke cognitive impairment (PSCI). This study was to investigate the impact of BP levels in the early phase of ischemic stroke and stroke subtype on PSCI. METHODS: Seven hundred and ninety-six patients with acute ischemic stroke were included. Cognitive function was assessed after stroke onset using the Montreal Cognitive Assessment. Patients were divided into quintiles according to systolic BP and diastolic BP levels in the early phase. Subtype analyses were according to Trial of ORG 10172 in Acute Stroke Treatment classification (infarct cause) and Oxfordshire Community Stroke Project classification (infarct location). RESULTS: After adjusting for multiple variables, the quintiles with the lowest systolic BP (Q1, 102-127 mm Hg) and with the highest systolic BP (Q5, 171-215 mm Hg) were associated with increased PSCI risk (odds ratio, 1.83; 95% confidence interval, 1.64-2.28; P=0.007 in Q1; odds ratio, 2.32; 95% confidence interval, 1.74-2.90; P<0.001 in Q5) at 3 months as compared with the middle quintile (Q3, 143-158 mm Hg). Similar association was found in diastolic BP quintiles. The analysis of cerebral infarction subtype demonstrated that both large artery atherosclerosis and total anterior circulation infarct were associated with increased risk of PSCI at 3 months after adjusting for multiple variables (large artery atherosclerosis: odds ratio, 1.42; 95% confidence interval, 1.06-1.90; P=0.031; total anterior circulation infarct: odds ratio, 1.68; 95% confidence interval, 1.32-2.15; P=0.001). CONCLUSIONS: Lower or higher BP in the early phase of ischemic stroke was correlated with increased PSCI risk at 3 months. Maintaining systolic/diastolic BP in the levels of 143 to 158/93 to 102 mm Hg might be beneficial to reduce the occurrence of PSCI. Moreover, large artery atherosclerosis subtype and total anterior circulation infarct subtype were correlated with increased PSCI risk at 3 months. CLINICAL TRIAL REGISTRATION: URL: https://www.chictr.org. Unique identifier: ChiCTR-TRC-14004804.

Serum Trimethylamine N-Oxide Concentration Is Positively Associated With First Stroke in Hypertensive Patients.

Background and Purpose- Trimethylamine N-oxide (TMAO)-a gut derived metabolite-has been shown to be atherogenic. It remains unknown whether TMAO is associated with the risk of first stroke. We aimed to determine the association between serum TMAO levels and first stroke in hypertensive patients without major cardiovascular diseases and examine any possible effect modifiers. Methods- We used a nested case-control design, using data from the CSPPT (China Stroke Primary Prevention Trial), including 622 patients with first stroke and 622 matched controls. The study was conducted from May 2008 to August 2013. The primary outcome was a first stroke. Results- After adjusting for choline, L-carnitine, and other important covariates, including baseline systolic blood pressure and time-averaged systolic blood pressure, during the treatment period, the risk of first stroke increased with each increment of TMAO level (per natural log [TMAO] increment: odds ratio, 1.22; 95% CI, 1.02-1.46). Consistently, compared with participants in the lowest tertile (<1.79 µmol/L) of serum TMAO levels, a significantly higher risk of first stroke was found in those in higher TMAO tertiles (≥1.79 µmol/L; odds ratio, 1.34; 95% CI, 1.00-1.81) or in TMAO tertile 3 (≥3.19 µmol/L; odds ratio, 1.43; 95% CI, 1.02-2.01). In the exploratory analysis, we observed an interaction between TMAO and folate levels (≥7.7 [median] versus <7.7 ng/mL) on first stroke ( P for interaction, 0.030). Conclusions- Higher TMAO levels were associated with increased risk of first stroke in hypertensive patients. Our finding, if further confirmed, calls for a carefully designed clinical trial to further evaluate the role of higher TMAO levels on outcomes in hypertensive patients. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT00794885.

Impact of achieved blood pressure on renal function decline and first stroke in hypertensive patients with chronic kidney disease.

Background: The effect of achieved blood pressure (BP) on first stroke and renal function decline among hypertensive patients with mild to moderate chronic kidney disease (CKD) is still uncertain. Methods: In total, 3230 hypertensive patients with estimated glomerular filtration rate 30-60 mL/min/1.73 m2 and/or proteinuria were included in the present analyses. Eligible participants were randomly assigned to a daily treatment of a combined enalapril 10 mg and folic acid 0.8 mg tablet or an enalapril 10 mg tablet alone. Participants were followed up every 3 months. The study outcomes included first stroke and the progression of CKD. Results: The median antihypertensive treatment duration was 4.7 years. Compared with participants with a time-averaged on-treatment systolic blood pressure (SBP) of 135 to ≤140 mmHg, the incidence of total first stroke [1.7% versus 3.3%; hazard ratio (HR), 0.51; 95% confidence interval (CI): 0.26-0.99] and ischemic stroke (1.3% versus 2.8%; HR, 0.46; 95% CI: 0.22-0.98) decreased significantly in those with a time-averaged SBP of ≤135 mmHg. Furthermore, a time-averaged diastolic blood pressure (DBP) of ≤80 mmHg, compared with a time-averaged DBP level of 80 to ≤90 mmHg, was significantly related to a decreased risk of hemorrhagic stroke (0.2% versus 0.9%; HR, 0.18; 95% CI: 0.04-0.80). However, compared with participants with a time-averaged SBP of 135 to ≤140 mmHg, a lower but non-significant trend of CKD progression was found in those with a time-averaged SBP of ≤130 mmHg. Conclusions: A BP treatment level of ≤135/80 mmHg, compared with a BP treatment level of 135-140/80-90 mmHg, could lead to a decreased risk of first stroke in hypertensive patients with mild-to-moderate CKD.

Effect of long-term low-dose folic acid supplementation on degree of total homocysteine-lowering: major effect modifiers.

We sought to examine the potential modifiers in the association between long-term low-dose folic acid supplementation and the reduction of serum total homocysteine (tHcy) among hypertensive patients, using data from the China Stroke Primary Prevention Trial (CSPPT). This analysis included 16 867 participants who had complete data on tHcy measurements at both the baseline and exit visit. After a median treatment period of 4·5 years, folic acid treatment significantly reduced the tHcy levels by 1·6 µmol/l (95 % CI 1·4, 1·8). More importantly, after adjustment for baseline tHcy and other important covariates, a greater degree of tHcy reduction was observed in certain subgroups: males, the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype, higher baseline tHcy levels (≥12·5 (median) v. <12·5 µmol/l), lower folate levels (<8·0 (median) v. ≥8·0 ng/ml), estimated glomerular filtration rate (eGFR) <60 ml/min per 1·73 m2 (v. 60-<90 and ≥90 ml/min per 1·73 m2), ever smokers and concomitant use of diuretics (P for all interactions <0·05). The degree of tHcy reduction associated with long-term folic acid supplementation can be significantly affected by sex, MTHFR C677T genotypes, baseline folate, tHcy, eGFR levels and smoking status.

Antihypertensive Therapy in the Acute Phase of Lacunar Infarcts.

BACKGROUND The optimal medical regimen for managing hypertension during acute phase of lacunar infarcts has not yet been clarified in real world setting. The aim of this study was to evaluate blood pressure lowering regimens on neurological progression and clinical outcomes during the acute phase of lacunar infarcts. MATERIAL AND METHODS For this study, 411 patients with first-episode lacunar infarcts and hypertension within 24 hours of symptom onset were included. All patients received antihypertension therapies, with different regimens, as well as routine medication during first 7 days after onset. There were 6 proposed antihypertensive treatments: calcium channel blockers (CCB), angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), ß-blocker (ß-B), and diuretic drug (DD) alone or in combination. Neurological progression was defined as worsening by ≥1 point in the National Institute of Health Stroke Scale (NIHSS) for motor function. The outcome was assessed using the modified Rankin Scale (mRS): favorable outcome (mRS of 0-1) or unfavorable outcome (mRS 2-5). RESULTS Logistic regression analysis showed that combination therapy with CCB, ACEI/ARB, and ß-B exhibited the lowest risk of deterioration (OR=0.48, P=0.019) and unfavorable outcomes (OR=0.50, P=0.022). Similarly, combination therapy with CCB, ACEI/ARB, and DD exhibited lower risk of deterioration (OR=0.63, P=0.033) and unfavorable outcome (OR=0.77, P=0.042) at 3 months. CONCLUSIONS Rational blood pressure lowering was beneficial to the functional outcomes of patients during acute phase of lacunar infarcts, and combination therapy was better than mono-drug therapy.

Homocysteine and Stroke Risk: Modifying Effect of Methylenetetrahydrofolate Reductase C677T Polymorphism and Folic Acid Intervention.

BACKGROUND AND PURPOSE: Elevated blood homocysteine concentration increases the risk of stroke, especially among hypertensive individuals. Homocysteine is largely affected by the methylenetetrahydrofolate reductase C677T polymorphism and folate status. Among hypertensive patients, we aimed to test the hypothesis that the association between homocysteine and stroke can be modified by the methylenetetrahydrofolate reductase C677T polymorphism and folic acid intervention. METHODS: We analyzed the data of 20 424 hypertensive adults enrolled in the China Stroke Primary Prevention Trial. The participants, first stratified by methylenetetrahydrofolate reductase genotype, were randomly assigned to receive double-blind treatments of 10-mg enalapril and 0.8-mg folic acid or 10-mg enalapril only. The participants were followed up for a median of 4.5 years. RESULTS: In the control group, baseline log-transformed homocysteine was associated with an increased risk of first stroke among participants with the CC/CT genotype (hazard ratio, 3.1; 1.1-9.2), but not among participants with the TT genotype (hazard ratio, 0.7; 0.2-2.1), indicating a significant gene-homocysteine interaction (P=0.008). In the folic acid intervention group, homocysteine showed no significant effect on stroke regardless of genotype. Consistently, folic acid intervention significantly reduced stroke risk in participants with CC/CT genotypes and high homocysteine levels (tertile 3; hazard ratio, 0.73; 0.55-0.97). CONCLUSIONS: In Chinese hypertensive patients, the effect of homocysteine on the first stroke was significantly modified by the methylenetetrahydrofolate reductase C677T genotype and folic acid supplementation. Such information may help to more precisely predict stroke risk and develop folic acid interventions tailored to individual genetic background and nutritional status. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.

Prospective study of serum uric acid levels and stroke in a Chinese hypertensive cohort.

Our aim was to investigate the association between serum uric acid (SUA) levels and the risk of first stroke in a Chinese population of hypertensive patients. This prospective study enrolled 20,577 hypertensive participants who without a history of stroke, and was conducted from May 2008 to August 2013 in Anqing and Lianyungang (China). A total of 632 (3.1%) first stroke events (510 ischemic events, 120 hemorrhagic events and 2 unspecified stroke events) were identified during a mean 4.5-year follow-up period. The risk of first stroke was not significantly associated with the increased SUA levels; this conclusion was also found after adjustment for gender and age. However, a statistically significant decreased risk of hemorrhagic stroke for the second SUA quartile (Q2) compared to the first quartile (Q1) (HR 0.56, 95%CI: 0.32-0.97, P = 0.037) was found. In addition, when grouped by tertiles of diastolic blood pressure (DBP), the results showed that high SUA lowered the risk of total stroke in participants in the third SUA quartile (Q3) (HR 0.69, 95%CI: 0.49-0.96, P = 0.028) and fourth SUA quartile (Q4) (HR 0.70, 95%CI: 0.50-0.99, P = 0.043) as compared with that in the first quartile (Q1). To sum up, no significant evidence in present study indicates that increased SUA levels are predictive of first stroke in a Chinese population of hypertensive patients.

Folic Acid Therapy Reduces the First Stroke Risk Associated With Hypercholesterolemia Among Hypertensive Patients.

BACKGROUND AND PURPOSE: We sought to determine whether folic acid supplementation can independently reduce the risk of first stroke associated with elevated total cholesterol levels in a subanalysis using data from the CSPPT (China Stroke Primary Prevention Trial), a double-blind, randomized controlled trial. METHODS: A total of 20 702 hypertensive adults without a history of major cardiovascular disease were randomly assigned to a double-blind daily treatment of an enalapril 10-mg and a folic acid 0.8-mg tablet or an enalapril 10-mg tablet alone. The primary outcome was first stroke. RESULTS: The median treatment duration was 4.5 years. For participants not receiving folic acid treatment (enalapril-only group), high total cholesterol (≥200 mg/dL) was an independent predictor of first stroke when compared with low total cholesterol (<200 mg/dL; 4.0% versus 2.6%; hazard ratio, 1.52; 95% confidence interval, 1.18-1.97; P=0.001). Folic acid supplementation significantly reduced the risk of first stroke among participants with high total cholesterol (4.0% in the enalapril-only group versus 2.7% in the enalapril-folic acid group; hazard ratio, 0.69; 95% confidence interval, 0.56-0.84; P<0.001; number needed to treat, 78; 95% confidence interval, 52-158), independent of baseline folate levels and other important covariates. By contrast, among participants with low total cholesterol, the risk of stroke was 2.6% in the enalapril-only group versus 2.5% in the enalapril-folic acid group (hazard ratio, 1.00; 95% confidence interval, 0.75-1.30; P=0.982). The effect was greater among participants with elevated total cholesterol (P for interaction=0.024). CONCLUSIONS: Elevated total cholesterol levels may modify the benefits of folic acid therapy on first stroke. Folic acid supplementation reduced the risk of first stroke associated with elevated total cholesterol by 31% among hypertensive adults without a history of major cardiovascular diseases. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.

Prestroke glycemic status is associated with the functional outcome in spontaneous intracerebral hemorrhage.

Admission hyperglycemia is thought to be related to poor neurological function and high mortality in patients with spontaneous intracerebral hemorrhage (sICH). However, it is not known whether prestroke glycemic status affects functional outcome of sICH. The study was aimed to disclose the association between prestroke glycemic status and outcome in patients with sICH. The study included 288 patients with sICH. Prestroke glycemic status was represented by hemoglobin A1c (HbA1c) values measured the next day after admission. Correlations between HbA1c and age, hematoma volume, NIHSS, and mRS were analyzed using Spearman's correlation analysis. Patients were categorized into two groups according to hematoma volume (≤25 mL or >25 mL), mRS values (≤2 or >2), or hematoma location (lobar hematoma or deep hematoma). Logistic regression analyses were used to determine the relative independent risk factors for hematoma volume, hematoma location, and mRS values. In patients with sICH, HbA1c was significantly correlated with hematoma volume, NIHSS, and mRS. High HbA1c levels were independently associated with large hematoma volume, deep ICH, and poor outcome. When patients were stratified by history of diabetes, the predictive effect of HbA1c on outcomes was only observed in patients with diabetes. Admission glucose was also related to hematoma volume, but failed to predict outcome. Although both admission glucose and HbA1c independently predicted hematoma volume in patients with sICH, HbA1c alone could serve as a better predictor of poor outcome in diabetic patients after sICH.

Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial.

IMPORTANCE: Uncertainty remains about the efficacy of folic acid therapy for the primary prevention of stroke because of limited and inconsistent data. OBJECTIVE: To test the primary hypothesis that therapy with enalapril and folic acid is more effective in reducing first stroke than enalapril alone among Chinese adults with hypertension. DESIGN, SETTING, AND PARTICIPANTS: The China Stroke Primary Prevention Trial, a randomized, double-blind clinical trial conducted from May 19, 2008, to August 24, 2013, in 32 communities in Jiangsu and Anhui provinces in China. A total of 20,702 adults with hypertension without history of stroke or myocardial infarction (MI) participated in the study. INTERVENTIONS: Eligible participants, stratified by MTHFR C677T genotypes (CC, CT, and TT), were randomly assigned to receive double-blind daily treatment with a single-pill combination containing enalapril, 10 mg, and folic acid, 0.8 mg (n = 10,348) or a tablet containing enalapril, 10 mg, alone (n = 10,354). MAIN OUTCOMES AND MEASURES: The primary outcome was first stroke. Secondary outcomes included first ischemic stroke; first hemorrhagic stroke; MI; a composite of cardiovascular events consisting of cardiovascular death, MI, and stroke; and all-cause death. RESULTS: During a median treatment duration of 4.5 years, compared with the enalapril alone group, the enalapril-folic acid group had a significant risk reduction in first stroke (2.7% of participants in the enalapril-folic acid group vs 3.4% in the enalapril alone group; hazard ratio [HR], 0.79; 95% CI, 0.68-0.93), first ischemic stroke (2.2% with enalapril-folic acid vs 2.8% with enalapril alone; HR, 0.76; 95% CI, 0.64-0.91), and composite cardiovascular events consisting of cardiovascular death, MI, and stroke (3.1% with enalapril-folic acid vs 3.9% with enalapril alone; HR, 0.80; 95% CI, 0.69-0.92). The risks of hemorrhagic stroke (HR, 0.93; 95% CI, 0.65-1.34), MI (HR, 1.04; 95% CI, 0.60-1.82), and all-cause deaths (HR, 0.94; 95% CI, 0.81-1.10) did not differ significantly between the 2 treatment groups. There were no significant differences between the 2 treatment groups in the frequencies of adverse events. CONCLUSIONS AND RELEVANCE: Among adults with hypertension in China without a history of stroke or MI, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke. These findings are consistent with benefits from folate use among adults with hypertension and low baseline folate levels. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00794885.