No abstract

Stroke is the second most common cause of cognitive impairment and dementia. Vascular dementia (VaD), a cognitive impairment following a stroke, is common and significantly impacts the quality of life. We recently demonstrated via gut microbe transplant studies that the gut microbe-dependent trimethylamine-N-oxide (TMAO) pathway impacts stroke severity, both infarct size and long-term cognitive outcomes. However, the molecular mechanisms that underly the role of the microbiome in VaD have not been explored in depth. To address this issue, we performed a comprehensive RNA-sequencing analysis to identify differentially expressed (DE) genes in the ischemic cerebral cortex of mouse brains at pre-stroke and post-stroke day 1 and day 3. A total of 4016, 3752 and 7861 DE genes were identified at pre-stroke and post-stroke day 1 and day 3, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated pathways of neurodegeneration in multiple diseases, chemokine signaling, calcium signaling, and IL-17 signaling as the key enriched pathways. Inflammatory response genes interleukin-1 beta (Il-1β), chemokines (C–X–C motif chemokine ligand 10 (Cxcl10), chemokine ligand 2 (Ccl2)), and immune system genes (S100 calcium binding protein 8 (S100a8), lipocalin-2 (Lcn2)) were among the most significantly upregulated genes. Hypocretin neuropeptide precursor (Hcrt), a neuropeptide, and transcription factors such as neuronal PAS domain protein 4 (Npas4), GATA binding protein 3 (Gata3), and paired box 7 (Pax7) were among the most significantly downregulated genes. In conclusion, our results indicate that higher plasma TMAO levels induce differential mRNA expression profiles in the ischemic brain tissue in our pre-clinical stroke model, and the predicted pathways provide the molecular basis for regulating the TMAO-enhanced neuroinflammatory response in the brain.

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BACKGROUND: Previous studies have documented that Black patients have worse outcomes after lower extremity revascularization procedures compared with White patients. However, the association of race on carotid endarterectomy (CEA) outcomes is not well described. The aim of this study was to compare perioperative outcomes of CEA for Black vs White patients with asymptomatic carotid artery stenosis. STUDY DESIGN: All patients who underwent CEA for asymptomatic carotid stenosis in the ACS-NSQIP targeted vascular database (2011-2019) were included. Perioperative (30-day) outcomes were compared for Black vs White patients using multivariable logistic regression adjusting for age/sex, comorbidities, and disease characteristics. RESULTS: Of 16,764 asymptomatic CEA patients, 95.2% (N = 15,960) were White and 4.8% (N = 804) were Black. Black patients were slightly younger (mean age 71.4 ± 0.1 vs 69.9 ± 0.3 years, P < 0.001) and more frequently had high-grade carotid artery stenosis compared to White patients (79.5% vs 74.0%, p = 0.001). Comorbidities including hypertension, diabetes, kidney disease, congestive heart failure, and coronary artery disease were all more prevalent among Black patients (p ≤ 0.01). Crude perioperative stroke (2.4% vs 1.3%, p = 0.007) and stroke/death (2.6% vs 1.4%, p = 0.003) were higher for Black patients, but myocardial infarction (1.7% vs 1.5%, p = 0.67) and death (0.4% vs 0.2%, p = 0.12) were similar. After adjusting for baseline differences between groups, the risk of perioperative stroke (odds ratio 1.66, 95% CI 1.01 to 2.73) and stroke/death (odds ratio 1.75, 95% CI 1.10 to 2.81) remained significantly higher for Black patients compared with White patients. CONCLUSIONS: Black patients undergoing CEA for asymptomatic carotid artery stenosis had more severe stenosis, more comorbidities, and worse perioperative outcomes compared to White patients. Overall, our data suggest substantial differences in the treatment and outcomes of asymptomatic carotid artery stenosis based on race.