Metformin monotherapy versus predominantly older non-metformin antidiabetic medications for cerebrovascular risk in early type 2 diabetes management.

AIM: Choosing the initial treatment for type 2 diabetes (T2D) is pivotal, requiring consideration of solid clinical evidence and patient characteristics. Despite metformin's historical preference, its efficacy in preventing cerebrovascular events lacked empirical validation. This study aimed to evaluate the associations between first-line monotherapy (metformin or non-metformin antidiabetic medications) and cerebrovascular complications in patients with T2D without diabetic complications. METHODS: We analysed 9090 patients with T2D without complications who were prescribed either metformin or non-metformin medications as initial therapy. Propensity score matching ensured group comparability. Cox regression analyses, stratified by initial metformin use, assessed cerebrovascular disease risk, adjusting for multiple covariates and using competing risk analysis. Metformin exposure was measured using cumulative defined daily doses. RESULTS: Metformin users had a significantly lower crude incidence of cerebrovascular diseases compared with non-users (p < .0001). Adjusted hazard ratios (aHRs) consistently showed an association between metformin use and a lower risk of overall cerebrovascular diseases (aHRs: 0.67-0.69) and severe events (aHRs: 0.67-0.69). The association with reduced risk of mild cerebrovascular diseases was significant across all models (aHRs: 0.73-0.74). Higher cumulative defined daily doses of metformin correlated with reduced cerebrovascular risk (incidence rate ratio: 0.62-0.94, p < .0001), indicating a dose-dependent effect. CONCLUSION: Metformin monotherapy is associated with a reduced risk of cerebrovascular diseases in early-stage T2D, highlighting its dose-dependent efficacy. However, the observed benefits might also be influenced by baseline differences and the increased risks associated with other medications, such as sulphonylureas. These findings emphasize the need for personalized diabetes management, particularly in mitigating cerebrovascular risk in early T2D stages.

Prevalence and determinants of self-reported low-fat-, low-salt-, and vegetarian diets in patients with cardiovascular disease between 1996 and 2019.

BACKGROUND AND AIMS: Guidelines no longer recommend low-fat diets and currently recommend more plant-based diets to reduce atherosclerotic cardiovascular disease (ASCVD) risk. Furthermore, these guidelines have consistently recommended salt-reduced diets. This article describes current self-reported use and time-trends in the self-reported use of low-fat, low-salt and vegetarian diets in ASCVD patients and examines patient characteristics associated with each diet. METHODS AND RESULTS: 9005 patients with ASCVD included between 1996 and 2019 in the UCC-SMART cohort were studied. The prevalence of self-reported diets was assessed and multi-variable logistic regression was used to identify the determinants of each diet. Between 1996-1997 and 2018-2019, low-fat diets declined from 22.4 % to 3.8 %, and low-salt diets from 14.7 % to 4.6 %. The prevalence of vegetarian diets increased from 1.1 % in 1996-1997 to 2.3 % in 2018-2019. Patients with cerebrovascular disease (CeVD) and peripheral artery disease or an abdominal aortic aneurysm (PAD/AAA) were less likely to report a low-salt diet than coronary artery disease (CAD) patients (OR 0.62 [95%CI 0.49-0.77] and 0.55 [95%CI 0.41-0.72]). CONCLUSION: In the period 1996 to 2019 amongst patients with ASCVD, the prevalence of self-reported low-fat diets was low and decreased in line with changes in recommendations in major guidelines. The prevalence of self-reported vegetarian diets was low but increased in line with societal and guideline changes. The prevalence of self-reported low-salt diets was low, especially in CeVD and PAD/AAA patients compared to CAD patients, and decreased over time. Renewed action is needed to promote low-salt diets in ASCVD patients.

Salutogenesis intervention improves cardio-cerebrovascular health in at-risk office workers: A quasi-experimental study.

OBJECTIVE: Cardio-cerebrovascular disease is the major cause of work-related deaths. Salutogenesis indicates individual differences in health levels occur owing to differences in the sense of coherence (SOC). A salutogenesis-based intervention may promote cardio-cerebrovascular health at work. This study examined the effects of a SOC promotion program based on salutogenesis. DESIGN: Quasi-experimental study. SAMPLE: Fifty-six office workers who were above the "low risk" of cardio-cerebrovascular disease from two workplaces were included in the final analysis. MEASUREMENTS: Data collected pre- and postintervention. To determine the intervention's effectiveness, repeated-measures analysis of variance was used. INTERVENTION: The intervention group was provided with the SOC promotion program, whereas the control group was provided with educational materials alone for 12 weeks. RESULTS: Generalized resistance resources (GRRs; knowledge of cardio-cerebrovascular disease prevention, stress-coping strategies, and social support) and SOC significantly improved in the intervention group. The intervention group showed significant improvements in occupational stress, physical activity, dietary behavior, total cholesterol level, fasting glucose level, hemoglobin A1C level, body mass index, waist circumference, diastolic and systolic blood pressure, and cardio-cerebrovascular risk. CONCLUSIONS: Systematic salutogenesis-based SOC promotion programs should be established to enhance the cardio-cerebrovascular health of office workers at-risk of cardio-cerebrovascular diseases. TRIAL REGISTRATION: Trial Registration Number is KCT0007029. The date of registration is February 23, 2022.

Analysis of status quo and influencing factors for health-promoting lifestyle in the rural populace with high risk of cardiovascular and cerebrovascular diseases.

OBJECTIVE: To explore the status quo and influencing factors for health-promoting lifestyle in the rural populace with high risk of cardiovascular and cerebrovascular diseases, and to provide reference for developing primary prevention strategies for cardiovascular and cerebrovascular diseases. METHOD: Questionnaire-based survey of 585 cases of high-risk cardiovascular and cerebrovascular population in 11 administrative villages in Fuling of Lishui city was conducted using the Health Promoting Lifestyle Profile-II (HPLP II), Perceived Social Support from Family Scale (PSS-Fa), General Health Questionnaire (GHQ-12), and other questionnaire tools. RESULTS: The total score of the health-promoting lifestyle in the rural populace with high risk of cardiovascular disease is 125.55 ± 20.50, which is at an average level, and the mean scores of each dimension in descending order are-nutrition, interpersonal support, self-actualization, stress management, health responsibility, and exercise. Monofactor analysis revealed that age, education level, marriage, monthly per capita household income, physical activity based on the International Physical Activity Questionnaire (IPAQ), family support function, carotid intima-media thickness, and blood pressure were influencing factors for the health-promoting lifestyle in the rural populace with high risk of cardiovascular and cerebrovascular diseases (P < 0.05). Multiple stepwise regression analysis showed that monthly per capita household income, family support function, physical activity based on the IPAQ, and education level were positively correlated with the level of the health-promoting lifestyle. CONCLUSION: The health-promoting lifestyle level of the rural populace with high risk of cardiovascular and cerebrovascular diseases needs to be improved. When assisting patients to improve their health-promoting lifestyle level, it is imperative to pay attention to improving patients' physical activity level, emphasizing the influence of the family environment on patients, and focusing on patients with economic difficulties and low education level.

Inflammation and the Link to Vascular Brain Health: Timing Is Brain.

Inflammation and its myriad pathways are now recognized to play both causal and consequential roles in vascular brain health. From acting as a trigger for vascular brain injury, as evidenced by the COVID-19 pandemic, to steadily increasing the risk for chronic cerebrovascular disease, distinct inflammatory cascades play differential roles in varying states of cerebrovascular injury. New evidence is regularly emerging that characterizes the role of specific inflammatory pathways in these varying states including those at risk for stroke and chronic cerebrovascular injury as well as during the acute, subacute, and repair phases of stroke. Here, we aim to highlight recent basic science and clinical evidence for many distinct inflammatory cascades active in these varying states of cerebrovascular injury. The role of cerebrovascular infections, spotlighted by the severe acute respiratory syndrome coronavirus 2 pandemic, and its association with increased stroke risk is also reviewed. Rather than converging on a shared mechanism, these emerging studies implicate varied and distinct inflammatory processes in vascular brain injury and repair. Recognition of the phasic nature of inflammatory cascades on varying states of cerebrovascular disease is likely essential to the development and implementation of an anti-inflammatory strategy in the prevention, treatment, and repair of vascular brain injury. Although advances in revascularization have taught us that time is brain, targeting inflammation for the treatment of cerebrovascular disease will undoubtedly show us that timing is brain.

Trials and Treatments for Vascular Brain Health: Risk Factor Modification and Cognitive Outcomes.

There is robust evidence linking vascular health to brain health, cognition, and dementia. In this article, we present evidence from trials of vascular risk factor treatment on cognitive outcomes. We summarize findings from randomized controlled trials of antihypertensives, lipid-lowering medications, diabetes treatments (including antidiabetic drugs versus placebo, and intensive versus standard glycemic control), and multidomain interventions (that target several domains simultaneously such as control of vascular and metabolic factors, nutrition, physical activity, and cognitive stimulation etc). We report that evidence on the efficacy of vascular risk reduction interventions is promising, but not yet conclusive, and several methodological limitations hamper interpretation. Evidence mainly comes from high-income countries and, as cognition and dementia have not been the primary outcomes of many trials, evaluation of cognitive changes have often been limited. As the cognitive aging process occurs over decades, it is unclear whether treatment during the late-life window is optimal for dementia prevention, yet older individuals have been the target of most trials thus far. Further, many trials have not been powered to explore interactions with modifiers such as age, race, and apolipoprotein E, even though sub-analyses from some trials indicate that the success of interventions differs depending on patient characteristics. Due to the complex multifactorial etiology of dementia, and variations in risk factors between individuals, multidomain interventions targeting several risk factors and mechanisms are likely to be needed and the long-term sustainability of preventive interventions will require personalized approaches that could be facilitated by digital health tools. This is especially relevant during the COVID-19 pandemic, where intervention strategies will need to be adapted to the new normal, when face-to-face engagement with participants is limited and public health measures may create changes in lifestyle that affect individuals' vascular risk profiles and subsequent risk of cognitive decline.

tPA Deficiency Underlies Neurovascular Coupling Dysfunction by Amyloid-ß.

The amyloid-ß (Aß) peptide, a key pathogenic factor in Alzheimer's disease, attenuates the increase in cerebral blood flow (CBF) evoked by neural activity (functional hyperemia), a vital homeostatic response in which NMDA receptors (NMDARs) play a role through nitric oxide, and the CBF increase produced by endothelial factors. Tissue plasminogen activator (tPA), which is reduced in Alzheimer's disease and in mouse models of Aß accumulation, is required for the full expression of the NMDAR-dependent component of functional hyperemia. Therefore, we investigated whether tPA is involved in the neurovascular dysfunction of Aß. tPA activity was reduced, and the tPA inhibitor plasminogen inhibitor-1 (PAI-1) was increased in male mice expressing the Swedish mutation of the amyloid precursor protein (tg2576). Counteracting the tPA reduction with exogenous tPA or with pharmacological inhibition or genetic deletion of PAI-1 completely reversed the attenuation of the CBF increase evoked by whisker stimulation but did not ameliorate the response to the endothelium-dependent vasodilator acetylcholine. The tPA deficit attenuated functional hyperemia by suppressing NMDAR-dependent nitric oxide production during neural activity. Pharmacological inhibition of PAI-1 increased tPA activity, prevented neurovascular uncoupling, and ameliorated cognition in 11- to 12-month-old tg2576 mice, effects associated with a reduction of cerebral amyloid angiopathy but not amyloid plaques. The data unveil a selective role of the tPA in the suppression of functional hyperemia induced by Aß and in the mechanisms of cerebral amyloid angiopathy, and support the possibility that modulation of the PAI-1-tPA pathway may be beneficial in diseases associated with amyloid accumulation.SIGNIFICANCE STATEMENT Amyloid-ß (Aß) peptides have profound neurovascular effects that may contribute to cognitive impairment in Alzheimer's disease. We found that Aß attenuates the increases in blood flow evoked by neural activation through a reduction in tissue plasminogen activator (tPA) caused by upregulation of its endogenous inhibitor plasminogen inhibitor-1 (PAI-1). tPA deficiency prevents NMDA receptors from triggering nitric oxide production, thereby attenuating the flow increase evoked by neural activity. PAI-1 inhibition restores tPA activity, rescues neurovascular coupling, reduces amyloid deposition around blood vessels, and improves cognition in a mouse model of Aß accumulation. The findings demonstrate a previously unappreciated role of tPA in Aß-related neurovascular dysfunction and in vascular amyloid deposition. Restoration of tPA activity could be of therapeutic value in diseases associated with amyloid accumulation.

Comparing Warfarin and 4 Direct Oral Anticoagulants for the Risk of Dementia in Patients With Atrial Fibrillation.

Background and Purpose: Atrial fibrillation is a risk factor for dementia, and oral anticoagulant use is associated with a decreased risk of dementia in patients with atrial fibrillation. We aimed to investigate whether the risk of dementia would be different between patients treated with direct oral anticoagulants (DOACs) compared with those with warfarin. Methods: Using the Korean nationwide claims database from January 2014 to December 2017, we identified oral anticoagulant­naive nonvalvular atrial fibrillation patients aged ≥40 years. For the comparisons, warfarin and DOAC groups were balanced using the inverse probability of treatment weighting method. The primary outcome was incident dementia. Results: Among 72 846 of total study patients, 25 948 were treated with warfarin, and 46 898 were treated with DOAC (17 193 with rivaroxaban, 9882 with dabigatran, 11 992 with apixaban, and 7831 with edoxaban). During mean 1.3±1.1 years of follow-up, crude incidence of dementia was 4.87 per 100 person-years (1.20 per 100 person-years for vascular dementia and 3.30 per 100 person-years for Alzheimer dementia). Compared with warfarin, DOAC showed a comparable risks of dementia, vascular dementia, and Alzheimer dementia. In subgroup analyses, DOAC was associated with a lower risk of dementia than warfarin, particularly in patients aged 65 to 74 years (hazard ratio, 0.815 [95% CI, 0.709­0.936]) and in patients with prior stroke (hazard ratio, 0.891 [95% CI, 0.820­0.968]). When comparing individual DOACs with warfarin, edoxaban was associated with a lower risk of dementia (hazard ratio, 0.830 [95% CI, 0.740­0.931]). Conclusions: In this large Asian population with atrial fibrillation, DOAC showed a comparable risk of dementia with warfarin overall. DOACs appeared more beneficial than warfarin, in those aged 65 to 74 years or with a history of stroke. For specific DOACs, only edoxaban was associated with a lower risk of dementia than warfarin.

The impact of the 24-h movement spectrum on vascular remodeling in older men and women: a review.

Aging is associated with increased risk of cardiovascular and cerebrovascular events, which are preceded by early, negative remodeling of the vasculature. Low physical activity is a well-established risk factor associated with the incidence and development of disease. However, recent physical activity literature indicates the importance of considering the 24-h movement spectrum. Therefore, the purpose of this review was to examine the impact of the 24-h movement spectrum, specifically physical activity (aerobic and resistance training), sedentary behavior, and sleep, on cardiovascular and cerebrovascular outcomes in older adults, with a focus on recent evidence (<10 yr) and sex-based considerations. The review identifies that both aerobic training and being physically active (compared with sedentary) are associated with improvements in endothelial function, arterial stiffness, and cerebrovascular function. Additionally, there is evidence of sex-based differences in endothelial function: a blunted improvement in aerobic training in postmenopausal women compared with men. While minimal research has been conducted in older adults, resistance training does not appear to influence arterial stiffness. Poor sleep quantity or quality are associated with both impaired endothelial function and increased arterial stiffness. Finally, the review highlights mechanistic pathways involved in the regulation of vascular and cerebrovascular function, specifically the balance between pro- and antiatherogenic factors, which mediate the relationship between the 24-h movement spectrum and vascular outcomes. Finally, this review proposes future research directions: examining the role of duration and intensity of training, combining aerobic and resistance training, and exploration of sex-based differences in cardiovascular and cerebrovascular outcomes.

A cannabinoid type 2 (CB2) receptor agonist augments NOS-dependent responses of cerebral arterioles during type 1 diabetes.

While activation of cannabinoid (CB2) receptors has been shown to be neuroprotective, no studies have examined whether this neuroprotection is directed at cerebral arterioles and no studies have examined whether activation of CB2 receptors can rescue cerebrovascular dysfunction during a chronic disease state such as type 1 diabetes (T1D). Our goal was to test the hypothesis that administration of a CB2 agonist (JWH-133) would improve impaired endothelial (eNOS)- and neuronal (nNOS)-dependent dilation of cerebral arterioles during T1D. In vivo diameter of cerebral arterioles in nondiabetic and T1D rats was measured in response to an eNOS-dependent agonist (adenosine 5'-diphosphate; ADP), an nNOS-dependent agonist (N-methyl-d-aspartate; NMDA), and an NOS-independent agonist (nitroglycerin) before and 1 h following JWH-133 (1 mg/kg IP). Dilation of cerebral arterioles to ADP and NMDA was greater in nondiabetic than in T1D rats. Treatment with JWH-133 increased responses of cerebral arterioles to ADP and NMDA in both nondiabetic and T1D rats. Responses of cerebral arterioles to nitroglycerin were similar between nondiabetic and T1D rats, and JWH-133 did not influence responses to nitroglycerin in either group. The restoration in responses to the agonists by JWH-133 could be inhibited by treatment with a specific inhibitor of CB2 receptors (AM-630; 3 mg/kg IP). Thus, activation of CB2 receptors can potentiate reactivity of cerebral arterioles during physiologic and pathophysiologic states. We speculate that treatment with CB2 receptor agonists may have potential therapeutic benefits for the treatment of cerebral vascular diseases via a mechanism that can increase cerebral blood flow.

Propionic acid and not caproic acid, attenuates nonalcoholic steatohepatitis and improves (cerebro) vascular functions in obese Ldlr-/- .Leiden mice.

The obesity epidemic increases the interest to elucidate impact of short-chain fatty acids on metabolism, obesity, and the brain. We investigated the effects of propionic acid (PA) and caproic acid (CA) on metabolic risk factors, liver and adipose tissue pathology, brain function, structure (by MRI), and gene expression, during obesity development in Ldlr-/- .Leiden mice. Ldlr-/- .Leiden mice received 16 weeks either a high-fat diet (HFD) to induce obesity, or chow as reference group. Next, obese HFD-fed mice were treated 12 weeks with (a) HFD + CA (CA), (b) HFD + PA (PA), or (c) a HFD-control group. PA reduced the body weight and systolic blood pressure, lowered fasting insulin levels, and reduced HFD-induced liver macrovesicular steatosis, hypertrophy, inflammation, and collagen content. PA increased the amount of glucose transporter type 1-positive cerebral blood vessels, reverted cerebral vasoreactivity, and HFD-induced effects in microstructural gray and white matter integrity of optic tract, and somatosensory and visual cortex. PA and CA also reverted HFD-induced effects in functional connectivity between visual and auditory cortex. However, PA mice were more anxious in open field, and showed reduced activity of synaptogenesis and glutamate regulators in hippocampus. Therefore, PA treatment should be used with caution even though positive metabolic, (cerebro) vascular, and brain structural and functional effects were observed.

Neurovascular and Cognitive Dysfunction in Hypertension.

Hypertension has emerged as a leading cause of age-related cognitive impairment. Long known to be associated with dementia caused by vascular factors, hypertension has more recently been linked also to Alzheimer disease-the major cause of dementia in older people. Thus, although midlife hypertension is a risk factor for late-life dementia, hypertension may also promote the neurodegenerative pathology underlying Alzheimer disease. The mechanistic bases of these harmful effects remain to be established. Hypertension is well known to alter in the structure and function of cerebral blood vessels, but how these cerebrovascular effects lead to cognitive impairment and promote Alzheimer disease pathology is not well understood. Furthermore, critical questions also concern whether treatment of hypertension prevents cognitive impairment, the blood pressure threshold for treatment, and the antihypertensive agents to be used. Recent advances in neurovascular biology, epidemiology, brain imaging, and biomarker development have started to provide new insights into these critical issues. In this review, we will examine the progress made to date, and, after a critical evaluation of the evidence, we will highlight questions still outstanding and seek to provide a path forward for future studies.

Differences in the prevention and control of cardiovascular and cerebrovascular diseases.

At present, the prevention and control of cardiovascular diseases (CAVDs) has made initial advancements, although the prevention and control of cerebrovascular diseases (CEVDs) has not yet achieved the desired progress. In this paper, we review the prevention and control of CEVDs and CAVDs, and analyze the differences in prevention effects, and the pathological and physiological structures pertaining to CEVDs and CAVDs. Combined with the different effects of low-dose aspirin in the primary prevention of CEVDs and CAVDs by meta-analysis, aspirin plays a more important role in the primary prevention of CAVDs than CEVDs. We recognize the misunderstandings and blind spots concerning prevention and control of CEVDs, which can be summarized as follows: (1) CEVDs and CAVDs can be controlled by the same methods and drugs; (2) considering the same pathological factors for cardiovascular diseases; (3) a lack of understanding of the particularity of CEVDs; (4) a focus on platelets and neglect of cerebrovascular protection. In summary, our research clarifies the differences in the prevention measures and drugs used for CEVDs and CAVDs. Of particular concern is the serious lack of preventive drugs for CEVDs in clinical use. An ideal drug for the prevention of CEVDs should have protective effects on the blood, the vascular endothelium, the blood-brain barrier (BBB), and other related factors. Our review aims to highlight several issues in the current prevention of CEVDs and CAVDs, and to provide an optimized plan for preventive drug discovery.

Rosiglitazone restores nitric oxide synthase-dependent reactivity of cerebral arterioles in rats exposed to prenatal alcohol.

BACKGROUND: Prenatal exposure to alcohol leads to a greater incidence of many cardiovascular-related diseases, presumably via a mechanism that may involve increased oxidative stress. An agonist of peroxisome proliferator-activated receptor gamma (PPARγ; rosiglitazone) has been shown to suppress alcohol-induced neuroinflammation and oxidative stress. The goal of this study was to determine whether acute and chronic treatment with rosiglitazone could restore or prevent impaired nitric oxide synthase (NOS)-dependent responses of cerebral arterioles in male and female adult (14-16 weeks old) rats exposed to alcohol in utero. METHODS: We fed Sprague-Dawley dams a liquid diet with or without 3% ethanol for the duration of their pregnancy (21-23 days). In the first series of studies, we examined the reactivity of cerebral arterioles to eNOS- (ADP), nNOS-dependent (NMDA), and NOS-independent agonists in male and female adult rats before and during acute (1 hour) topical application of rosiglitazone (1 µM). In a second series of studies, we examined the influence of chronic treatment with rosiglitazone (3 mg/kg/day in drinking water for 2-3 weeks) on the responses of cerebral arterioles in male and female adult rats exposed to alcohol in utero. RESULTS: We found that in utero exposure to alcohol similarly reduced responses of cerebral arterioles to ADP and NMDA, but not to nitroglycerin in male and female adult rats. In addition, acute treatment of the male and female adult rats with rosiglitazone similarly restored this impairment in cerebral vascular function to that observed in controls. We also found that chronic treatment with rosiglitazone prevented impaired vascular function in male and female adult rats that were exposed to alcohol in utero. CONCLUSIONS: PPARγ activation may be an effective and relevant treatment to reverse or prevent cerebral vascular abnormalities associated with prenatal exposure to alcohol.

Eprosartan: A closer insight into its neuroprotective activity in rats with focal cerebral ischemia-reperfusion injury.

Eprosartan (EPRO), an angiotensin receptor type-1 (AT-1) blocker, exhibited neuroprotective activities in ischemic stroke resulting from focal cerebral ischemia in rats. The current study aimed to clarify the neuroprotective role of EPRO in middle carotid artery occlusion (MCAO)-induced ischemic stroke in rats. Fifty-six male Wistar rats were divided into four groups (n = 14 per group): sham-operated group, sham receiving EPRO (60 mg/kg/day, po) group, ischemia-reperfusion (IR) group, and IR receiving EPRO (60 mg/kg/day, po) group. MCAO led to a remarkable impairment in motor function together with stimulation of inflammatory and apoptotic pathways in the hippocampus of rats. After MCAO, the AT1 receptor in the brain was stimulated, resulting in activation of Janus kinase 2/signal transducers and activators of transcription 3 signaling generating more neuroinflammatory milieu and destructive actions on the hippocampus. Augmentation of caspase-3 level by MCAO enhanced neuronal apoptosis synchronized with neurodegenerative effects of oxidative stress biomarkers. Pretreatment with EPRO opposed motor impairment and decreased oxidative and apoptotic mediators in the hippocampus of rats. The anti-inflammatory activity of EPRO was revealed by downregulation of nuclear factor-kappa B and tumor necrosis factor-ß levels and (C-X-C motif) ligand 1 messenger RNA (mRNA) expression. Moreover, the study confirmed the role of EPRO against a unique pathway of hypoxia-inducible factor-1α and its subsequent inflammatory mediators. Furthermore, upregulation of caveolin-1 mRNA level was also observed along with decreased oxidative stress marker levels and brain edema. Therefore, EPRO showed neuroprotective effects in MCAO-induced cerebral ischemia in rats via attenuation of oxidative, apoptotic, and inflammatory pathways.

Allisartan isoproxil reduces mortality of stroke-prone rats and protects against cerebrovascular, cardiac, and aortic damage.

Stroke is a common cause of death and disability. Allisartan isoproxil (ALL) is a new angiotensin II receptor blocker and a new antihypertensive drug discovered and developed in China. In the present study we investigated the therapeutic effects of ALL in stroke-prone renovascular hypertensive rats (RHR-SP) and the underlying mechanisms. The model rats were generated via two-kidney two-clip (2K2C) surgery, which led to 100% of hypertension, 100% of cerebrovascular damage as well as 100% of mortality 1 year after the surgery. Administration of ALL (30 mg · kg-1 · d-1 in diet, for 55 weeks) significantly decreased stroke-related death and prolonged lifespan in RHR-SP, but the survival ALL-treated RHR-SP remained of hypertension and cardiovascular hypertrophy compared with sham-operated normal controls. In addition to cardiac, and aortic protection, ALL treatment for 10 or 12 weeks significantly reduced cerebrovascular damage incidence and scoring, along with a steady reduction of blood pressure (BP) in RHR-SP. Meanwhile, it significantly decreased serum aldosterone and malondialdehyde levels and cerebral NAD(P)H oxidase expressions in RHR-SP. We conducted 24 h continuous BP recording in conscious freely moving RHR-SP, and found that a single intragastric administration of ALL produced a long hypotensive effect lasting for at least 12 h on systolic BP. Taken together, our results in RHR-SP demonstrate that ALL can be used for stroke prevention via BP reduction and organ protection, with the molecular mechanisms related to inhibition of angiotensin-aldosterone system and oxidative stress. This study also provides a valuable scoring for evaluation of cerebrovascular damage and drug efficacy.

Cardiovascular diseases mortality and alcohol control policy in Lithuania: exploring a possible link.

BACKGROUND: Lithuania possesses one of the highest alcohol per capita consumption and has previously implemented alcohol control policies to reduce the alcohol-attributable burden. The aim of this study was to investigate Lithuanian cardiovascular disease (CVD) mortality rate trends between 2001 and 2018 and to explore a possible link between CVD mortality rate and alcohol control policy implementation. METHODS: Lithuanian population mortality and alcohol consumption data for 2001-2018 were obtained from Statistics Lithuania and The State Register of Death Cases and Their Causes, Institute of Hygiene. Sex-specific CVD mortality rates were directly standardized to the European standard population by five-year age groups and categorized according to the ICD-10 codes for all CVDs (I00-I99), ischemic heart disease (IHD) (I20-I25), cerebrovascular diseases (I60-I69) and alcoholic cardiomyopathy (ACM) (I42.6). Joinpoint regression analyses were performed to identify points of inflection to explore their alignment with five selected alcohol policy enactments. RESULTS: Overall, the 2001-2018 yearly mortality rates for all CVDs significantly decreased on average by - 1.6% (95% CI -2.0, - 1.2%) among men and - 2.1% (95% CI -2.5, - 1.8%) among women. Yearly changes in all CVDs, IHD, cerebrovascular diseases and ACM mortality rates were insignificant prior to their respective critical year points in 2006, 2005, 2008 and 2007, but significantly decreased afterwards by an average of - 2.4% (95% CI -2.7, - 2.0%), - 1.6% (95% CI -2.1, - 1.1%), - 1.2% (95 CI -1.7, - 0.6%) and - 4.5% (95% CI -7.3, - 1.6%) among men, and by - 2.7% (95% CI -3.0, - 2.3%), - 2.0% (95% CI -2.6, - 1.4%), - 1.8% (95% CI 2.4, - 1.3%) and - 6.6% (95% CI -10.7, - 2.2%) among women, respectively. The changes in the mortality rate trends for all CVDs, IHD, cerebrovascular diseases and especially ACM coincided with alcohol policies enacted on the January 1, 2008, January 1, 2009, April 1, 2014 and March 1, 2017. CONCLUSIONS: Yearly mortality rates for all CVDs, IHD, cerebrovascular diseases and ACM have declined in Lithuania between 2001 and 2018, and declining trends were more prominent in women than in men. Among the ICD-10 CVD categories investigated, the points of inflection identified for the ACM mortality rate trend coincided best with the selected alcohol policy enactment dates.

Vitreoretinal Surgery in the Prevention and Treatment of Toxic Tumour Syndrome in Uveal Melanoma: A Systematic Review.

Toxic tumour syndrome (TTS) is a particularly aggressive form of secondary vasculopathy occurring after radiation therapy of uveal melanoma due to the persistence of the necrotic tumour mass inside the eye. The development of TTS confers a particularly unfavourable functional and anatomical ocular prognosis, ultimately requiring enucleation in most cases if untreated. Vitreoretinal (VR) surgery has been successfully applied for treatment and prevention of TTS using both resecting and non-resecting techniques. In this systematic review, we aim to define characteristics of uveal melanomas benefiting the most from secondary VR surgery and to outline the optimal type and timing of VR intervention in such cases. Analysis of the literature reveals that endoresection should be performed within 3 months after radiotherapy to tumours thicker than 7 mm and with a largest basal diameter between 8 mm and 15 mm with post-equatorial location, especially after proton beam treatment. Alternatively, endodrainage remains a valid therapeutic option in eyes with macula-off retinal detachment, tumour diameter larger than 15 mm or ciliary body involvement. VR surgery can be successful in the management of TTS following radiotherapy for uveal melanoma when timing and indication are appropriately evaluated.

COVID-19 and Major Organ Thromboembolism: Manifestations in Neurovascular and Cardiovascular Systems.

COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been shown to cause multisystemic damage. We undertook a systematic literature review and comprehensive analysis of a total of 55 articles on arterial and venous thromboembolism in COVID-19 and articles on previous pandemics with respect to thromboembolism and compared the similarities and differences between them. The presence of thrombosis in multiple organ systems points to thromboembolism being an integral component in the pathogenesis of this disease. Thromboembolism is likely to be the main player in the morbidity and mortality of COVID -19 in which the pulmonary system is most severely affected. We also hypothesize that D-dimer values could be used as an early marker for prognostication of disease as it has been seen to be raised even in the pre-symptomatic stage. This further strengthens the notion that thromboembolism prevention is necessary. We also examined literature on the neurovascular and cardiovascular systems, as the manifestation of thromboembolic phenomenon in these two systems varied, suggesting different pathophysiology of damage. Further research into the role of thromboembolism in COVID-19 is important to advance the understanding of the virus, its effects and to tailor treatment accordingly to prevent further casualties from this pandemic.

Hyperglycemic Condition Causes Pro-Inflammatory and Permeability Alterations Associated with Monocyte Recruitment and Deregulated NFκB/PPARγ Pathways on Cerebral Endothelial Cells: Evidence for Polyphenols Uptake and Protective Effect.

Hyperglycemia alters the function of cerebral endothelial cells from the blood-brain barrier, increasing the risk of cerebrovascular complications during diabetes. This study evaluated the protective effect of polyphenols on inflammatory and permeability markers on bEnd3 cerebral endothelial cells exposed to high glucose concentration. Results show that hyperglycemic condition increased nuclear factor kappa B (NFκB) activity, deregulated the expression of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-10 (IL-10) and endothelial-leukocyte adhesion molecule (E-selectin) genes, raised MCP-1 secretion and elevated monocyte adhesion and transendothelial migration. High glucose decreased occludin, claudin-5, zona occludens-1 (ZO-1) and zona occludens-2 (ZO-2) tight junctions production and altered the endothelial permeability. Characterized polyphenolic extracts from the French medicinal plants Antirhea borbonica, Ayapana triplinervis, Dodonaea viscosa and Terminalia bentzoe, and their major polyphenols quercetin, caffeic, chlorogenic and gallic acids limited the pro-inflammatory and permeability alterations caused by high glucose. Peroxisome proliferator-activated receptor gamma (PPARγ) agonist also attenuated these damages while PPARγ antagonist aggravated them, suggesting PPARγ protective action. Interestingly, polyphenols improved PPARγ gene expression lowered by high glucose. Moreover, polyphenols were detected at the intracellular level or membrane-bound to cells, with evidence for breast cancer resistance protein (BCRP) efflux transporter role. Altogether, these findings emphasize the ability of polyphenols to protect cerebral endothelial cells in hyperglycemic condition and their relevance for pharmacological strategies aiming to limit cerebrovascular disorders in diabetes.