Cerebrovascular Effects Research Articles

Extracellular vesicles as signaling mediators in type 2 diabetes mellitus.

Diabetes mellitus type 2, a chronic metabolic disease, has globally increased in incidence and prevalence throughout the lifespan due to the rise in obesity and sedentary lifestyle. The end-organ cardiovascular and cerebrovascular effects of diabetes mellitus result in significant morbidity and mortality that increases with age. Thus, it is crucial to fully understand how molecular mechanisms are influenced by diabetes mellitus and may influence the development of end-organ complications. Circulating factors are known to play important physiological and pathological roles in diabetes. Recent data have implicated extracellular vesicles (EVs) as being circulating mediators in type 2 diabetes. These small lipid-bound vesicles are released by cells into the circulation and can carry functional cargo, including lipids, proteins, and nucleic acids, to neighboring cells or between tissues. In this review, we will summarize the current evidence for EVs as promising diagnostic and prognostic factors in diabetes, the mechanisms that drive EV alterations with diabetes, and the role EVs play in the pathology associated with diabetes.

Incorporation of vasculature in a head injury model lowers local mechanical strains in dynamic impact

Cerebral vasculature is several orders of magnitude stiffer than the brain tissue. However, only a handful of studies have investigated its potential stiffening effect on dynamic brain strains; yet, they report contradictory findings. Here, we reanalyze the cerebrovascular stiffening effect by incorporating vasculature derived from the latest neuroimaging atlases into a re-meshed Worcester Head Injury Model using an embedded element method. Regional brain strains with and without vasculature were simulated using a reconstructed, predominantly sagittal head impact. Using the two previously adopted linear or non-linear vessel material models, we reproduced the earlier conflicting results (~40% vs. ~1–6% in regional strain reductions). Nevertheless, with refitted non-linear material models chosen to represent the average dynamic tension behaviors of arteries and veins, respectively, inclusion of vasculature reduced regional brain strains by ~13–36% relative to the baselines without vasculature. Compared to the whole brain baseline response, inclusion of vasculature led to an element-wise linear regression slope of 0.8 and a Pearson correlation coefficient of 0.8. The vascular stiffening effect appears mild for the whole brain but more significant locally, which should not be ignored in head injury models. Nevertheless, more work is necessary to investigate the cerebrovascular mechanical behaviors and loading environment to allow for more biofidelic modeling of the brain in the future.

Age-related differences in functional brain network segregation are consistent with a cascade of cerebrovascular, structural, and cognitive effects.

Age-related declines in cognition are associated with widespread structural and functional brain changes, including changes in resting-state functional connectivity and gray and white matter status. Recently we have shown that the elasticity of cerebral arteries also explains some of the variance in cognitive and brain health in aging. Here, we investigated how network segregation, cerebral arterial elasticity (measured with pulse-DOT—the arterial pulse based on diffuse optical tomography) and gray and white matter status jointly account for age-related differences in cognitive performance. We hypothesized that at least some of the variance in brain and cognitive aging is linked to reduced cerebrovascular elasticity, leading to increased cortical atrophy and white matter abnormalities, which, in turn, are linked to reduced network segregation and decreases in cognitive performance. Pairwise comparisons between these variables are consistent with an exploratory hierarchical model linking them, especially when focusing on association network segregation (compared with segregation in sensorimotor networks). These findings suggest that preventing or slowing age-related changes in one or more of these factors may induce a neurophysiological cascade beneficial for preserving cognition in aging.

Effects of Vasopressors on Cerebral Circulation and Oxygenation: A Narrative Review of Pharmacodynamics in Health and Traumatic Brain Injury.

The clinical use of vasoactive drugs aims to improve hemodynamic variables and thereby maintain or restore adequate perfusion and oxygenation in accordance with metabolic demands. A main focus in the management of patients with brain pathology during surgery and neurointensive care is restoring and/or maintaining adequate cerebral perfusion pressure in order to ensure cerebral blood flow in accordance with metabolic demands. One commonly used clinical strategy is the administration of vasoactive drugs aiming to increase mean arterial blood pressure and thereby cerebral perfusion pressure. Here, we first describe the anatomic and physiological basis for the cerebrovascular effects of vasopressor agents. Next, we review the pharmacodynamics of commonly used vasopressors under normal circumstances and in the presence of head injury. We further discuss the role of blood-brain barrier disruption and microvascular dysfunction with regard to the effects of the reviewed vasopressor agents.

An electrochemical investigation into the effects of local and systemic administrations of sodium nitroprusside in brain extracellular fluid of mice

Sodium nitroprusside (SNP) is a nitric oxide (NO)-donor drug used clinically to treat severe hypertension, however, there are limitations associated with its mechanism of action that prevent widespread adoption. In particular, its impact on cerebral hemodynamics is controversial and direct evidence on its effects are lacking. Electrochemical methods provide an attractive option to undertake real time neurochemical measurements in situ using selective microsensors. Herein, we report the novel application of an existing platinum (Pt)-Nafion® sensor to measure the release of NO from SNP under in vitro and in vivo conditions. Initially, the temporal release of NO was measured and the effect of the reducing agent, ascorbic acid (AA), was elucidated in vitro. A combined microdialysis/NO sensor construct was implanted into the striatum of anaesthetised mice and the local perfusion of 10 mM SNP with/without AA resulted in increased NO concentration detected using the Pt-Nafion® sensor. Subsequently, the NO sensor, coupled with carbon paste electrodes (CPEs) for the electrochemical measurement of O2, were applied to investigate SNP effects in freely moving mice. A complex mechanism of action was identified that infers NO inhibition and biphasic O2 dynamics. The preliminary findings within support a strong cerebrovascular effect of systemic SNP administration that warrants careful consideration for clinical use.

Marijuana Use Among Young Adults (18-44 Years of Age) and Risk of Stroke: A Behavioral Risk Factor Surveillance System Survey Analysis.

Background and Purpose- Amidst legalization of therapeutic and recreational use of marijuana/cannabis in the United States, cerebrovascular effects of marijuana use remain largely unknown, especially among young adults. We aimed to examine the association between marijuana use (18-44 years) among young adults and stroke events. Methods- The study analyzed pooled data from the Behavioral Risk Factor Surveillance System (2016-2017)-a nationally representative cross-sectional survey collected by the Centers for Disease Control and Prevention. Weighted logistic regression models were used to examine an association of recent marijuana use (within the last 30 days) and stroke in young adults (18-44 years) adjusting for patient demographics, risk behavior, and relevant comorbidities. Results- Overall, 13.6% of participants (n=43 860; weighted 35.5 million; 49.9% men) reported using marijuana recently (in the last month), with 63.3% of them being men. Compared with nonusers, marijuana users were often younger (18-34 years; 73.8% versus 61%), non-Hispanic white or black, and with some college education. Marijuana users were often physically active (81.8% versus 77.5%), heavy drinkers (16.8% versus 4.9%), current combustible cigarette users (37.9% versus 15%) and had lower prevalence of hypertension, diabetes mellitus, and hyperlipidemia as compared with nonusers (P<0.01). Young adults with recent marijuana use showed 1.82× higher odds (adjusted odds ratio, 1.82 [95% CI, 1.08-3.10]) of stroke compared with nonusers, which further increased to 2.45× higher (adjusted odds ratio, 2.45 [95% CI, 1.31-4.60]) among frequent marijuana users (>10 days/month). Compared with nonusers, stroke odds were even higher among frequent marijuana users with concomitant combustible cigarette use (adjusted odds ratio, 3.12 [95% CI, 1.40-6.97]) and e-cigarette use (adjusted odds ratio, 2.63 [95% CI, 1.07-6.46]), respectively. Conclusions- There may be a significantly higher odds of stroke in young marijuana users (18-44 years) as compared with nonusers with even greater odds among frequent users (>10 days/month).

ApoE (Apolipoprotein E) in Brain Pericytes Regulates Endothelial Function in an Isoform-Dependent Manner by Modulating Basement Membrane Components.

The ε4 allele of the APOE gene (APOE4) is the strongest genetic risk factor for Alzheimer disease when compared with the common ε3 allele. Although there has been significant progress in understanding how apoE4 (apolipoprotein E4) drives amyloid pathology, its effects on amyloid-independent pathways, in particular cerebrovascular integrity and function, are less clear. Approach and Results: Here, we show that brain pericytes, the mural cells of the capillary walls, differentially modulate endothelial cell phenotype in an apoE isoform-dependent manner. Extracellular matrix protein induction, tube-like structure formation, and barrier formation were lower with endothelial cells cocultured with pericytes isolated from apoE4-targeted replacement (TR) mice compared with those from apoE3-TR mice. Importantly, aged apoE4-targeted replacement mice had decreased extracellular matrix protein expression and increased plasma protein leakages compared with apoE3-TR mice. ApoE4 impairs pericyte-mediated basement membrane formation, potentially contributing to the cerebrovascular effects of apoE4.

Haemodynamic and cerebrovascular effects of intermittent lower-leg compression as countermeasure to orthostatic stress.

What is the central question of this study? Does smartly timed intermittent compression of the lower legs alter cerebral blood velocity and oxygenation during acute orthostatic challenges? What is the main finding and its importance? Intermittent compression timed to the local diastolic phase increased the blood flux through the legs and heart after two different orthostatic stress tests. Cerebral blood velocity improved during the first minute of recovery, and indices of cerebral tissue oxygenation remained elevated for 2min. These results provide promise for the use of lower-leg active compression as a therapeutic tool for individuals vulnerable to initial orthostatic hypotension and orthostatic stress. Intermittent compression of the lower legs provides the possibility of improving orthostatic tolerance by actively promoting venous return and improving central haemodynamics. We tested the hypothesis that intermittent compression of 65mmHg timed to occur only within the local diastolic phase of each cardiac cycle would attenuate the decrease in blood pressure and improve cerebral haemodynamics during the first minute of recovery from two different orthostatic stress tests. Fourteen subjects (seven female) performed four squat-to-stand transitions and four repeats of standing bilateral thigh-cuff occlusion and release (TCR), with intermittent compression of the lower legs applied in half of the trials. Blood flow in the superficial femoral artery, mean arterial pressure, Doppler ultrasound cardiac output, total peripheral resistance, middle cerebral artery blood velocity (MCAv) and cerebral tissue saturation index (TSI%) were monitored. With both orthostatic stress tests, there was a significant compression×time interaction for superficial femoral artery flow (P<0.001). The hypotensive state was attenuated with intermittent compression despite decreased total peripheral resistance (squat-to-stand, compression×time interaction, P<0.001; TCR, compression×time interaction, P=0.002) as a consequence of elevated cardiac output in both tests (P<0.001). Intermittent compression also increased MCAv (P=0.001) and TSI% (P<0.001) during the squat-to-stand transition and during TCR (MCAv and TSI%, compression×time interaction, P<0.001). Intermittent compression of the lower legs during quiet standing after an active orthostatic challenge augmented local, central and cerebral haemodynamics, providing potential as a therapeutic tool for individuals vulnerable to orthostatic stress.

Swimming-related effects on cerebrovascular and cognitive function.

Both acute and regular exercise influence vascular and cognitive function. Upright aquatic exercise increases mean middle cerebral artery blood velocity (MCAvmean) and has been suggested as favorable for cerebrovascular adaptations. However, MCAvmean has not been reported during swimming. Thus, we examined the cerebrovascular and cognitive effects of swimming. Ten land‐based athletes (22 ± 5 years) and eight swimmers (19 ± 1 years) completed three cognitive tasks and four conditions that were used to independently and collectively delineate the swimming‐related factors (i.e., posture, immersion, CO2 retention [end‐tidal CO2; PETCO2], and motor involvement). Measurements of MCAvmean and PETCO2 were taken throughout each condition. Prone posture increased MCAvmean by 11% (P < 0.01 vs. upright land). Water immersion independently increased MCAvmean when upright (12%; P < 0.01) but not prone (P = 0.76). The consequent rise in PETCO2 during head‐out, breast‐stroke swimming (50% heart rate range) independently increased MCAvmean by 14% (P < 0.01), while the motor involvement of swimming per se did not significantly change MCAvmean (P = 0.32). While accounting for sex, swimmers had ~17% lower MCAvmean during all rest conditions (P ≤ 0.05). However, in a subset of participants, both groups had similar internal carotid artery diameters (P = 0.99) and velocities (P = 0.97). Water immersion per se did not alter cognition (P ≥ 0.15), but 20 min of moderate‐intensity swimming improved visuomotor performance by 4% (P = 0.03), regardless of athlete group (P = 0.12). In conclusion, breast‐stroke swimming increased MCAvmean mostly due to postural and PETCO2 effects, with minimal contributions from water immersion or motor activity. Lastly, swimming improved cognitive functioning acutely, regardless of athlete group. Future research should explore the chronic effects of swimming on cerebrovascular function and cognition, particularly in aging.

Can Acupuncture Treatment of Hypertension Improve Brain Health? A Mini Review.

With age, cerebrovascular and neurodegenerative diseases (e.g., dementia and Alzheimer’s) are some of the leading causes of death in the United States. Related to these outcomes is the increased prevalence of hypertension, which independently increases the development of cerebrovascular and neurodegenerative diseases. While a direct mechanistic link between hypertension and poor brain health is unknown, many hypothesize that the etiology stems from poor blood pressure (BP) and cerebrovascular regulation. This dysfunction fosters hypoperfusion of the brain, causing stress to the tissue through a nutrient mismatch, subtly damaging the brain over many years. Current Western medical treatment relies on pharmacological treatment (mainly beta-blockers, angiotensin-converting enzyme inhibitors, or a combination of the two). However, Western treatments have not been successful in mitigating brain health outcomes and are burdened with unwanted side effects and non-adherence issues. Alternatively, traditional East Asia medicine has used acupuncture as a treatment for hypertension and may offer a promising approach in response to the limitations of conventional therapy. While detailed clinical and mechanistic experimental evidence is lacking, acupuncture has been observed to reduce BP and improve endothelial function in hypertensive adults. Further, acupuncture has been shown to have specific cerebrovascular effects, increasing cerebrovascular reactivity in healthy adults, highlighting possible neuroprotective properties. Therefore, our review is aimed at evaluating acupuncture as a treatment for hypertension and the potential impact on brain health. We will interrogate the current literature as well as discuss the proposed neural and vascular mechanisms by which acupuncture acts.

Cerebrovascular effects of endothelin-1 investigated using high-resolution magnetic resonance imaging in healthy volunteers

Endothelin-1 (ET-1) is a highly potent vasoconstrictor peptide released from vascular endothelium. ET-1 plays a major role in cerebrovascular disorders and likely worsens the outcome of acute ischaemic stroke and aneurismal subarachnoid haemorrhage through vasoconstriction and cerebral blood flow (CBF) reduction. Disorders that increase the risk of stroke, including hypertension, diabetes mellitus, and acute myocardial infarction, are associated with increased plasma levels of ET-1. The in vivo human cerebrovascular effects of systemic ET-1 infusion have not previously been investigated. In a two-way crossover, randomized, double-blind design, we used advanced 3 tesla MRI methods to investigate the effects of high-dose intravenous ET-1 on intra- and extracranial artery circumferences, global and regional CBF, and cerebral metabolic rate of oxygen (CMRO2) in 14 healthy volunteers. Following ET-1 infusion, we observed a 14% increase of mean arterial blood pressure, a 5% decrease of middle cerebral artery (MCA) circumference, but no effects on extracerebral arteries and no effects on CBF or CMRO2. Collectively, the findings indicate MCA constriction secondarily to blood pressure increase and not due to a direct vasoconstrictor effect of ET-1. We suggest that, as opposed to ET-1 in the subarachnoid space, intravascular ET-1 does not exert direct cerebrovascular effects in humans.

Abstract 050: Essential Role of Cerebral Endothelial AT1 Receptors in the Blood-Brain Barrier Disruption Induced by Angiotensin-II Hypertension

The blood-brain barrier (BBB) controls the molecular exchange between blood and brain and is critical for maintaining brain health. Although hypertension (HTN) is well known to disrupt the BBB, the underlying cellular bases and the susceptible cerebrovascular segments(s) remain unclear. Here, we addressed these open questions in male mice in which HTN was induced by angiotensin II (Ang II; 600ng/kg/min s.c.; n=9-14/group) for 14 days. HTN increased BBB permeability to 3000 MW FITC-dextran, measured spectrophotometrically in brain extracts (30 ± 1 vs 18 ± 0.5 ng/g in controls; p&lt;0.01). In vivo 2-photon microscopy revealed that dextran leaks out more from microvessels &gt;10ϒm (+38%; p&lt;0.05) than cerebral capillaries (+7%; p&gt;0.05). Electron microscopy showed that HTN induces tight junction remodeling (length -25%; complexity: -11%), and increases endothelial transcytosis (capillaries 1.9 and arterioles 3.5 folds; p&lt;0.05), which is consistent with the downregulation of tight junction proteins (occludin: -17%; claudin-5: -30%) and of the transcytosis inhibitor Msfd2a (-43%). Since AT1 receptors (AT1R) on brain perivascular macrophages (PVM) mediate the deleterious cerebrovascular effects of Ang II HTN (JCI 126:4674), we tested if PVM also mediate the BBB dysfunction. However, PVM depletion (icv clodronate) or deletion of AT1R on PVM (bone marrow chimeras), attenuated the BBB dysfunction only partially (-60% and -49%, respectively; p&lt;0.05), whereas AT1R-/- mice harboring AT1R+ PVM were completely protected (19 ± 1 ng/g; p&gt;0.05 vs control), pointing to a key role of endothelial AT1R. Consistent with this prediction, cerebral endothelial AT1R deletion using a cerebral endothelial specific AAV-BR1-iCre in AT1R floxed mice prevented the BBB disruption completely (21 ± 1 ng/g; p&gt;0.05 vs control). We conclude that AT1 signaling in cerebral endothelial cells initiates the BBB opening induced by Ang II HTN by increasing both paracellular and vesicular transport mainly in arterioles and venules, and that AT1 signaling in PVM, presumably from circulating Ang II crossing the BBB, amplifies the dysfunction. Such increase in BBB permeability to circulating agents may contribute to the cerebrovascular and cognitive dysfunction associated with HTN.

Dementia Risk Elevates Brain Activity During Memory Retrieval: A Functional MRI Analysis of Middle Aged and Older Adults.

Longitudinal research suggests that genetic, lifestyle, and environmental factors enhance one's risk for developing Alzheimer's disease and related dementias (ADRD). However, it is not known how an accumulation of such factors impact brain functioning. One barrier to this research is that increased risk for ADRD affects the cerebrovascular system and, therefore, alters the link between neural activity and the fMRI BOLD signal. To better interpret fMRI findings, several steps were taken to adjust fMRI activity thereby reducing such cerebrovascular effects. We hypothesized that as the number of ADRD risk factors increase, brain regions within the medial temporal lobes and the default mode network would exhibit altered brain activity during an episodic memory retrieval task. Middle-aged and older adults (aged 50-74) free of dementia were recruited with varying levels of risk and underwent a neuropsychological battery and fMRI. In the memory task, participants viewed a pair of pictures. In an alternative-forced-choice test, participants viewed a picture cue and had to determine which of four pictures was paired with the cue. Increased dementia risk was positively associated with brain activity in regions of interest within the default mode network, the hippocampus, and the entorhinal cortex during memory retrieval. Whole-brain analyses revealed additional positive associations in prefrontal and occipito-temporal cortices. Risk factors most contributing to these elevated levels of brain activity included hypertension, diabetes, obesity, and cholesterol. We also ruled out confounds due to in-scanner performance and premorbid ability. Cumulative risk might represent early signs of burnout in brain regions underlying episodic memory.

Abstract 497: Studying Cardiovascular Effects of Marijuana on Healthy Individuals Using Human Derived Induced Pluripotent Stem Cells

Marijuana is the most widely used illicit drug worldwide. Epidemiological studies indicate that marijuana increases the risk of coronary artery disease (CAD). Adverse cerebrovascular and peripheral vascular effects are also associated with marijuana use. In addition, three synthetic cannabis drugs have been approved by the FDA for treating chemotherapy-induced nausea and vomiting, which also show cardiovascular side effects. Thus, both medical and recreational marijuana have adverse cardiovascular side effects. Cannabinoid CB1 receptor signaling is involved in a variety of pathophysiological processes and selective CB1 antagonists show therapeutic potential. However, the current repertoire of CB1 antagonists has psychiatric side effects and limited application. Therefore, developing new CB1 antagonists are an unmet and growing clinical need with marijuana use on the rise. Here we found compound JW-1, an isoflavone abundantly presenting in soybeans, partially docked into the CB1 receptor and inhibited CB1 activity, suggesting that compound JW-1 was a novel CB1 antagonist. Human endothelial cells were more sensitive to Δ 9 -tetrahydrocannabinol (Δ 9 -THC) than cardiomyocytes and cardiac fibroblasts. To determine the mechanism of Δ 9 -THC pathological effects on the vasculature, we generated human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) from 5 healthy individuals. CB1 receptor was expressed in all hiPSC-ECs, whilst CB2 expression was low. Δ 9 -THC induced inflammation and oxidative stress via NF-κB signaling activated in hiPSC-ECs. Knockdown of CB1 receptor with siRNA, abrogation of receptor expression with CRISPRi and compound JW-1 treatment could rescue the effect of Δ 9 -THC. Furthermore, compound JW-1 blocked Δ 9 -THC-induced endothelial dysfunction in mice models. Our investigations reveal that Δ 9 -THC causes endothelial dysfunction via the CB1 receptor. Compound JW-1 is a novel CB1 antagonist that can be used for preventing Δ 9 -THC-induced side effects.

Effect of sevoflurane on systemic and cerebral circulation, cerebral autoregulation and CO2 reactivity

BackgroundSevoflurane is one of the most frequently used inhaled anesthetics for general anesthesia. Previously it has been reported that at clinically used doses of sevoflurane, cerebral vasoreactivity is maintained. However, there are no data how sevoflurane influences systemic and cerebral circulation in parallel. The aim of our study was to assess systemic and cerebral hemodynamic changes as well as cerebral CO2-reactivity during sevoflurane anesthesia.MethodsTwenty nine patients undergoing general anesthesia were enrolled. Anesthesia was maintained with 1 MAC sevoflurane in 40% oxygen. Ventilatory settings (respiratory rate and tidal volume) were adjusted to reach and maintain 40, 35 and 30 mmHg EtCO2 for 5 min respectively. At the end of each period, transcranial Doppler and hemodynamic parameters using applanation tonometry were recorded.ResultsSystemic mean arterial pressure significantly decreased during anesthetic induction and remained unchanged during the entire study period. Central aortic and peripherial pulse pressure and augmentation index as markers of arterial stiffness significantly increased during the anesthetic induction and remained stable at the time points when target CO2 levels were reached. Both cerebral autoregulation and cerebral CO2-reactivity was maintained at 1 MAC sevoflurane.DiscussionCerebral autoregulation and CO2-reactivity is preserved at 1 MAC sevoflurane. Cerebrovascular effects of anesthetic compounds have to be assessed together with systemic circulatory effects.Trial registrationThe study was registered at http://www.clinicaltrials.gov, identifier: NCT02054143, retrospectively registered. Date of registration: February 4, 2014.

Effects of Nilvadipine on Cerebral Blood Flow in Patients With Alzheimer Disease.

Cerebrovascular changes, including reduced cerebral blood flow (CBF), occur early in the development of Alzheimer disease and may accelerate disease progression. This randomized, double-blind, placebo-controlled study investigated how 6 months of treatment with the calcium antagonist nilvadipine would affect CBF in patients with mild-to-moderate Alzheimer disease. CBF was measured with magnetic resonance arterial spin labeling in whole-brain gray matter and in a priori defined regions of interest including the hippocampus. Fifty-eight patients were randomly assigned (29 in each group), of whom 22 in both groups had no magnetic resonance exclusion criteria and were medication compliant over 6 months. Mean age was 72.8±6.2 years, mean mini-mental state examination was 20.4±3.4. Nilvadipine treatment lowered systolic blood pressure (Δ=-11.5 [95% CI, -19.7 to -3.2] mm Hg; P<0.01), while whole-brain gray-matter CBF remained stable (Δ=5.4 [95% CI, -6.4 to 17.2] mL/100 g per minute; P=0.36). CBF in the hippocampus increased (left: Δ=24.4 [95% CI, 4.3-44.5] mL/100 g per minute; P=0.02; right: Δ=20.1 [95% CI, -0.6 to 40.8] mL/100 g per minute; P=0.06). There was no significant change in CBF in the posterior cingulate cortex (Δ=5.2 [95% CI, -16.5 to 27.0] mL/100 g per minute; P=0.63) or other regions of interest. In conclusion, nilvadipine reduced blood pressure and increased CBF in the hippocampus, whereas other regions showed stable or small nonsignificant increases in CBF. These findings not only indicate preserved cerebral autoregulation in Alzheimer disease but also point toward beneficial cerebrovascular effects of antihypertensive treatment. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02017340.

Metformin metabolic and vascular effects in overweight/moderately obese hyperinsulinemic PCOS patients treated with contraceptive vaginal ring: a pilot study

The aim of this pilot study was to assess how metformin, associated with a contraceptive vaginal ring, may influence lipid and carbohydrate metabolism, fat distribution, and surrogate markers of arterial function. Among 62 patients, 25 were treated with vaginal ring plus metformin and 37 women with only vaginal ring. The effects were assessed after 6 months. The patients were submitted to evaluation of lipid and carbohydrate metabolism; extended view ultrasonographic evaluation of fat distribution; Doppler analysis of ophthalmic artery; brachial artery flow-mediated vasodilatation; oral glucose tolerance test. After 6 months, the body mass index and waist/hip ratio resulted significantly better in patients who associated metformin to vaginal ring. The fasting glucose, insulin, and glucose/insulin ratio, HOMA-IR, glucose, and insulin AUC 120 were significantly improved in metformin group. The ultrasonographic fat analysis resulted significantly better after metformin. The ophthalmic artery PI significantly improved in metformin group. The brachial artery vasodilation was better in metformin treated patients. In conclusion, metformin, associated with vaginal ring, improves the insulin and carbohydrate metabolism, reduces the body weight and android fat distribution. This, associated with the significant improvements of surrogate markers of arterial function, may be responsible of possible cardiovascular and cerebrovascular protective effects.

Preeclampsia and Cerebrovascular Disease.

Preeclampsia and Cerebrovascular Disease.

Abstract 214: Stroke Epidemiology in the State of Maine 2010-2014

Purpose: Maine’s stroke prevalence/mortality is highest of New England states, yet US mortality rates are in decline overall. We hypothesized that the epidemiology of stroke in Maine has unique characteristics to explain the disparity; that a high mortality rate is due to geography, aging and non-traditional factors such as polysubstance abuse or cancer. Objective: This study aims to identify local determinants for in hospital mortality stroke in Maine, comparing demographics, clinical factors and access to certified stroke centers. Design/ Methods: As a descriptive study using all Maine inpatient stroke related discharge data: demographics, diagnosis, procedure codes and disposition from Maine Health Data Organization (MHDO), stroke was classified as ischemic, hemorrhagic, and Transient Cerebral Ischemia. Traditional risk factors include: age, sex, hypertension, diabetes mellitus, tobacco use, atrial fibrillation, left ventricular hypertrophy and dyslipidemia. Clinical nontraditional risk factors: sleep apnea, neoplasm, mental disorders and polysubstance and alcohol abuse. Zip codes were used to determine driving distance of one hour or more from certified stroke centers; Maine has only three. Statistical Analysis: Cases with complete data were included. Excluded were diagnostic codes for pregnancy, childbirth, puerperium, preeclampsia, eclampsia or traumatic brain injury; cases of ICD-9-CM codes for epidural and subdural hematoma; and ill-defined cerebrovascular disease or late effects of cerebrovascular disease. Descriptive statistics identified stroke characteristic. Multiple linear regression analyses identified associations between in hospital mortality due to stroke and age, gender, clinical factors, and driving distances to identify the independent predictors. Analyses were done using SPSS software version 21. Results: From 2010-2014, 13,857 hospital stroke diagnoses represented 2% of all Maine discharges. Mean age for all stroke events was 73 (± 14 years), and 52% were female. Overall, ischemic strokes accounted for 66% of all stroke discharges followed by TIA (19%) and hemorrhagic (15%). There were no statistically significant changes in mortality rate during the five year period. A Multiple logistic regression model showed associations with older age, atrial fibrillation, neoplasm, and more than one hour to a certified stroke center; and a negative trend for traditional factors. Maine had lower prevalence of Hypertension, Diabetes mellitus and tobacco use when compared with national rates (50% vs. 74%; 24.6% vs. 30%; 13.6% vs. 17% respectively). Conclusion: Maine local determinants for in hospital stroke mortality include: limited access to a certified stroke center and an older population. Other concomitants conditions for risk include atrial fibrillation and neoplasm.

The impact of dihydropyridine derivatives on the cerebral blood flow response to somatosensory stimulation and spreading depolarization.

A new class of dihydropyridine derivatives, which act as co-inducers of heat shock protein but are devoid of calcium channel antagonist and vasodilator effects, has recently been developed with the purpose of selectively targeting neurodegeneration. Here, we evaluated the action of one of these novel compounds LA1011 on neurovascular coupling in the ischaemic rat cerebral cortex. As a reference, we applied nimodipine, a vasodilator dihydropyridine and well-known calcium channel antagonist. Rats were treated with LA1011 or nimodipine, either by chronic, systemic (LA1011), or acute, local administration (LA1011 and nimodipine). In the latter treatment group, global forebrain ischaemia was induced in half of the animals by bilateral common carotid artery occlusion under isoflurane anaesthesia. Functional hyperaemia in the somatosensory cortex was created by mechanical stimulation of the contralateral whisker pad under α-chloralose anaesthesia. Spreading depolarization (SD) events were elicited subsequently by 1 M KCl. Local field potential and cerebral blood flow (CBF) in the parietal somatosensory cortex were monitored by electrophysiology and laser Doppler flowmetry. LA1011 did not alter CBF, but intensified SD, presumably indicating the co-induction of heat shock proteins, and, perhaps an anti-inflammatory effect. Nimodipine attenuated evoked potentials and SD. In addition to the elevation of baseline CBF, nimodipine augmented hyperaemia in response to both somatosensory stimulation and SD, particularly under ischaemia. In contrast to the CBF improvement achieved with nimodipine, LA1011 seems not to have discernible cerebrovascular effects but may up-regulate the stress response.