Shuyu Zhou

Notable epigenetic role of hyperhomocysteinemia in atherogenesis

Atherosclerosis is associated with multiple genetic and modifiable risk factors. There is an increasing body of evidences to indicate that epigenetic mechanisms also play an essential role in atherogenesis by influencing gene expression. Homocysteine is a sulfur-containing amino acid formed during methionine metabolism. Elevated plasma level of homocysteine is generally termed as hyperhomocysteinemia. As a potential risk factor for cardiovascular diseases, hyperhomocysteinemia may initiate or motivate atherogenesis by modification of DNA methylation. The underlying epigenetic mechanism is still unclear with controversial findings. This review focuses on epigenetic involvement and mechanisms of hyperhomocysteinemia in atherogenesis. Considering the potential beneficial effects of anti-homocysteinemia treatments in preventing atherosclerosis, further studies on the role of hyperhomocysteinemia in atherogenesis are warranted.

Mitochondrial DNA haplogroups and short-term neurological outcomes of ischemic stroke

Stroke is one of the leading causes of death and long-term disability worldwide. Mitochondrial DNA (mtDNA) is a potential contributor for the sex differences of ischemic stroke heritability. Although mtDNA haplogroups were associated with stroke onset, their impacts on stroke outcomes remain unclear. This study aimed to evaluate the impacts of mtDNA haplogroups on short-term outcomes of neurological functions in patients with ischemic stroke. A total of 303 patients were included, and their clinical data and mtDNA sequences were analyzed. Based on the changes between baseline and 14-day follow-up stroke severity, our results showed that haplogroup N9 was an independent protective factor against neurological worsening in acute ischemic stroke patients. These findings supported that mtDNA variants play a role in post-stroke neurological recovery, thus providing evidences for future pharmacological intervention in mitochondrial function.

The Relationship between Neutrophil-to-Lymphocyte Ratio and Aortic Arch Calcification in Ischemic Stroke Patients

BACKGROUND Inflammation plays a central role in atherogenesis and artery calcification. Although neutrophil-to-lymphocyte ratio (NLR) has been introduced as an inflammatory marker for atherosclerosis, the relationship between NLR and aortic arch calcification (AAC) has not been studied. This study aimed to determine the association between NLR and AAC. METHODS A total of 749 participants were enrolled. Demographic and clinical data were collected. Degree of AAC in each enrolled patient was determined with Agatston method based on a neck computed tomography angiography. NLR was divided into 4 groups according to quartile values. Generalized linear model (ordinal probit) was performed to assess the association between NLR quartiles and severity of AAC. RESULTS There were 151 (20.2%), 153 (20.4%), and 445 (59.4%) patients classified as without AAC, with mild AAC, and with severe AAC, respectively. Patients with severe AAC had the highest NLR values (2.37[1.79-3.42] versus 2.29[1.55-2.96] versus 2.17[1.64-2.91], P = .025) compared to patients without AAC and with mild AAC. In age- and sex-adjusted models, patients with the highest NLR (quartile 4) were correlated with severer AAC (β = .348 ± .128, P = .006) compared to those with the lowest levels (quartile 1). The correlation between NLR quartile 4 and severer AAC still existed (β = .335 ± .129, P = .009) in multivariable-adjusted model. CONCLUSIONS This study suggested that NLR may reflect the severity of AAC. NLR may be considered as a valuable predictor of the degree of artery calcification.

The impacts of premorbid hypertension treatment on functional outcomes of ischemic stroke

BACKGROUND AND PURPOSE The low rate of hypertension control is a major cause for the high rate of stroke morbidity and mortality in China. This study aimed to evaluate the impacts of premorbid hypertension treatment on the functional outcomes in patients with acute ischemic stroke and hypertension. METHODS Patients with first-ever ischemic stroke and hypertension were screened from Nanjing Stroke Registry Program for eligibility. Functional outcomes were followed at 3 months with modified Rankin Scale (mRS). A good functional outcome was defined as mRS≤2. Potential factors associated with good functional outcomes were analyzed with multivariate logistic regression. RESULTS A total of 660 patients with both ischemic stroke and hypertension were included, of whom 284 (43.0%) were on antihypertensives before stroke. In univariate analysis, more patients with hypertension treatments had good outcomes than those without (47.7% vs 31.0%, P=0.0001). After adjusted for age, heart diseases, baseline stroke severity, systolic blood pressure at admission, pneumonia, intravenous thrombolysis, and hospital stay, multivariate logistic regression indicated that premorbid hypertension treatment was related to an increased likelihood of good functional outcomes (OR: 2.21, 95% CI: 1.30 to 3.74, P=0.003). CONCLUSIONS Less than half of the Chinese patients with hypertension were on drug treatment prior to stroke onset. Lack of premorbid hypertension treatment may have deteriorated functional outcomes of stroke. These findings emphasized the importance of improving hypertension treatment in Chinese, especially in whom at high risk of cerebrovascular diseases.

Premorbid dietary intake of protein is associated with early outcomes but not with severity of ischemic stroke

BACKGROUND AND OBJECTIVES Dietary protein intake has been associated with reduced risk of stroke. This study aimed to examine the relationship between premorbid dietary intake of protein and both stroke severity and neurological outcomes in patients with acute ischemic stroke. METHODS AND STUDY DESIGN Consecutive patients with first-ever ischemic stroke in Jinling Hospital were screened for eligibility of participation. A validated foodfrequency questionnaire (FFQ) was performed to collect necessary data for calculating pre-stroke dietary intakes. Stroke severity was assessed by the National Institutes of Health Stroke Scale (NIHSS) at baseline. Neurological outcomes were assessed by the modified Rankin scale (mRS) 90 days after stroke onset. Multivariable logistical regression was applied to analyze the impacts of dietary protein intake on stroke severity or neurological outcomes. RESULTS Of the 201 enrolled patients, 110 (54.7%) were classified as minor (NIHSS ≤5) and 91 (45.3%) as major stroke (NIHSS ≥6). After adjusting for potential confounders, multivariable logistic regression did not detect significant association between total (odds ratio (OR)=0.98, p=0.15), animal (OR=1.01, p=0.87) or plant protein intake (OR=0.96, p=0.07) and stroke severity. According to the 90-day mRS, 127 patients (63.2%) were determined with good (mRS ≤2), and 74 (36.8%) with poor outcomes (mR 3-6). Multivariable logistic regression detected that premorbid dietary intake of total protein was positively associated with good neurological outcomes (OR=1.05, p=0.04). CONCLUSIONS Higher level of premorbid protein intake may be associated with favorable neurological outcomes independent of stroke severity.

Association between PTGS1 polymorphisms and functional outcomes in Chinese patients with stroke during aspirin therapy: Interaction with smoking

PURPOSE Prostaglandin-Endoperoxide Synthase 1 (PTGS1) and smoking may play important roles in aspirin nonresponsiveness, but the effect of their interaction on stroke outcomes remains largely unknown. We examined the effects of PTGS1 polymorphisms, smoking status, and their interaction on functional outcomes in a cohort of Chinese Han patients with stroke during aspirin therapy. METHODS A total of 617 ischemic stroke patients taking aspirin were enrolled. Three single nucleotide polymorphisms (SNPs) rs1330344, rs3842788, and rs5788 in PTGS1 were determined for genotyping. Poor functional outcomes were defined as a modified Rankin Scale (mRS) of 3-6 at 90-day follow-up. The influence of PTGS1 gene-smoking interaction on functional outcomes was examined. RESULTS Poor functional outcomes occurred in 145 (23.5%) patients. When adjusting multiple factors by logistic regression, CC genotype of rs1330344 was associated with poor functional outcomes (risk ratio [RR]=1.73; 95% confidence interval [CI]: 1.17-2.37). A similar connection was found in the CGC haplotype (RR=1.40; 95% CI: 1.08-1.77). Furthermore, we found a significant interaction between rs1330344 and smoking status (Pinteraction=0.018); the interaction effect between the PTGS1 haplotype and smoking also showed statistical significance (Pinteraction=0.040). CONCLUSIONS In Chinese Han stroke patients with aspirin therapy, the adverse effect of PTGS1 polymorphisms on functional outcomes may be modulated by the smoking status. PTGS1 gene-smoking interaction might in part reflect the heterogeneity in the prognosis of patients treated with aspirin.

CDKN2B Methylation and Aortic Arch Calcification in Patients with Ischemic Stroke

Aim: CDKN2A/2B near chromosome 9p21 has been proposed as a potential genetic etiology for both atherosclerosis and arterial calcification. DNA methylation, which can change the expression of CDKN2A/2B, may be an underlying mechanism for this association. This study aimed to evaluate whether CDKN2A/2B methylation is related to aortic arch calcification (AAC) in patients with ischemic stroke. Methods: DNA methylation levels of CDKN2A/2B was measured using venous blood samples in 322 patients with ischemic stroke. A total of 36 CpG sites around promoter regions of CDKN2A/2B were examined. AAC was quantified with Agatston score based on results of computed tomography angiography. Results: There were 248 (77.0%) patients with and 74 (23.0%) patients without evident AAC. Compared with patients without AAC, patients with AAC had higher methylation levels of CDKN2B (5.72 vs 4.94, P < 0.001). Using a generalized linear model, positive correlation between methylation levels and log-transformed calcification scores was detected at CDKN2B (β = 0.275 ± 0.116, P = 0.018). Conclusion: Patients with higher levels of DNA methylation of CDKN2B may bear increased risk for AAC. Further studies to reveal the underlying mechanisms of this association are warranted for establishing a cause–effect relationship.