Associations of lipid profiles with the risk of ischemic and hemorrhagic stroke: A systematic review and meta-analysis of prospective cohort studies.

Background and purpose: The associations of lipid profiles with the risk of ischemic stroke (IS) or hemorrhagic stroke (HS) are controversial. In this study, we aimed to illustrate the optimal level for lipid levels in the risk of IS and HS. Materials and methods: We searched the electronic database of PubMed, Embase, and the Cochrane library from inception until November 2020. Prospective cohort studies published in English for the associations of lipid profiles (TC, TG, LDL-C, HDL-C, and non-HDL-C) with the risk of IS and HS were eligible for this study, and the publication status was not restricted. We calculated the pooled effect estimates using the random-effects model. We tested the associations of lipid profiles with IS and HS and compared their differences. Results: We retrieved 50 prospective cohort studies containing 3,301,613 individuals. An increase in total cholesterol (TC) is associated with an increased IS risk (P < 0.001) and a reduced HS risk (P < 0.001). Similarly, an increase in triglyceride links with a greater IS risk (P < 0.001) but with a lower HS risk (P = 0.014). On the opposite, high-density lipoprotein cholesterol (HDL-C) correlates with a reduced IS risk (P = 0.004) but has no significant association with the HS risk (P = 0.571). Moreover, an increase in low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol has no statistically significant effect on both IS and HS. The pooled effect estimates on the risk of IS and HS revealed that TC and LDL-C levels should be controlled under 6.0 and 3.5 mmol/L, respectively, to reduce worsening effects on the IS risk while maintaining potential beneficial effects on reducing the HS risk. Conclusion: We revealed comprehensive relationships between lipid profiles and the risk of stroke, suggesting controlling the TC and LDL-C levels under 6.0 and 3.5 mmol/L, respectively, to balance both the IS and HS risk.

Low T3 syndrome is associated with peripheral neuropathy in patients with type 2 diabetes mellitus.

INTRODUCTION/AIMS: Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes mellitus. Diabetic patients often have thyroid dysfunction. The aim of this study was to investigate the association between low triiodothyronine (T3) syndrome and DPN in patients with type 2 diabetes mellitus (T2DM). METHODS: A retrospective review was performed of 928 patients with T2DM for whom data was available for clinical manifestations and nerve conduction studies (NCS), and of 134 non-diabetic controls. The composite Z scores of conduction velocity and amplitude were calculated. Low T3 syndrome was defined as T3 levels below the lower limit of the reference interval. RESULTS: Among the patients with T2DM, 632 (68.1%) had DPN, and a larger proportion of these patients presented with low T3 syndrome than patients without DPN. After adjusting for potential confounders, low T3 syndrome was independently associated with the occurrence of DPN (odds ratio [OR] = 2.049, 95% confidence interval [CI] 1.319-3.181, p = .001) and the severity of DPN (OR = 1.597, 95% CI 1.030-2.476, p = .036). Adding the criterion of low T3 syndrome improved the prognostic performance of the traditional model (age + gender + diabetic duration + glycated hemoglobin [HbA1c]) for predicting DPN. DISCUSSION: Low T3 syndrome is associated with a higher risk and increased severity of DPN in patients with T2DM. These findings suggest that low T3 syndrome could be a predictor for risk stratification in patients with T2DM.

Undertreatment of Anticoagulant Therapy in Hospitalized Acute Ischemic Stroke Patients With Atrial Fibrillation.

Background: This study aimed to investigate the prevalence and factors associated with the initiation of oral anticoagulation among patients with acute ischemic stroke (AIS) and concurrent atrial fibrillation (AF) at discharge in China. Methods: We continuously included hospitalized patients with AIS with an AF diagnosis registered in the computer-based Online Database of Acute Stroke Patients for Stroke Management Quality Evaluation (CASE II) from January 2016 to December 2020 and divided them into a and non-anticoagulant groups according to the medications at discharge. Binary logistic regression was used to determine the factors associated with the prescription of anticoagulants in patients with AF. Results: A total of 16,162 patients were enrolled. The mean age was 77 ± 9 years, 8,596 (53.2%) were males, and the median baseline National Institute of Health Stroke Scale score was 5 (2-12). Of the 14,838 patients without contraindications of antithrombotic therapy, 6,335 (42.7%) patients were initiated with anticoagulation treatment at discharge. Prior history of hemorrhagic stroke (OR 0.647, p < 0.001) and gastrointestinal bleeding (OR 0.607, p = 0.003) were associated with a lower rate of anticoagulation at discharge. Patients with any intracranial hemorrhage (OR 0.268, p < 0.001), gastrointestinal bleeding (OR 0.353, p < 0.001), or pneumonia during hospitalization (OR 0.601, p < 0.001) were less likely to receive anticoagulants at discharge. Among 7,807 patients with previously diagnosed AF and high risk of stroke (CHA2DS2-VASc ≥2), only 1,585 (20.3%) had been receiving anticoagulation treatment prior to the onset of stroke. However, the mean international normalized ratio (INR) was 1.5 on the first test during hospitalization in patients receiving warfarin. Patients complicated with a previous history of ischemic stroke/transient ischemic attack (TIA; OR 2.303, p < 0.001) and peripheral artery disease (OR 1.456, p = 0.003) were more common to start anticoagulants. Conclusions: Less than half of patients with AIS and concurrent AF initiated guideline-recommended oral anticoagulation at discharge, while only 20% of patients with previously diagnosed AF with a high risk of stroke had been using anticoagulants prior to the onset of stroke, which highlights a large care gap in hospitalized stroke patients and the importance of AF management.

Corticospinal Tract Hypoperfusion Associated With Unexplained Early Neurological Deterioration After Intravenous Thrombolysis.

Background and Purpose: Early neurological deterioration (END) occurs in 10% among patients with acute ischemic stroke (AIS) who are receiving intravenous thrombolysis (IVT). Over half of them have no straightforward causes, which is referred to as unexplained END. We aimed to explore whether the presence of baseline corticospinal tract (CST) hypoperfusion could predict the development of unexplained END at 24 h in patients with AIS after receiving IVT. Methods: We retrospectively analyzed the clinical and imaging data from patients with AIS who received IVT. Unexplained END was defined as ≥ 2-point increase of National Institutes of Health Stroke Scale (NIHSS) from baseline to 24 h without straightforward causes. Hypoperfusion lesions involving CST and other cerebral areas were identified on perfusion maps. Results: Among 807 patients, CST hypoperfusion and non-CST hypoperfusion occurred in 488 (60.5%) and 319 (39.5%) patients, respectively. Patients with CST hypoperfusion were more likely to have unexplained END compared with patients with non-CST hypoperfusion (16.6 vs. 2.8%, P < 0.001). Binary logistics regression analysis showed that CST hypoperfusion was independently associated with unexplained END after IVT (OR = 5.64; 95% CI: 2.699-11.785; P < 0.001) after adjusting for baseline NIHSS, onset to needle time, baseline hypoperfusion volume, atrial fibrillation, and hypertension. Conclusions: Patients with CST hypoperfusion were more likely to suffer from unexplained END after IVT, implying potential mechanisms and potential prevention of unexplained END.

Prediction of Acute Myocardial Infarction in Asian Patients With Acute Ischemic Stroke: The CTRAN Score.

Background: Patients with acute ischemic stroke (AIS) are susceptible to acute myocardial infarction (AMI), which would lead to a dramatic increase of in-hospital mortality. Objectives: The authors established and validated an easy-used model to stratify the risk of in-hospital AMI among patients with AIS. Methods: We consecutively included patients with AIS who were admitted within 7 days from symptom onset in our prospectively maintained database (NCT04487340) from January 2016 to December 2020. In the derivation cohort from 70 centers, we developed a score to predict in-hospital AMI by integrating the bedside-accessible predictors identified via multivariable logistic regression. Then in the validation cohort from 22 centers, we externally evaluated the performance of this score. Results: Overall, 96,367 patients were included. In-hospital AMI occurred in 392 (0.41%) patients. The final model, named CTRAN, incorporated 5 predictors including the history of coronary heart disease, malignant tumor, renal insufficiency, age, and baseline National Institutes of Health Stroke Scale score. The CTRAN score was confirmed in the validation cohort using receiver operating characteristic curve, which yielded an area under the curve of 0.758 (95% CI: 0.718-0.798). Conclusions: The CTRAN score could be a good tool for clinicians to identify patients with AIS at high in-hospital AMI risk.

Exosomal miR-211 contributes to pulmonary hypertension via attenuating CaMK1/PPAR-γaxis.

AIM: Exsomes play a significant role in increasing pathophysiological processes by delivering their content. Recently, a variety of studies have showed exosomal microRNAs (miRNAs) are involved in pulmonary hypertension (PH) notably. In this study, we found that exosomal miR-211 was overexpressed in hypoxia-induced PH rats but its intrinsic regulation was unclear. Therefore, our aim was to reveal the underlying mechanism which overexpressed exosomal miR-211 targeted in the development of PH. METHODS: 18 male SD rats were randomly divided into normoxia and hypoxia group, housed in normal or hypoxic chamber for 3 weeks respectively. Then, mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance(PVR), right ventricular hypertrophy index(RV/(LV + S)), the percentage of medial wall area (WA%) and the percentage of medial wall thickness (WT%) were measured. Expression of miR-211 in exosomes was detected by qRT-PCR. Expression of Ca2+/calmodulin-dependent kinase1(CaMK1)and peroxisome proliferator-activated receptors-γ(PPAR-γ)in lung tissue were detected by Western blot(WB); After miR-211 overexpressed exosomes were injected to rats through caudal vein, mPAP, PVR, RV/(LV + S), WA% and WT% were also measured. Sequentially, hypoxia rats were injected with lentivirus riched in miR-211 inhibitor via tail vein, and PH-related indicators were measured. In vitro, after miR-211 was positively or negatively regulated in pulmonary arterial smooth muscle cell (PASMC) by plasmid transfection, proliferation of PASMC was detected by CCK8, as well as the expression of CaMK1 and PPAR- γ. Further, the relationship between CaMK1 and miR-211 was verified by Dual-Luciferase assay. And the regulatory relationship of CaMK1/PPAR- γ aixs was demonstrated in PASMC. RESULTS: Evident increases of mPAP, PVR, RVHI, WT% and WA% were observed with hypoxia administration. And the concentration of plasma exosomes in hypoxia rats was increased and positively correlated with the above indexes. miR-211 in exosomes of PH was upregulated while the expression of CaMK1 and PPAR-γ decreased in lung tissues. Further, injection of exosomes overexpressed with miR-211 demonstrated that exosomal miR-211 aggravated PH while inhibition of miR-211 attenuated PH in rats. In vitro, overexpression of miR-211 promoted the proliferation of PASMC and inhibited expression of CaMK1 and PPAR-γ in PASMC. And Dual-luciferase assay demonstrated that CaMK1 was a downstream gene of miR-211. Plasmid transfection experiments indicated that CaMK1 can promote PPAR-γ expression. CONCLUSION: Exosomal miR-211 promoted PH via inhibiting CaMK1/PPAR-γ axis, promoting PASMC proliferation in rats.

[Effects of apple polyphenols on monocrotaline-induced pulmonary vascular remodeling in rats and its mechanism].

OBJECTIVE: To investigate the effects of apple polyphenols on pulmonary vascular remodeling in rats with pulmonary arterial hypertension and its mechanism. METHODS: Rats were randomly divided into 4 groups:control (Con) group, monocrotaline (MCT) group, apple polyphenol (APP) group,monocrotaline + apple polyphenol (MCT+APP) group. In Con group, rats received a subcutaneous injection of physical saline. In APP group, rats received intraperitoneal injection of 20 mg/kg APP, every other day. In MCT group, rats received a single subcutaneous injection of MCT(60 mg/kg). In MCT+APP group, rats received subcutaneous injection of 60 mg/kg MCT followed by an intraperitoneal injection of 20 mg/kg APP every other day. All the disposal lasted 3 weeks. Then the PAH-relevant indicators, such as mean pulmonary artery pressure(mPAP), pulmonary vascular resistance(PVR), right ventricular hypertrophy index (RVHI) ,wall thickness (WT%) and wall area (WA%) were tested. After that, the inflammatory pathway related indicators, such as interleukin1(IL-1),interleukin1(IL-6), tumor necrosis factor α(TNF-α), cyclooxygenase 2(COX-2) and myeloperoxidase(MPO) in pulmonary tissue and free intracellular Ca2+ in pulmonary smooth muscle cell(PASMC), content of eNOS and NO in endothelial cells were determined. RESULTS: Compared with the control group, the levels of mPAP, PVR, RVHI, WA%, WT%, and IL-1, IL-6, TNF-α, COX-2, MPO in tissue and the expression of Ca2 + in PASMC of MCT group were increased significantly, while the contents of eNOS and NO in endothelial cells were decreased significantly (P＜0.05). Compared with the MCT group, the apple polyphenol treatment could improve the above mentioned situation, and the COX-2 and Ca2+ indicators of the apple polyphenol treatment group were decreased significantly (P＜0.05). CONCLUSION: MCT can increase COX-2 expression and intracellular Ca2+ in pulmonary artery smooth muscle cells, decrease the contents of eNOS and NO in endothelial cells, while apple polyphenols can significantly inhibit these effects.

Grape seed proanthocyanidin inhibits monocrotaline-induced pulmonary arterial hypertension via attenuating inflammation: in vivo and in vitro studies.

Inflammation in pulmonary arterioles initiates and maintains pathological processes in pulmonary arterial hypertension (PAH), and inhibition of it attenuates PAH development. Grape seed proanthocyanidin (GSP) is believed to be effective in protecting vascular system via inhibiting inflammation, while its effect on pulmonary circulation remains inconclusive. In this study, we made observations in monocrotaline (MCT)-induced PAH rats and found decreases in mean pulmonary arterial pressure, pulmonary vessel resistance, right ventricular hypertrophy index, percentage of medial wall thickness, percentage of medial wall area, and lung weight of wet and dry tissue ratio after GSP administration in vivo. At the cellular and molecular levels, we also found several effects of GSP on MCT-induced PAH: (a) endothelial nitric oxide synthase expression in lung tissue and plasma NO level were increased; (b) Ca2+ level in pulmonary arterial smooth muscle cell (PASMC) was decreased; (c) transcription of inflammatory factors such as myeloperoxidase, interleukin (IL)-1ß, IL-6 and tumor necrosis factor alpha (TNF-α) was down-regulated in lung tissue; (d) nuclear factor-κB pathway was inhibited as IκBα was less phosphorylated; (e) TNFα-induced PASMC overproliferation could be inhibited. These results indicated a possible mechanism of GSP reversing pulmonary vascular remodeling and vascular contraction by inhibiting inflammation, and it may be useful for preventing PAH development.

Apple polyphenol relieves hypoxia-induced pulmonary arterial hypertension via pulmonary endothelium protection and smooth muscle relaxation: In vivo and in vitro studies.

AIM: This study aims to test the effect of apple polyphenol (APP) on hypoxia-induced pulmonary arterial hypertension (PAH) and explore its possible underlying mechanisms. METHODS AND RESULTS: Rats were treated with control, APP, hypoxia (8 h/d), hypoxia + APP. Mean pulmonary arterial pressure (mPAP) and pulmonary vessel resistance (PVR) were examined. Phenylephrine (PE)-pretreated pulmonary vessel rings were prepared for observation of APP administration. eNOS, sGC inhibitors (L-NAME, MB), Ca2+ channel blockers (NiCl2, Calhex231), K+ channel blockers (4-AP, 5-HD, TEA, BaCl2) were applied to pulmonary vessel rings and pulmonary arterial smooth muscle cell (PASMC). Flow cytometry analysis and CCK-8 assay were applied to detect apoptosis of pulmonary artery endothelium cell (PAEC). Caspase-3, NO, eNOS, iNOS were detected in PAEC. APP reversed mPAP and PVR elevation in vivo. Contraction of pulmonary vessel rings with/without endothelium induced by hypoxia were inhibited by APP. APP effect was hindered by L-NAME or MB, and could be reduced by K+channel blockers. Further, APP was found to decrease cytosolic Ca2+ in PASMC and protect PAEC from apoptosis. In PAEC, Caspase-3, iNOS were decreased and NO, eNOS were increased after APP administration. CONCLUSIONS: APP reverses pulmonary vasoconstriction through enzyme expression and cation channel activities, thus has effects of PASMC relaxation and PAEC protection.