Association of albumin levels with the risk of intracranial atherosclerosis.

OBJECTIVE: Intracranial artery stenosis from atherosclerosis is one of the etiologies of ischemic stroke. There is a correlation between serum albumin level and atherosclerosis. We aimed to investigate whether serum albumin level is related to intracranial atherosclerosis and its significance. METHODS: A retrospective analysis of 150 individuals who underwent cervical cerebral angiography after admission, including clinical data, imaging data, and laboratory data. Since atherosclerosis cannot be used as a good quantitative indicator, we choose the degree of arterial stenosis to reflect atherosclerosis. SPSS 24 software was used for data analysis, and P < .05 was considered statistically significant. RESULTS: Univariate analysis showed that age, diabetes, and serum albumin level were risk factors for intracranial atherosclerosis (P < .05). Multivariate analysis showed that diabetes and serum albumin levels were independent risk factors for intracranial atherosclerosis (P< 0.05). The average serum albumin level in the non-severe group was 39.80 g/L, and the average serum albumin level in the severe group was 37.60 g/L. The area under the ROC curve of serum albumin was 0.667 (95%CI 0.576-0.758, P = .001), the cutoff value was 0.332176, the sensitivity was 75.9%, and the specificity was 57.3%. CONCLUSION: Serum albumin level is an independent risk factor for intracranial atherosclerosis, and provides a new direction for clinical prevention and treatment.

Recurrent Ischemic Stroke - A Systematic Review and Meta-Analysis.

OBJECTIVES: Recurrent stroke remains a challenge though secondary prevention is initiated immediately post-stroke. Stroke subtype may determine the risk of recurrent stroke and require specific preventive measures. We aimed to identify subtype-specific stroke recurrence and associated risk factors over time. METHODS AND MATERIALS: A systematic review was performed using PubMed and Embase for studies including adults >18 years, first-ever ischemic stroke in population-based observational studies or registries, documented TOAST-criteria and minimum 1-year follow-up. Meta-analysis on stroke recurrence rate was performed. Final search: November 2019. RESULTS: The search retrieved 26 studies (between 1997 and 2019). Stroke recurrence rate ranged from 5.7% to 51.3%. Recurrent stroke was most frequent in large artery atherosclerosis (LAA) and cardioembolic (CE) stroke with recurrent stroke similar to index stroke subtype. We identified a lower recurrence rate for small vessel occlusion (SVO) stroke with recurrence frequently of another stroke subtype. Based on a meta-analysis the summary proportion recurrence rate of recurrent stroke in studies using TOAST-criteria = 0.12 and = 0.14 in studies using TOAST-like criteria. Hypertension, diabetes mellitus, atrial fibrillation previous transient ischemic attack, and high stroke severity were independent risk factors for recurrence. CONCLUSION: Stroke recurrence rates seem unchanged over time despite the use of secondary prevention. The highest recurrence rate is in LAA and CE stroke eliciting same subtype recurrent stroke. A lower recurrence rate is seen with SVO stroke with a more diverse recurrence pattern. Extensive workup is important in all stroke subtypes - including SVO stroke. Future research needs to identify better preventive treatment and improve compliance to risk factor prevention to reduce stroke recurrence.

Remote ischemic conditioning for stroke: clinical data, challenges, and future directions.

Despite great improvement during the past several decades, the management of stroke is still far from satisfactory, which warrants alternative or adjunctive strategies. Remote ischemic conditioning (RIC), an easy-to-use and noninvasive therapy, can be performed in various clinical scenarios (e.g., prehospital transportation, intrahospital, and at home), and it has been widely investigated for stroke management. RIC has been demonstrated to be well tolerated in patients with acute ischemic stroke and aneurysm subarachnoid hemorrhage, and it may benefit these patients by improving clinical outcomes; in patients with intracranial atherosclerosis, long-term repeated RIC could be safely performed and benefit patients by reducing recurrent ischemic stroke and transient ischemic attack, as well as improving cerebral perfusion status; long-term repeated RIC may also benefit patients with cerebral small vessel disease by slowing cognitive decline and reducing volume of white matter hyperintensities on brain MRI; in patients with severe carotid atherosclerotic stenosis undergoing stenting, preprocedural RIC could reduce the odds of new brain lesions on postprocedural MRI. Previous clinical studies suggest broad future prospects of RIC in the field of cerebrovascular diseases. However, the optimal RIC protocol and the mechanisms that RIC protects the brain is not fully clear, and there is lack of sensitive and specific biomarkers of RIC, all these dilemmas prevent RIC from entering clinical practice. This review focuses on recent advances in clinical studies of RIC in stroke management, its challenges, and the potential directions of future studies.

Canadian stroke best practice recommendations: Secondary prevention of stroke, sixth edition practice guidelines, update 2017.

The 2017 update of The Canadian Stroke Best Practice Recommendations for the Secondary Prevention of Stroke is a collection of current evidence-based recommendations intended for use by clinicians across a wide range of settings. The goal is to provide guidance for the prevention of ischemic stroke recurrence through the identification and management of modifiable vascular risk factors. Recommendations include those related to diagnostic testing, diet and lifestyle, smoking, hypertension, hyperlipidemia, diabetes, antiplatelet and anticoagulant therapies, carotid artery disease, atrial fibrillation, and other cardiac conditions. Notable changes in this sixth edition include the development of core elements for delivering secondary stroke prevention services, the addition of a section on cervical artery dissection, new recommendations regarding the management of patent foramen ovale, and the removal of the recommendations on management of sleep apnea. The Canadian Stroke Best Practice Recommendations include a range of supporting materials such as implementation resources to facilitate the adoption of evidence to practice, and related performance measures to enable monitoring of uptake and effectiveness of the recommendations. The guidelines further emphasize the need for a systems approach to stroke care, involving an interprofessional team, with access to specialists regardless of patient location, and the need to overcome geographic barriers to ensure equity in access within a universal health care system.

Omega-3 fatty acid supplement prevents development of intracranial atherosclerosis.

OBJECTIVES: Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide and, in particular, has been implicated as a leading cause of recurrent ischemic stroke. We adapted a rat model of atherosclerosis to study brain intracranial atherosclerosis, and further investigated the effect of omega-3 fatty acids (O3FA) in attenuating development of ICAS. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were divided into control normal-cholesterol or high-cholesterol diet groups with or without O3FA for up to 6weeks. During the first 2weeks, NG-nitro-l-arginine methyl ester (l-NAME, 3mg/mL) was added to the drinking water of the high-cholesterol groups. The rats received supplementation with O3FA (5mg/kg/day) by gavages. Blood lipids including low density lipoprotein (LDL), cholesterol (CHO), triglycerides (TG) and high density lipoprotein (HDL) were measured at 3 and 6weeks. The lumen of middle cerebral artery (MCA) and the thickness of the vessel wall were assessed. Inflammatory molecular markers were assessed by Western blot. RESULTS: A high-cholesterol diet exhibited a significant increase in the classic blood markers (LDL, CHO, and TG) for atherosclerosis, as well as a decrease in HDL. These markers were found to be progressively more severe with time. Lumen stenosis and intimal thickening were increased in MCA. O3FA showed attenuation of blood lipids with an absence of morphological changes. O3FA significantly reduced the inflammatory marker CD68 in MCA and prevented monocyte chemotactic protein (MCP-1) and interferon-γ (IFN-γ) expression in the brain. O3FA similarly decreased inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6), markers affiliated with monocyte activity in atherosclerosis. Furthermore, O3FA significantly inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1), a marker for endothelial activation. Lastly, O3FA increased ATP-binding cassette transporter A1 (ABCA1) protein expression via silent information regulator 1 (SIRT1) activation, thus increasing cholesterol efflux from macrophages to HDL. CONCLUSIONS: Long-term O3FA dietary supplementation prevents the development of intracranial atherosclerosis. This O3FA effect appears to be mediated by its prevention of macrophage infiltration into the vessel wall, therefore reducing inflammation and intimal thickening. While similar effects in humans need to be determined, O3FA dietary supplement shows promising results in the prevention of ICAS.

New Insight into the Dietary Cause of Atherosclerosis: Implications for Pharmacology.

At present, the guideline approach to the medical treatment and prevention of atherosclerotic cardiovascular disease (ASCVD) is to classify patients by risk and treat the known risk factors (contributory causes), e.g., hypertension, diabetes, obesity, smoking, and poor diet, as appropriate. All high-risk patients should receive statins. This approach has had substantial success but ASCVD still remains the number one cause of death in the United States. Until recently, the underlying cause of ASCVD remained unknown, although a potential dietary cause was suggested by the fact that vegetarians, especially vegans, have a much lower incidence of ASCVD than animal flesh eaters. Recently, consistent with the vegetarian data, substantial evidence for a cause of ASCVD in animals and humans has been discovered. Trimethylamine (TMA)-containing dietary compounds in meat, milk, and other animal foods (e.g., lecithin, choline, and carnitine) are converted by closely related gut bacterial TMA lyases to TMA, which is absorbed and converted predominantly by flavin mono-oxygenase 3 to the toxic trimethylamine N-oxide (TMAO). TMAO causes atherosclerosis in animals and is elevated in patients with coronary heart disease. Inhibition of bacterial lyases in mice prevents TMA and secondarily TMAO formation and atherosclerosis, strong evidence for the TMAO hypothesis. At present, the challenge for the pharmaceutical industry is to discover and develop a potent "broad spectrum" bacterial lyase inhibitor that, along with diet and exercise, could, if the TMAO hypothesis is correct, revolutionize the preventive treatment of ASCVD.

Tissue Kallikrein Prevents Restenosis After Stenting of Severe Atherosclerotic Stenosis of the Middle Cerebral Artery: A Randomized Controlled Trial.

In-stent restenosis (ISR) following intracranial artery stenting affects long-term clinical outcome. This randomized controlled trial sought to identify the long-term efficacy of exogenous tissue kallikrein (TK) for preventing ISR after intracranial stenting of symptomatic middle cerebral artery (MCA) atherosclerotic stenosis.Sixty-one patients successfully treated with intracranial stenting for symptomatic MCA M1 segment stenosis (>70%) were enrolled and randomized into 2 groups: control group and TK group. Patients in the TK group received human urinary kallidinogenase for 7 days, followed by maintenance therapy of pancreatic kallikrein for 6 months. The primary end point was angiographically verified ISR at 6 months, and secondary end points included vascular events and death within 12 months. Endogenous TK plasma concentrations of patients were measured before stenting and at the 6-month follow-up time-point.Patients in the TK group had lower occurrence rates of ISR and vascular events than patients in the control group. There was no difference in endogenous TK levels in plasma at 6 months postoperatively between the TK and control groups. Further subgroup analysis revealed that patients without ISR had higher endogenous TK levels at baseline and lower concentrations at 6 months postoperatively compared with patients who underwent ISR.Exogenous TK is effective for the prevention of ISR after intracranial stenting.

Evidence for the prevention and treatment of stroke in dialysis patients.

The risks of both ischemic and hemorrhagic stroke are particularly high in dialysis patients of any age and outcomes are poor. It is therefore important to identify strategies that safely minimize stroke risk in this population. Observational studies have been unable to clarify the relative importance of traditional stroke risk factors such as blood pressure and cholesterol in those on dialysis, and are affected by biases that usually make them an inappropriate source of data on which to base therapeutic decisions. Well-conducted randomized trials are not susceptible to such biases and can reliably investigate the causal nature of the association between a potential risk factor and the outcome of interest. However, dialysis patients have been under-represented in the cardiovascular trials which have proven net benefit of commonly used preventative treatments (e.g., antihypertensive treatments, low-dose aspirin, carotid revascularization, and thromboprophylaxis for atrial fibrillation), and there remains uncertainty about safety and efficacy of many of these treatments in this high-risk population. Moreover, the efficacy of renal-specific therapies that might reduce cardiovascular risk, such as modulators of mineral and bone disorder, online hemodiafiltration, and daily (nocturnal) hemodialysis, have not been tested in adequately powered trials. Recent trials have also demonstrated how widespread current practices could be causing stroke. Therefore, it is important that reliable information on the prevention and treatment of stroke (and other cardiovascular disease) in dialysis patients is generated by performing large-scale randomized trials of many current and future treatments.

The clinical research for Ganoderan's effect on preventing and treating cerebral arteriosclerosis through inhibiting NADPH oxidizing enzyme expression.

A lot of researches have verified that produced excessive reactive oxygen is one of the hazard factors causing atherosclerosis. NADPH oxidase is the main protease of vascular cell's producing reactive oxygen, the expression of its relevant subunits is closely correlated with the occurring and development process of atherosclerosis. Oxidizing reaction could damage organism tissue cells, ganoderan has very significant effect on the anti-oxidizing function of cell. The pharmaceutical research of ganoderan has significant meaning in curing diabetes mellitus, preventing and controlling arteriosclerosis. This paper is mainly to discuss the effect of anoderan's inhibiting NADPH oxidizing enzyme expression on preventing and treating cerebral arteriosclerosis and its action mechanism.

Secondary prevention of atherothrombotic cerebrovascular events.

Secondary prevention of atherosclerotic stroke and transient ischemic attack includes both conventional approaches to vascular risk factor management (blood pressure lowering, cholesterol reduction with statins and smoking cessation), antiplatelet therapy and more specific interventions, such as carotid revascularization. The objective of this review is to discuss effective interventions for optimal secondary prevention of atherosclerotic stroke.

Resveratrol attenuates high-fat diet-induced disruption of the blood-brain barrier and protects brain neurons from apoptotic insults.

The blood-brain barrier (BBB) maintains brain microenvironment. Our previous study showed that oxidized low-density lipoprotein (oxLDL) can damage the BBB by inducing apoptosis of cerebrovascular endothelial cells. This study was aimed at evaluating the effects of resveratrol on high-fat diet-induced insults to the BBB and brain neurons. Exposure of mice to a high-fat diet for 8 weeks increased levels of serum total cholesterol (146 ± 13) and LDL (68 ± 8), but resveratrol decreased such augmentations (119 ± 6; 45 ± 8). Permeability assays showed that a high-fat diet induced breakage of the BBB (88 ± 21). Meanwhile, resveratrol alleviated this interruption (16 ± 6). Neither resveratrol nor a high-fat diet caused the death of cerebrovascular endothelial cells. Instead, exposure to a high-fat diet disrupted the polymerization of occludin and zonula occludens (ZO)-1, but resveratrol significantly attenuated those injuries. Neither a high-fat diet nor resveratrol changed the levels of occludin or ZO-1 in brain tissues. Resveratrol protected brain neurons against high-fat diet-induced caspase-3 activation and genomic DNA fragmentation. This study shows that resveratrol can attenuate the high-fat diet-induced disruption of the BBB via interfering with occludin and ZO-1 tight junctions, and protects against apoptotic insults to brain neurons.

Effects of bazedoxifene, conjugated equine estrogens, and a tissue-selective estrogen complex containing both bazedoxifene and conjugated equine estrogens on cerebral artery atherosclerosis in postmenopausal monkeys.

OBJECTIVE: This study aims to evaluate the effects of a new selective estrogen receptor modulator (bazedoxifene acetate [BZA]) and a tissue-specific estrogen complex (BZA combined with conjugated equine estrogens [CEE]) on the extent and severity of cerebral artery atherosclerosis. METHODS: Ninety-eight surgically postmenopausal monkeys (Macaca fascicularis) were fed a moderately atherogenic diet and randomized to receive no treatment or women's equivalent doses of BZA (20 mg/d), CEE (0.45 mg/d), or BZA + CEE. After an experimental period of 20 months (approximately equivalent to 5 years of participant experience), the extent and severity of atherosclerosis in the common carotid artery, carotid bifurcation, internal carotid artery, and basilar artery were determined. Lesion severity was determined using the American Heart Association grading system (grades 0-V). RESULTS: BZA had no consistent adverse effects on the extent and severity of atherosclerosis in the cerebral arteries and did not attenuate the beneficial effects of CEE on the severity of common carotid artery atherosclerosis. Although CEE had only modest beneficial effects on the extent of carotid bifurcation atherosclerosis, the severity of lesions and the number of affected cases in the common carotid artery were reduced with CEE treatment. As reported previously, plasma lipid profiles did not differ among the treatment groups. CONCLUSIONS: In this long-term (equivalent to 5 human patient-years) nonhuman primate trial, BZA shows no consistent adverse effect on cerebral artery atherosclerosis and does not attenuate the modest beneficial effect of CEE on the common carotid artery. Furthermore, CEE inhibits the development of complicated plaques in the common carotid artery.

Tissue kallikrein preventing the restenosis after stenting of symptomatic MCA atherosclerotic stenosis (KPRASS).

RATIONALE: Many recent studies suggest that the kallikrein-kinin system play a protective role in the impairment of vascular smooth muscle cells and vascular endothelial cell. AIMS: The study aims to determine whether tissue kallikrein is efficacy for preventing the long-term in-stent restenosis after stenting of symptomatic atherosclerotic stenosis of the middle cerebral artery M1 segment. DESIGN: This is a Phase II, randomized, single-blinded, controlled trial. In line with SAMMPRIS stenting indications, patients (n = 90) with the symptomatic the middle cerebral artery M1 segment stenosis ≥ 70% and successfully treated with stent will be enrolled. Eligible patients will be randomized using computer generated numbers, and allocated to receive tissue kallikrein treatment or not. Patients in tissue kallikrein treatment group will be prescribed with intravenous infusion of tissue kallikrein (0.15 PNAU/d, dissolved in 100 ml saline) for 7 days after stenting and then oral administration of pancreatic kallikrein enteric-coated tablet (240 U, 3/d) to the end of study. As the foundation treatment, all the enrolled patients will receive aspirin (100 mg/d), clopidogrel (75 mg/d), and atorvastatin (20 mg/d) for the first 6 months and continue with the combination of aspirin and atorvastatin at the previous dosage. STUDY OUTCOMES: Patients will be evaluated at 1, 6 and 12 months after stenting. The primary outcomes are the in-stent restenosis rate, new stroke or aggravation of the previous ischemic stroke ipsilateral to the severe stenotic artery. Secondary outcomes include stroke of other artery territories, myocardial infarction and vascular death. Modification of stroke knowledge, exercise and diet habit, smoking cessation and available laboratory data will also be recorded. CONCLUSION: As our pilot study, tissue kallikrein would be expected to prevent the long-term in-stent restenosis after stenting of the symptomatic middle cerebral artery dramatically.

Omnipresent atherosclerotic disease: time to depart from analysis of individual vascular beds.

Atherosclerotic vascular disease not only remains the leading cause of death in the Western countries, but it has become the most common cause of morbidity and mortality in the low- and middle-income countries as well. Therefore, better understanding of the pathogenesis of atherosclerotic disease and its prevention are of fundamental importance. It is well known that it affects sequentially the aorta followed by coronary, carotid, peripheral, and intracerebral arteries, with some individual variability. The mechanisms of progression are similar in each of the beds, with increasing lipid accumulation in the arterial wall along with macrophages and T-cell infiltration, paucity of smooth-muscle cell proliferation and collagen deposition, and endothelial-cell dysfunction and hypercoagulability playing an important role at the time of acute manifestations of the disease. Fundamental to this inflammatory process is the presence of classic risk factors, regardless of the involved territory. Therefore, the concept of palliative treatment must be reserved for only those who have progressed beyond preventive measures.

Plasma phospholipid fatty acid composition in ischemic stroke: importance of docosahexaenoic acid in the risk for intracranial atherosclerotic stenosis.

OBJECTIVE: While data on the relationship between fatty acid (FA) composition and the risk for total stroke have accumulated, the association between FA composition and the risk for intracranial atherosclerotic stenosis (ICAS) has never been studied. We compared plasma phospholipid FA composition between non-stroke control and ischemic stroke in Korean population, to discern the FA that distinguishes ICAS from total ischemic stroke patients. METHODS: Non-stroke controls (n = 215) and stroke patients (no cerebral atherosclerotic stenosis, NCAS: n = 144 and ICAS: n = 104) were finally included in the analysis. Plasma phospholipid FA compositions were analyzed. RESULTS: Age, coexistence of hypertension/diabetes were significantly different among the groups. Phospholipid FA compositions were significantly different between non-stroke control and ischemic stroke patients, and interestingly, between NCAS and ICAS in stroke patients. Pattern analysis showed that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the ω3-polyunsaturated FAs were important FAs in distinguishing NCAS and ICAS in strokes. Particularly, the risk of ICAS was inversely associated with levels of DHA contents in phospholipids (OR: 0.590, 95% CI: 0.350-0.993, p < 0.05), indicating that the risk may be increased at lower levels of DHA contents. CONCLUSION: DHA and EPA are important FAs for distinguishing NCAS and ICAS in strokes. Additionally, the risk of ICAS was inversely associated with the levels of phospholipid DHA, which indicates that sufficient amounts of DHA in plasma or in diet may reduce the risk of ICAS.

One-year atherothrombotic vascular events rates in outpatients with recent non-cardioembolic ischemic stroke: the EVEREST (Effective Vascular Event REduction after STroke) registry.

BACKGROUND: Patients with recent ischemic stroke may have higher risk of atherothrombosis than stable patients with established vascular events. Our aims were to investigate 1-year atherothrombotic vascular event rates and to assess the risk factors for recurrent ischemic stroke in this population. METHODS: This prospective cohort study was conducted between January 2007 and July 2009 at 313 hospitals in Japan. Outpatients who were at least 45 years of age and who had received oral antiplatelet therapy were enrolled within 2 weeks to 6 months from the last onset of noncardioembolic ischemic stroke. At 12 ± 3 months after enrollment, data on presence/absence of atherothrombotic vascular events were collected. The primary endpoint was the occurrence of fatal or nonfatal ischemic stroke. RESULTS: A total of 3452 patients were enrolled, and 3411 patients who had baseline data were included in the analysis. The 1-year event rate was 3.81% (95% confidence interval 3.15-4.48%) for fatal or nonfatal ischemic stroke and 0.84% (95% confidence interval 0.52-1.15%) for all-cause mortality. The annual rate of recurrent ischemic stroke was significantly higher in patients who had ischemic stroke at least twice than in patients who had first-ever ischemic stroke (5.02% vs 3.59%; P = .0313). In the multivariable Cox regression analysis, recurrent ischemic stroke was significantly associated with age (P = .0033), the presence of diabetes (P = .0129), and waist circumference ≥80 cm (P = .0056). CONCLUSIONS: Patients with recent ischemic stroke have a higher risk of stroke recurrence than stable patients enrolled in the REduction of Atherothrombosis for Continued Health (REACH) registry even though they received antiplatelet therapy. The rigorous management of risk factors is needed.

Intracranial angioplasty and stent placement after stenting and aggressive medical management for preventing recurrent stroke in intracranial stenosis (SAMMPRIS) trial: present state and future considerations.

OBJECTIVE: The results of prematurely terminated stenting and aggressive medical management for preventing recurrent stroke in intracranial stenosis (SAMMPRIS) due to excessively high rate of stroke and death in patients randomized to intracranial stent placement is expected to affect the practice of endovascular therapy for intracranial atherosclerotic disease. The purpose of this report is to review the components of the designs and methods SAMMPRIS trial and to describe the influence of those components on the interpretation of trial results. METHODS: A critical review of the patient population included in SAMMPRIS is conducted with emphasis on "generalizability of results" and "bias due to cherry picking phenomenon." The technical aspects of endovascular treatment protocol consisting of intracranial angioplasty and stent placement using the Gateway balloon and Wingspan self-expanding nitinol stent and credentialing criteria of trial interventionalists are reviewed. The influence of each component is estimated based on previous literature including multicenter clinical trials reporting on intracranial angioplasty and stent placement. RESULTS: The inclusion criteria used in the trial ensured that patients with adverse clinical or angiographic characteristics were excluded. Self-expanding stent as the sole stent, technique of prestent angioplasty, periprocedural antiplatelet treatment, and intraprocedural anticoagulation are unlikely to adversely influence the results of intracranial stent placement. A more permissive policy toward primary angioplasty as an acceptable treatment option may have reduced the overall periprocedural complication rates by providing a safer option in technically challenging lesions. The expected impact of a more rigorous credentialing process on periprocedural stroke and/or death rate following intracranial stent placement in SAMMPRIS such as the one used in carotid revascularization endarterectomy versus stenting trial remains unknown. CONCLUSION: The need for developing new and effective treatments for patients with symptomatic intracranial stenosis cannot be undermined. The data support modification but not discontinuation of our approach to intracranial angioplasty and/or stent placement for intracranial stenosis. There are potential patients in whom angioplasty and/or stent placement might be the best approach, and a new trial with appropriate modifications in patient selection and design may be warranted.

Catechin prevents severe dyslipidemia-associated changes in wall biomechanics of cerebral arteries in LDLr-/-:hApoB+/+ mice and improves cerebral blood flow.

Endothelial dysfunction and oxidative stress contribute to the atherosclerotic process that includes stiffening of large peripheral arteries. In contrast, our laboratory previously reported a paradoxical increase in cerebrovascular compliance in LDLr(-/-):hApoB(+/+) atherosclerotic (ATX) mice (7). We hypothesized that prevention of cerebral artery endothelial dysfunction with a chronic dietary antioxidant intake would normalize the changes in cerebral artery wall structure and biomechanics and prevent the decline in basal cerebral blood flow associated with atherosclerosis. Three-month-old ATX mice were treated, or not, for 3 mo with the polyphenol (+)-catechin (CAT; 30 mg·kg(-1)·day(-1)) and compared with wild-type controls. In isolated, pressurized cerebral arteries from ATX mice, CAT prevented endothelial dysfunction (deterioration of endothelium-dependent, flow-mediated dilations; P < 0.05), the inward hypertrophic structural remodeling (increase in the wall-to-lumen ratio; P < 0.05), and the rise in cerebrovascular compliance (rightward shift of the stress-strain curve measured in passive conditions, reflecting mechanical properties of the arterial wall; P < 0.05). Doppler optical coherence tomography imaging in vivo confirmed these findings, showing that cerebral compliance was higher in ATX mice and normalized by CAT (P < 0.05). CAT also prevented basal cerebral hypoperfusion in ATX mice (P < 0.05). Active remodeling of the cerebrovascular wall in ATX mice was further suggested by the increase (P < 0.05) in pro-metalloproteinase-9 activity, which was normalized by CAT. We conclude that, by preserving the endothelial function, a chronic treatment with CAT prevents the deleterious effect of severe dyslipidemia on cerebral artery wall structure and biomechanical properties, contributing to preserving resting cerebral blood flow.