Hyperhomocysteinemia (HHcy) is an independent risk factor of atherosclerosis and other cardiovascular diseases. Unfortunately, Hcy-lowering strategies were found to have limited effects in reducing cardiovascular events. The underlying mechanisms remain unclear. Increasing evidence reveals a role of inflammation in the pathogenesis of HHcy. Homocysteine (Hcy) is a precursor of hydrogen sulfide (H₂S), which is formed via the transsulfuration pathway catalyzed by cystathionine β-synthase and cystathionine γ-lyase (CSE) and serves as a novel modulator of inflammation. In the present study, we showed that methionine supplementation induced mild HHcy in mice, associated with the elevations of TNF-α and IL-1β in the plasma and reductions of plasma H₂S level and CSE expression in the peritoneal macrophages. H₂S-releasing compound GYY4137 attenuated the increases of TNF-α and IL-1β in the plasma of HHcy mice and Hcy-treated raw264.7 cells while CSE inhibitor PAG exacerbated it. Moreover, the in vitro study showed that Hcy inhibited CSE expression and H₂S production in macrophages, accompanied by the increases of DNA methyltransferase (DNMT) expression and DNA hypermethylation in cse promoter region. DNMT inhibition or knockdown reversed the decrease of CSE transcription induced by Hcy in macrophages. In sum, our findings demonstrate that Hcy may trigger inflammation through inhibiting CSE-H₂S signaling, associated with increased promoter DNA methylation and transcriptional repression of cse in macrophages.

Background: Triglyceride glucose (TyG) index was recently reported to be associated with an increased risk of the development and recurrence of cardiovascular events, and atherosclerosis is a main speculative mechanism. However, data on the relationship between TyG index and atherosclerosis, especially in the setting of ischemic stroke, is rare. We aimed to explore the association between TyG index and carotid atherosclerosis in patients with ischemic stroke. Methods: A total of 1523 ischemic stroke patients with TyG index and carotid artery imaging data were enrolled in this analysis. The TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. Carotid atherosclerosis was measured by common carotid artery intima-media thickness (cIMT), and abnormal cIMT was defined as a mean cIMT and maximum cIMT value ≥ 1 mm. Multivariable logistic regression models and restricted cubic spline models were used to assess the relationships between TyG index and abnormal cIMT. Risk reclassification and calibration of models with TyG index were analyzed. Results: The multivariable-adjusted odds ratios (95% CIs) in quartile 4 versus quartile 1 of TyG index were 1.56 (1.06–2.28) for abnormal mean cIMT and 1.46 (1.02–2.08) for abnormal maximum cIMT, respectively. There were linear relationships between TyG index and abnormal mean cIMT (P for linearity = 0.005) and abnormal maximum cIMT (P for linearity = 0.027). In addition, the TyG index provided incremental predictive capacity beyond established risk factors, shown by an increase in net reclassification improvement and integrated discrimination improvement (all P < 0.05). Conclusions: A higher TyG index was associated with carotid atherosclerosis measured by cIMT in patients with ischemic stroke, suggesting that TyG could be a promising atherosclerotic marker.

Background: This study was conducted to determine optimal predictive ability of National Institutes of Health Stroke Scale (NIHSS) measurements at baseline, 24 hours, and change from baseline to 24 hours after thrombolysis on functional recovery in patients with acute ischemic stroke who participated in the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study). Methods and Results: ENCHANTED was an international, multicenter, 2×2 quasifactorial, prospective, randomized open trial of low‐dose versus standard‐dose intravenous alteplase and intensive versus guideline‐recommended blood pressure lowering in thrombolysis‐eligible patients with acute ischemic stroke. Absolute (baseline minus 24 hours) and percentage (absolute change/baseline × 100) changes in NIHSS scores were calculated. Receiver operating characteristic curve analyses assessed performance of different NIHSS measurements on 90‐day favorable functional recovery (modified Rankin Scale [mRS] score 0–2) and excellent functional recovery (mRS score 0–1). Youden index was used to identify optimal predictor cutoff points. A total of 4410 patients in the ENCHANTED trial were enrolled. The 24‐hour NIHSS score had the highest discriminative ability for predicting favorable 90‐day functional recovery (mRS score 0–2; area under the curve 0.866 versus 0.755, 0.689, 0.764; P <0.001) than baseline, absolute, and percentage change of NIHSS score, respectively. The optimal cutoff point of 24‐hour NIHSS score for predicting favorable functional recovery was ≤4 (sensitivity 66.5%, specificity 87.1%, adjusted odds ratio, 9.44 [95% CI, 7.77–11.48]). The 24‐hour NIHSS score (≤3) was the best predictor of 90‐day excellent functional recovery (mRS score 0–1). Findings were consistent across subgroups, including sex, race, baseline NIHSS score, stroke subtype, and age. Conclusions: In thrombolysis‐eligible patients with acute ischemic stroke, 24‐hour NIHSS score (optimal cutpoint of 4) is the strongest predictor of 90‐day functional recovery over baseline and early change of NIHSS score. Registration: URL: https://clinicaltrials.gov . Unique Identifier: NCT01422616.

High white blood cell (WBC) count and high blood glucose level are risk factors for mortality and pneumonia after acute ischemic stroke (AIS). We investigated the combined effect of high WBC count and high blood glucose level on hospital admission and in-hospital mortality and pneumonia in acute AIS patients. A total of 3124 AIS patients enrolled from December 2013 to May 2014 across 22 hospitals in Suzhou city were included in the present study. We divided patients into four groups according to their level of WBC count and blood glucose: NWNG (normal WBC count and normal glucose), NWHG (normal WBC count and higher glucose), HWNG (higher WBC count and normal glucose), and HWHG (higher WBC count and higher glucose). Cox proportional hazard model and logistic regression model were used to estimate the combined effect of WBC count and blood glucose on all-cause in-hospital mortality and pneumonia in AIS patients. HWHG was associated with a 2.22-fold increase in the risk of in-hospital mortality in comparison to NWNG (adjusted hazard ratio [HR] 2.22; 95% confidence interval [CI], 1.21–4.07; P trend = 0.003). The risk of pneumonia was significantly higher in patients with HWHG compared to those with NWNG (adjusted odds ratio [OR] 2.61; 95% CI, 1.66–4.10; P trend < 0.001). The C-statistic for the combined WBC count and blood glucose was higher than WBC count or blood glucose alone for prediction of in-hospital mortality and pneumonia (all p < 0.01). High WBC count combined with high blood glucose level at admission was independently associated with in-hospital mortality and pneumonia in AIS patients. Moreover, the combination of WBC count and blood glucose level appeared to be a better predictor than WBC count or blood glucose alone.

Jiang QM, et al. J Clin Neurol. 2022 May;18(3):298-307. https://doi.org/10.3988/jcn.2022.18.3.298