Cerebral Vasodilator Responses Research Articles

The impact of increased daily peanut consumption on indices of peripheral and cerebral vascular function in non-Hispanic Black individuals

Cardiovascular disease, neurocognitive conditions, and cerebral vascular diseases including cognitive impairment, stroke, and Alzheimer’s disease and related dementias disproportionately impact the Non-Hispanic Black (BL) population. The mechanisms are multifactorial but is related to reduced vascular function/health. Our lab, and others, have demonstrated that reduced nitric oxide (NO) bioavailability secondary to oxidative stress, systemic inflammation, and reduced L-arginine bioavailability contributes to reduced vascular function/health in this population. Increased dietary peanut consumption improves various physiological outcomes including blood pressure, cholesterol, type II diabetes, cognitive health, NO bioavailability, and vascular function/health. This improvement is related to increased bioavailability of L-arginine, reduced systemic inflammation, and antioxidant capacity. This study hypothesized that increased daily peanut consumption would improve indices of peripheral and cerebral vascular function/health in a cohort of BL individuals. Methods: Seventeen people participated (11 non-Hispanic White (WH) and 6 BL (age: WH 25±8, BL 21±2; BMI: WH 23±3, BL 22 ± 4; p>0.05 for both). Measures were made before (pre) and after (post) 56 days of daily lightly salted peanut consumption (2 oz/day for females and 3 oz/day for males). Peripheral macro and microvascular function/health was assessed as brachial artery vasodilation (flow mediated dilation, %FMD) and forearm reactive hyperemia (peak mean forearm blood velocity (FBVmean) respectively following 5-min of suprasystolic cuff inflation. Cerebral vascular function/health was assessed as the cerebral vasodilator response during a hypercapnic challenge, i.e., the slope of % cerebral vascular conductance index (CVCi) relative to the change in end-tidal carbon dioxide concentration (ΔPETCO2). Results: There was no effect of race on peripheral macrovascular function assessed as %FMD (WH: 5.3 ±0.89, BL: 6.3 ±1.9 %, p=0.31) or peripheral microvascular function assessed as FBVmean (WH: 82.90 ± 4.5, BL: 72 ± 6.7 cm·s−1, p=0.13). Likewise, there no effect of treatment on %FMD (Pre: 5.4 ± 0.7, Post: 6.2 ± 2.1 %, p=0.46) or FBVmean (Pre: 81.4 ± 6.7, Post: 73.4 ± 8.8 cm·s−1, p=0.27). Lastly, there were no effect of race (WH: 4.0 ± 0.36, BL: 3.9 ± 0.6 %, p=0.85) or treatment (Pre: 3.9 ± 0.56, Post: 4.0 ± 0.39 %, p=0.79) on cerebral vascular function assessed as %CVCi during hypercapnia. Conclusion: The preliminary data suggest that 56 days of increased daily peanut consumption does not induce measurable improvements in indices of vascular function in a cohort of relatively young BL individuals. Future work will continue to assess this effect in a larger cohort of individuals as well as in individuals with existing conditions or diseases (i.e., hypertension, type II diabetes, etc.). Funding: Peanut Institute (982307). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impaired cerebrovascular CO2 reactivity at high altitude in prematurely born adults.

Premature birth impairs cardiac and ventilatory responses to both hypoxia and hypercapnia, but little is known about cerebrovascular responses. Both at sea level and after 2days at high altitude (3375m), 16 young preterm-born (gestational age, 29 ± 1weeks) and 15 age-matched term-born (40 ± 0weeks) adults were exposed to two consecutive 4min bouts of hyperoxic hypercapnic conditions (3% CO2 -97% O2 ; 6% CO2 -94% O2 ), followed by two periods of voluntary hyperventilation-induced hypocapnia. We measured middle cerebral artery blood velocity, end-tidal CO2 , pulmonary ventilation, beat-by-beat mean arterial pressure and arterialized capillary blood gases. Baseline middle cerebral artery blood velocity increased at high altitude compared with sea level in term-born (+24 ± 39%, P=0.036), but not in preterm-born (-4 ± 27%, P=0.278) adults. The end-tidal CO2 , pulmonary ventilation and mean arterial pressure were similar between groups at sea level and high altitude. Hypocapnic cerebrovascular reactivity was higher at high altitude compared with sea level in term-born adults (+173 ± 326%, P=0.026) but not in preterm-born adults (-21 ± 107%, P=0.572). Hypercapnic reactivity was altered at altitude only in preterm-born adults (+125 ± 144%, P<0.001). Collectively, at high altitude, term-born participants showed higher hypocapnic (P=0.012) and lower hypercapnic (P=0.020) CO2 reactivity compared with their preterm-born peers. In conclusion, exposure to high altitude revealed different cerebrovascular responses in preterm- compared with term-born adults, despite similar ventilatory responses. These findings suggest a blunted cerebrovascular response at high altitude in preterm-born adults, which might predispose these individuals to an increased risk of high-altitude illnesses. KEY POINTS: Cerebral haemodynamics and cerebrovascular reactivity in normoxia are known to be similar between term-born and prematurely born adults. In contrast, acute exposure to high altitude unveiled different cerebrovascular responses to hypoxia, hypercapnia and hypocapnia. In particular, cerebral vasodilatation was impaired in prematurely born adults, leading to an exaggerated cerebral vasoconstriction. Cardiovascular and ventilatory responses to both hypo- and hypercapnia at sea level and at high altitude were similar between control subjects and prematurely born adults. Other mechanisms might therefore underlie the observed blunted cerebral vasodilatory responses in preterm-born adults at high altitude.

Pod-based e-cigarettes versus combustible cigarettes: The impact on peripheral and cerebral vascular function and subjective experiences.

The vaping epidemic in the US has been largely attributed to the emergence of pod-based e-cigarette devices. While these devices continue to be promoted as alternatives to cigarettes, their impact on cardiovascular and behavioral outcomes remains incompletely understood. This study assessed the impact of pod-based e-cigarettes on peripheral and cerebral vascular function, along with subjective experiences among adult cigarette smokers. In a crossover laboratory design study, a total of 19 (e-cigarette naïve) cigarette smokers (aged 21-43 years) attended two lab sessions. In one session, participants smoked a cigarette and in the other, vaped a pod-based e-cigarette. Participants completed questions assessing subjective experiences. Peripheral macrovascular and microvascular function was assessed via brachial artery FMD and reactive hyperemia, while cerebral vascular function was assessed as the blood velocity response of the middle cerebral artery during hypercapnia. Measurements were taken before and after exposure. Compared with baseline, there was a reduction in peripheral macrovascular function (indexed by FMD), following e-cigarette (pre=9.3±4.3%; post=6.4±4.1%) and cigarette use (pre=10.2±3.7%; post=6.8±3.8%; main effect of time p<0.0001). Cerebral vascular function (indexed by cerebral vasodilatory response during hypercapnia) was also reduced following e-cigarette (pre=53±19%; post=44±15%) and cigarette use (pre=54±21%; post=44±17%; main effect of time p<0.01). The magnitude of reduction in peripheral and cerebral vascular function was similar between conditions (condition × time, p>0.05). Compared with vaping an e-cigarette, participants scored higher for measures of satisfaction, taste, puff liking, and suppression of craving following smoking (p>0.05). Similar to smoking, vaping a pod-based e-cigarette leads to an impairment in peripheral and cerebral vascular function while providing a reduced subjective experience compared with a cigarette among adult smokers. While these data challenge the notion that e-cigarette use is a safe and satisfactory alternative to cigarette use, large longitudinal studies are needed to assess the long-term impact of pod-based e-cigarette devices on cardiovascular and behavioral outcomes.

Sickle cell cerebrovascular reactivity to a CO2 stimulus: Too little, too slow.

Background: Despite increased cerebral blood flow (CBF), cerebral infarcts occur in patients with sickle cell disease (SCD). This suggests increased CBF does not meet metabolic demand possibly due to compromised cerebral vasodilatory response. Hypothesis: In adult SCD patients, cerebrovascular reactivity (CVR) and speed of vasodilatory response (tau) to a standardized vasodilatory stimulus, are reduced compared to normal subjects. Methods: Functional brain imaging performed as part of routine care in adult SCD patients without known large vessel cerebral vasculopathy was reviewed retrospectively. CVR was calculated as the change in CBF measured as the blood-oxygenation-level-dependent (BOLD)-magnetic resonance imaging signal, in response to a standard vasoactive stimulus of carbon dioxide (CO2). The tau corresponding to the best fit between the convolved end-tidal partial pressures of CO2 and BOLD signal was defined as the speed of vascular response. CVR and tau were normalized using a previously generated atlas of 42 healthy controls. Results: Fifteen patients were included. CVR was reduced in grey and white matter (mean Z-score for CVR −0.5 [−1.8 to 0.3] and −0.6 [−2.3 to 0.7], respectively). Tau Z-scores were lengthened in grey and white matter (+0.9 [−0.5 to 3.3] and +0.8 [−0.7 to 2.7], respectively). Hematocrit was the only significant independent predictor of CVR on multivariable regression. Conclusion: Both measures of cerebrovascular health (CVR and tau) in SCD patients were attenuated compared to normal controls. These findings show that CVR represents a promising tool to assess disease state, stroke risk, and therapeutic efficacy of treatments in SCD and merits further investigation.

Quantitative cerebrovascular reactivity MRI in mice using acetazolamide challenge.

To develop a quantitative MRI method to estimate cerebrovascular reactivity (CVR) in mice. We described an MRI procedure to measure cerebral vasodilatory response to acetazolamide (ACZ), a vasoactive agent previously used in human clinical imaging. Vascular response was determined by cerebral blood flow (CBF) measured with phase-contrast or pseudo-continuous arterial spin labeling MRI. Vasodilatory input intensity was determined by plasma ACZ level using high-performance liquid chromatography. We verified the source of the CVR MRI signal by comparing ACZ injection to phosphate-buffered saline injection and noninjection experiments. Dose dependence and feasibility of regional CVR measurement were also investigated. Cerebral blood flow revealed an exponential increase following intravenous ACZ injection, with a time constant of 1.62 min. In contrast, phosphate-buffered saline or noninjection exhibited a slow linear CBF increase, consistent with a gradual accumulation of anesthetic agent, isoflurane, used in this study. When comparing different ACZ doses, injections of 30, 60, 120, and 180 mg/kg yielded a linear increase in plasma ACZ concentration (p < 0.0001). On the other hand, CBF changes under these doses were not different from each other (p=0.50). The pseudo-continuous arterial spin labeling MRI with multiple postlabeling delays revealed similar vascular responses at different postlabeling delay values. There was a regional difference in CVR (p=0.005), with isocortex (0.81 ± 0.17%/[μg/ml]) showing higher CVR than deep-brain regions. Mice receiving multiple ACZ injections lived for a minimum of 6months after the study without noticeable aberrant behavior or appearance. We demonstrated the proof-of-principle of a new quantitative CVR mapping technique in mice.

Abstract 13944: Young, Non-Hispanic Black Males and Females Exhibit Divergent Peripheral and Cerebral Vascular Reactivity

Introduction: In the U.S., cardiovascular and cerebrovascular diseases (CVD) remain more prominent in non-Hispanic black individuals than in other populations. Across most racial/ethnic groups, total CVD prevalence is ~10% lower in females; however, total CVD prevalence in black females (BF) is similar to that of black males (BM). Conversely, BM have ~23% higher age-adjusted stroke mortality compared to BF, a pattern not seen in other groups. While the mechanisms behind these race-by-sex differences are multifactorial, vascular dysfunction likely contributes. Our group and others have demonstrated reduced brachial artery and cerebrovascular vasodilation in black versus white individuals, though much of this work did not specifically address sex differences. To this end, we have recently investigated and reported divergent mechanisms of reduced cutaneous microvascular function in BM and BF; however, more work is needed to better understand whether such findings extend to other vascular regions. Hypothesis: We tested the hypothesis that BF and BM would have divergent degrees of reduced peripheral and cerebral vasodilator responsiveness. Methods: Eleven BF and 15 BM (22 ± 4 vs. 23 ± 3 yrs) underwent testing for brachial artery flow-mediated dilation (FMD; conduit artery function) and post-occlusive reactive hyperemia (PORH; microvascular function), along with cerebrovascular reactivity (CVR) to rebreathing-induced hypercapnia. Results: FMD was greater in BF versus BM (9.10 ± 3.49 vs. 5.84 ± 2.78%; P = 0.02), even when normalized to baseline diameter or shear rate ( P &lt; 0.05 for both). BF had similar PORH when assessed as peak blood velocity (77.1 ± 19.9 vs. 79.4 ± 19.6 cm • s -1 ; P &gt; 0.05) but lower peak blood flow (343.6 ± 169.8 vs. 495.4 ± 196.9 mL/min; P &lt; 0.05) and blood flow AUC (133.6 ± 61.1 vs. 220.3 ± 130.7 mL; P = 0.04) relative to BM. CVR was greater in BF versus BM (0.024 ± 0.010 vs. 0.012 ± 0.006 cm • s -1 • mmHg -1 • mmHg -1 ; P &lt; 0.01). Conclusion: These data suggest that young, BM have lower vascular reactivity than BF during some, but not all, tests of vascular function. More work in this area is needed to better understand the potential biological and social mechanisms influencing sex differences in vascular function and CVD risk in black individuals.

The fetal biometry and doppler parameters on ultrasound among pregnant women complicated with moderate and severe anemia in third trimester

Hypoxia-induced release of nitric oxide and opioids can account for much of the adenosine-independent cerebral vasodilatation in response to hypoxia in the fetus. Direct effects of hypoxia on cerebral arteries account for the remaining fraction, although the vascular endothelium contributes relatively little to hypoxic vasodilatation in the immature cerebral circulation. This was a hospital based cross sectional study and all cases of moderate to severely anaemic pregnant women in Obstetric and Gynaecology Department, with gestational age of 28 weeks and above were included in this study. In group 1, 67% had amniotic fluid index between 5-50thcentile, and there was no AFI <5th centile, while in group 2, AFI<5th centile was found in 21% which was statistically significant. The mean AFI for group 1 and 2 was 11.35+/-3.06cms and 9.19+/-2.34cms respectively (p=0.032).

Differences in Hypercapnia‐Induced Cerebral Vasodilation Between Young, Black Men and Women

In the U.S., stroke prevalence and age-adjusted mortality are greater in the black population than all other racial/ethnic groups. Further, black women (BW) exhibit an ~15% lower age-adjusted stroke mortality than black men (BM), suggesting either cerebrovascular protection in BW or cerebrovascular impairment in BM. While the mechanisms underlying the increased burden of stroke in black individuals remain incompletely understood, vascular dysfunction likely contributes to these negative health outcomes. Our group and others have previously demonstrated impaired vasodilation in the brachial artery, cutaneous microvasculature, and cerebral vasculature in black versus white men and women. However, investigations into gender differences in young, black individuals' cerebral vasodilatory responsiveness remain lacking. Therefore, this study tested the hypothesis that BW and BM exhibit divergent cerebral vasodilatory responses to a rebreathing-induced hypercapnic stimulus. To test this hypothesis, 11 BW and 15 BM (mean ± SD; age: 22 ± 4 vs. 23 ± 3) participated in this study. Each participant was instrumented for the continuous measurement of end-tidal carbon dioxide concentration (PETCO2; capnograph), beat-to-beat mean arterial pressure (MAP; finger photoplethysmography), and middle cerebral artery velocity (MCAv; transcranial Doppler ultrasound) at baseline and during rebreathing induced-hypercapnia. Absolute cerebral vascular conductance index (CVCi = MCAv/MAP) and percent change CVCi (ΔCVCi = [CVCiΔPETCO2 – CVCiBL]/CVCiBL • 100) were calculated at baseline and a ΔPETCO2 of 3, 6, 9, and 12 mmHg (only 8 BW were analyzed at 12 mmHg due to some individuals not reaching this stage). No differences in MAP were observed between BW and BM at baseline or any ΔPETCO2 (BL: 91 ± 9 vs. 89 ± 7 mmHg; Δ3: 88 ± 11 vs. 88 ± 9 mmHg; Δ6: 93 ± 8 vs. 89 ± 8 mmHg; Δ9: 94 ± 8 vs. 90 ± 9 mmHg; Δ12: 95 ± 10 vs. 91 ± 9 mmHg; interaction P = 0.11). At baseline, BW had a greater absolute CVCi than BM (0.80 ± 0.10 vs. 0.68 ± 0.13 cm/s/mmHg; P = 0.04). This pattern was also observed at each ΔPETCO2 stage (Δ3: 0.91 ± 0.11 vs. 0.67 ± 0.13 cm/s/mmHg; Δ6: 0.98 ± 0.10 vs. 0.71 ± 0.12 cm/s/mmHg; Δ9: 1.04 ± 0.09 vs. 0.78 ± 0.13 cm/s/mmHg; Δ12: 1.11 ± 0.11 vs. 0.80 ± 0.16 cm/s/mmHg; all P < 0.001). Despite the baseline differences between groups, BW still exhibited a greater ΔCVCi at each stage of ΔPETCO2 than BM (Δ3: 12.9 ± 5.3 vs. 0.1 ± 9.4%; Δ6: 23.0 ± 6.8 vs. 5.5 ± 10.2%; Δ9: 29.9 ± 12.9 vs. 16.0 ± 11.2%; Δ12: 40.7 ± 16.8 vs. 19.0 ± 12.3%; all P < 0.05). These data suggest that young, BW exhibit greater cerebrovascular responsiveness to a hypercapnic stimulus relative to young, BM, which may partially explain the lower age-adjusted stroke mortality in BW. However, the mechanisms responsible for these observed differences remain undetermined and should be the subject of future research.

Acute intermittent hypercapnic hypoxia and cerebral neurovascular coupling in males and females

The decline in cognition observed in obstructive sleep apnea is linked to intermittent hypercapnic hypoxia (IHH), which is known to impair cerebrovascular reactivity. Whether acute IHH impairs the matching of cerebral blood flow to metabolism (i.e., neurovascular coupling, NVC) is unknown. We hypothesized that acute IHH would reduce cerebral NVC. Healthy participants (N = 17, 8 females, 9 males; age: 22 ± 3 years) had cerebral NVC measured at baseline and following 40-min of IHH at 1-min cycles with 40-s of hypercapnic hypoxia (target PETO2 = 50 mmHg, PETCO2 = +4 mmHg above baseline) and 20-s of normoxia. Cerebral NVC was quantified as the absolute and relative posterior cerebral artery blood velocity (PCAV; transcranial Doppler) and conductance (PCACVC; PCAV/mean arterial pressure [MAP]) response to a visual stimulus paradigm. Following IHH, resting PCAV was unchanged, MAP increased (+4 ± 6 mmHg, P < 0.01) and PCACVC was reduced (−0.05 ± 0.04 cm/s/mmHg, P < 0.01). The peak PCAV response to visual stimuli was unchanged following IHH, but the absolute and relative peak PCACVC response was increased (+0.011 ± 0.019 cm/s/mmHg, P < 0.05 and +4.8 ± 6.1%, P < 0.01, respectively) suggesting an increased cerebral vasodilatory response. No change occurred in the plateau cerebral NVC response following IHH. Changes in resting MAP induced by IHH did not correlate with changes in relative peak PCACVC (r2 = 0.095, P = 0.23). Cerebral NVC did not differ between sexes across all time points and was unchanged following a time-matched air-breathing control. In summary, acute IHH increases peak but not plateau cerebral NVC potentially through IHH mediated neuroplasticity.

Cardiorespiratory Fitness And The Cerebrovascular Response To A Metabolic Stimulus Following Cyclooxygenase Inhibition

Cardiorespiratory fitness (CRF) is positively associated with cerebrovascular function and cognition. We have previously shown that prostaglandins play an important role in regulating the cerebral vasodilator response to hypercapnia, and that the magnitude of change in cerebral vasodilator responses during cyclooxygenase (COX) inhibition is associated with CRF in older adults. However, it is unknown if CRF also influences the cerebrovascular response to a metabolic stimulus in older adults. PURPOSE: To determine the effects of CRF on the cerebrovascular response to a metabolic stimulus before and during COX inhibition in older adults. METHODS: Thirty-five participants completed a maximal exercise test on a cycle ergometer. Participants were split into two groups, High CRF (10 men, 8 women, age = 62 ± 5y) or Low CRF (7 men, 10 women, age = 66 ± 7y), based on the median VO2max (ml/kg/min). All participants completed two levels of the Stroop Color Word Test. Beat-to-beat mean arterial pressure (MAP) and middle cerebral artery velocity (MCAv) were measured at baseline and in response to each level of the Stroop test before and after administration of the COX inhibitor Indomethacin (INDO). The maximum MAP, MCAv, and cerebral pulsatility index (PI) responses were calculated as the highest 3-beat average during each cognitive challenge. RESULTS: There were no differences between high and low CRF groups in MCAv at rest or in response to the metabolic stimulus. There was a trend for lower PI at rest (p = 0.09) and in response to the Stroop test (p = 0.09) in the high CRF group compared with the low CRF group. During INDO, MCAv decreased (Low CRF: -29 ± 4%, High CRF: -27 ± 3%; p < 0.01) and PI increased (Low CRF: 22 ± 3%, High CRF: 17 ± 3%; p < 0.01). During INDO, MCAv at rest was not different between groups; however, PI was lower in the high CRF compared to low CRF group (Low CRF: 0.98 ± 0.05, High CRF: 0.87 ± 0.03; p < 0.05). Lastly, the change in MCAv and PI in response to the metabolic stimulus did not differ between groups. CONCLUSION: In older adults, elevated levels of CRF may lead to a lower PI at rest and in response to a metabolic stimulus. Additionally, COX inhibition did not alter the cerebrovascular response to a metabolic stimulus. Supported by NIH Grant HL118154.

Repeatability of Cerebral Vasomotor Reactivity to Hypercapnia in Humans

Impaired cerebrovascular function is a risk factor for the development of various neurocognitive and cerebrovascular diseases including cognitive dysfunction, dementia, Alzheimer’s disease, and stroke. Since hypercapnia elicits a robust cerebral vasodilator response, cerebrovascular function is commonly assessed as an increase in cerebral blood flow to elevations in arterial carbon dioxide (i.e., cerebral vasomotor reactivity ‐ CVMR). Hypercapnia induced by a rebreathing protocol is one such technique used to assess cerebrovascular function. Although this technique is used to evaluate CVMR within and between subjects before and after interventions, to our knowledge, the repeatability of CVMR assessed by rebreathing has not been comprehensively investigated. Moreover, the National Institute of Health’s recent guidelines emphasize the need for rigor and reproducibility of data collection techniques. Accordingly, this study was designed to determine the within‐day repeatability of CVMR response to rebreathing‐induced hypercapnia. Eleven young healthy males (age = 24 ± 3 years, BMI = 24.3 ± 3.8 kgm−2, mean ± SEM) reported to the laboratory following an overnight fast and performed 3 trials of rebreathing‐induced hypercapnia each separated by approximately 2 hours. Heart rate (ECG), respiration (Pneumotrace), beat‐to‐beat blood pressure (Finometer), middle cerebral artery mean blood velocity (MCAv ‐ transcranial Doppler) and breath‐by‐breath end‐tidal carbon dioxide concentration (PETCO2 ‐ capnograph) were continuously measured. Cerebral vascular conductance index (CVCi) was calculated as MCAv divided by mean arterial pressure. CVMR was assessed as the slope of the linear regression between the increase in %MCAv and %CVCi across the range of change in PETCO2 (ΔPETCO2). The increase in %MCAv and %CVCi was also assessed at a ΔPETCO2 of 15 mmHg which was the highest common change in magnitude of hypercapnia achieved across all rebreathing trials among all participants. Repeatability between the 3 trials was assessed using intra class correlation coefficient (ICC). The slopes of %CVCi vs. ΔPETCO2 (3.9 ± 0.4, 3.8 ± 0.3 and 3.6 ± 0.3 %mmHg−1 for 1st, 2nd and 3rd trial respectively, p = 0.82) was not different and showed very good repeatability (ICC = 0.86, p &lt; 0.001) between the 3 rebreathing‐induced hypercapnia trials. Likewise, the % increase in CVCi at ΔPETCO2 of 15 mmHg was not different (40 ± 4, 38 ± 4 and 36 ± 4% for 1st, 2nd and 3rd trial respectively, p = 0.72) and also demonstrated very good repeatability between trials (ICC = 0.86, p &lt; 0.001). Similar results were obtained when MCAv was used as the dependent variable. These results suggest that within‐day CVMR assessed by rebreathing‐induced hypercapnia is highly repeatable and therefore can be used as a reliable index of cerebrovascular function.Support or Funding InformationSupported by UTA College of Nursing and Health Innovation

Association of Endothelial Biomarkers with Cerebral MRI Perfusion Analysis in Patients with Sickle Cell Disease

Introduction Sickle cell disease (SCD) is associated with silent cerebral infarcts (SCI) which are related to neurocognitive damage. One of the major causes of SCI is the impaired cerebral oxygenation, which makes cerebral blood flow (CBF) an essential parameter to measure. Previous hemodynamic studies have shown elevated CBF and reduced cerebrovascular reserve (CVR) in patients with SCD (Helton 2015; Václavů 2018). CVR is known as the increase of CBF in response to vasoactive stimulus, relative to the baseline. The reduced CVR renders SCD patients susceptible to cerebral ischemia, especially under hypotensive or hypoxic conditions. Possible factors contributing to microvascular damage and thus reduced CVR include hemoglobin S polymerization, neutrophil activation and endothelial activation and adhesion. Previous studies examined the role of these factors in patients with SCD (Sins 2017; Al Najjar 2017). However, the association between the endothelial biomarkers and hemodynamic parameters is unknown in adult patients with SCD. In this study, we investigated the correlation between CBF and CVR and the adhesion molecules including sVCAM-1, sP-selectin, VWF-Ag and ADAMTS13. Additionally, we studied the association of these endothelial biomarkers with standard laboratory parameters. Methods This study was performed in accordance with the Declaration of Helsinki and was approved by the Review Board of Amsterdam UMC. For this study, 33 steady state patients with SCD (mean age 32.1 ± 10.7, 64% male, 29 HbSS, 4 HbSß) and 10 healthy volunteers (mean age 36,4 ± 15.9, 60% male, 2 HbAS, 8 HbAA) were included. Hematologic laboratory parameters were assessed using standard laboratory procedures. Plasma levels of sVCAM-1 and sP-selectin were determined using ELISA (R&amp;D Systems, USA) and ADAMTS13 and VWF-Ag were measured with the INNOVANCE assay (Siemens Healthcare Diagnostics). For the CBF measurements, pseudo-continuous arterial spin labelling (pCASL) was acquired at 3T MRI (Philips Healthcare, The Netherlands). CBF was measured before and after acetazolamide (vasoactive stimulus) administration and subsequently CVR was calculated using the following equation: CVR = (CBFafter - CBFbefore) / CBFbefore x 100% Plasma levels of endothelial biomarkers were compared between groups using ANOVA test. Correlation between the parameters were measured using single regression model where p&lt;0.05 was considered as statistically significant. Results sVCAM-1 levels and VWF-Ag were significantly higher in SCD patients compared to healthy controls (p &lt; 0.01 and p = 0.01). ADAMTS13 and sP-selectin were not significantly different between the two groups (p = 0.06 and p = 0.33). sVCAM-1 was significantly associated with CBF, and parameters of hemolysis LDH and bilirubin in SCD patients (Fig. 1A and 2C). Negative correlation was observed between sVCAM-1 and hemoglobin (Fig. 1B). The relationship between sVCAM-1 and hemodynamic and laboratory parameters are shown in Table 1. No significant correlation was found between sVCAM-1, hemodynamic and standard laboratory parameters in healthy controls. VWF-Ag, ADAMTS13 and sP-selectin were not significantly associated with hemodynamic MRI parameters. Discussion Our results show elevated sVCAM-1 levels in sickle cell patients, strongly related to CBF. sVCAM-1 is an adhesion molecule and elevated plasma levels are found in patients with endothelial activation due to inflammation or atherosclerosis (Cook-Mills 2013; Cybulsky 2001). Previous studies showed elevated levels in sickle cell disease but no correlation with parameters of cerebral perfusion have been demonstrated yet (Antwi-Boasiako 2018; Kato 2005). The strong correlation with CBF is mostly related to the chronic hemolysis given the association found with hemoglobin levels and markers of hemolysis like LDH and bilirubin. In contrast to sVCAM-1, no such relation was found with other markers of endothelial activation such as VWF activity and sP-selectin levels. No correlation between endothelial markers and the CVR was demonstrated, suggesting that endothelial damage itself may not related to the impaired cerebral vasodilatation in response to a vasoactive stimulus. Conclusion Endothelial adhesion molecule sVCAM-1 showed a strong correlation with CBF and parameters of hemolysis, suggesting a relation between the hemolytic damage of endothelial cells and impaired cerebral perfusion. Disclosures Nur: Novartis Pharmaceuticals: Consultancy.

Memory and cerebrovascular deficits recovered following angiotensin IV intervention in a mouse model of Alzheimer's disease

Angiotensin II type 1 receptor antagonists like losartan have been found to lower the incidence and progression to Alzheimer's disease (AD), as well as rescue cognitive and cerebrovascular deficits in AD mouse models. We previously found that co-administration of an angiotensin IV (AngIV) receptor (AT4R) antagonist prevented losartan's benefits, identifying AT4Rs as a possible target to counter AD pathogenesis. Therein, we investigated whether directly targeting AT4Rs could counter AD pathogenesis in a well-characterized mouse model of AD. Wild-type and human amyloid precursor protein (APP) transgenic (J20 line) mice (4.5 months old) received vehicle or AngIV (~1.3 nmol/day, 1 month) intracerebroventricularly via osmotic minipumps. AngIV restored short-term memory, spatial learning and memory in APP mice. AngIV normalized hippocampal AT4R levels, increased hippocampal subgranular zone cellular proliferation and dendritic arborization, and reduced oxidative stress. AngIV rescued whisker-evoked neurovascular coupling, endothelial- and smooth muscle cell-mediated cerebral vasodilatory responses, and cerebrovascular nitric oxide bioavailability. AngIV did not alter blood pressure, neuroinflammation or amyloid-β (Aβ) pathology. These preclinical findings identify AT4R as a promising target to counter Aβ-related cognitive and cerebrovascular deficits in AD.

Propofol But Not Desflurane Maintains Rat Cerebral Arteriolar Responses to Acetylcholine During Acute Hyperglycemia.

Acute hyperglycemia causes vascular endothelial dysfunction in various organs including the cerebral vessels. It is associated with increased mortality and morbidity in the perioperative period. The impact of anesthetic agents on cerebral vasodilatory responses during hyperglycemia remains unclear. We investigated endothelial function in rat cerebral arterioles during acute hyperglycemia, under propofol or desflurane anesthesia. A closed cranial window preparation was used to measure changes in pial arteriole diameter induced by topical application of acetylcholine (ACh), an endothelium-dependent vasodilator, in rats anesthetized with propofol or desflurane. Pial arteriole responses to ACh were measured during normoglycemia and hyperglycemia. We then investigated whether the response of cerebral arterioles to acute hyperglycemia under propofol anesthesia were related to propofol or its vehicle, intralipid. ACh resulted in a dose-dependent dilation of cerebral arterioles during propofol and desflurane anesthesia under normoglycemic conditions. The vasodilatory effects of ACh were also maintained under hyperglycemic conditions during propofol anesthesia, but the vasodilator response to ACh was significantly impaired during hyperglycemia compared with normoglycemia with desflurane anesthesia. The vasodilatory effects of ACh were maintained during normoglycemia and hyperglycemia in rats receiving propofol or intralipid. Rat pial arteriole responses to ACh are maintained during conditions of acute hyperglycemia with propofol anesthesia but suppressed compared with normoglycemia with desflurane anesthesia.

Abstract WP22: A New Technique for the Assessment of Cerebral Vasodilatory Capacity as Part of Catheter-Based Cerebral Angiography

Background: Cerebral vasodilatory capacity assessment for risk stratification in patients with extracranial arterial stenosis or occlusion may be useful. We describe a new method that assesses cerebral vasodilatory capacity as part of catheter-based cerebral angiography. Methods: We prospectively assessed regional cerebral blood volume (rCBV) in the arterial distribution of interest using a controlled contrast injection in the common carotid or the subclavian arteries. rCBV maps were created using a predefined algorithm based on contrast distribution in the venous phase (voxel size 0.466 mm 3 ). rCBV maps were acquired again after selective administration of intra-arterial nicardipine (2.5 mg) distal to the stenosis. Two independent observers graded the change in rCBV in 10 predefined anatomical regions within the tributaries of the artery of interest (0=reduction, 1=no change, 2=increase) and total rCBV change scores were summated. The rCBV score values were averaged between the two observers for each patient. Mean arterial pressure was monitored at baseline and at 1 minute intervals post nicardipine administration for 5 minutes. Results: Twenty-five patients with internal carotid artery stenosis (n=18; 0%-90% in severity) or extracranial vertebral artery stenosis (n=7; 0%-100% in severity) were assessed. There was an increase in rCBV in a tributary of the artery of interest in 18 of 25 after intra-arterial nicardipine (mean score 11.98; range 0-19.5). There was no change or decrease in rCBV in 7 of 25 patients. The mean rCBV change score was similar in patients with assessment of internal carotid artery or vertebral artery distributions (12.2 ± 5.3; 11.4 ± 2.5; p=0.68 by ANOVA). There was an average (±SD) reduction of mean arterial pressure of 14mmHg ± 7.5 after intra-arterial nicardipine. There was no correlation between the magnitude of mean arterial pressure reduction post nicardipine (regression coefficient -0.13; p=0.38) or between the severity of stenosis (regression coefficient -0.04; p=0.29) and rCBV change scores. Conclusions: We describe a new technique for selective assessment of cerebral vasodilatory response in the affected arterial distribution during catheter-based cerebral angiography.

Resveratrol and cognitive decline: a clinician perspective

Resveratrol (3,5,4′-trihydroxystilbene) belongs to a family of polyphenolic compounds known as stilbenes, particularly concentrated in grape and red wine. The aim of our review was to critically review the available evidence of resveratrol effects on brain function and its potential impact on therapy. In preclinical models of cognitive decline, resveratrol displays potent antioxidant activity by scavenging free radicals, reducing quinone reductase 2 activity and upregulating endogenous enzymes. Resveratrol also inhibits pro-inflammatory enzyme expression, reduces nuclear factor-κB activation and cytokine release. Treatment with resveratrol can affect multiple signaling pathway effectors involved in cell survival, programmed cell death and synaptic plasticity. Direct and/or indirect activation of the deacetylase sirtuins by resveratrol has also been suggested. In humans, clinical evidence derived from randomized clinical trials suggests that resveratrol is able to improve cerebral blood flow, cerebral vasodilator responsiveness to hypercapnia, some cognitive tests, perceived performances, and the Aβ40 plasma and cerebrospinal fluid level.

Cerebral and Extracerebral Vasoreactivity in Patients With Different Clinical Manifestations of Cerebral Small-Vessel Disease: Data From the Significance of Hemodynamic and Hemostatic Factors in the Course of Different Manifestations of Cerebral Small-Vessel Disease Study.

Endothelial dysfunction has been implicated in the pathogenesis of cerebral small-vessel disease (SVD). Little is known about the relationship between SVD and measures of endothelium-dependent vasodilatation and cerebral vasomotor reactivity. The aim of this study was to evaluate cerebral and extracerebral endothelial dysfunction in patients with different manifestations of SVD and to assess the relationship between endothelial dysfunction and radiologic markers of SVD. The vasomotor reactivity reserve (VMRr), breath-holding index (BHI) of the middle cerebral arteries, and brachial artery flow-mediated dilatation (FMD) were measured with ultrasound techniques in 90 patients (30 in each group) older than 60 years with extensive white matter lesions (Fazekas grade ≥ 2) with a history of lacunar stroke, vascular dementia, or parkinsonism and 30 individuals with normal magnetic resonance imaging findings (control group). All groups were matched for age, sex, hypertension, and diabetes. The mean age ± SD (71.8 ± 3.4 versus 71.7 ± 3.4 years), sex distribution, and prevalence of the main vascular risk factors were similar in the SVD and control groups. The VMRr (56.6% ± 18.3% versus 77.1% ± 16.9%), BHI (0.8 ± 0.3 versus 1.1 ± 0.4), and FMD (5.8% ± 4 versus 12.1% ± 5.2%) were severely impaired in the SVD groups compared to the control group (P < .01). The vascular responses to all tests was similar in the SVD groups, but they were significantly decreased in patients with severe white matter lesions, marked brain atrophy, and enlarged perivascular spaces. This study was the first that simultaneously evaluated cerebral and extracerebral vasodilator responses in a well-phenotyped cohort of patients with lacunar stroke, vascular dementia, or parkinsonism. The VMRr, BHI, and FMD were more severely impaired in patients with SVD, regardless of its clinical manifestation, than in control participants. All measures were significantly lower in patients with severe white-matter lesions, brain atrophy, or enlarged perivascular spaces.

Antioxidant and Cerebroprotective Roles of Carbon Monoxide (CO) Against Cerebrovascular Injury Caused by Prolonged Neonatal Asphyxia

Asphyxia occurring in the fetus and newborn infant frequently leads to hypoxic‐ischemic encephalopathy (HIE) in survivors. The neonatal brain circulatory system is compromised by asphyxia/reventilation via a mechanism that may involve oxidative stress. CO, a gaseous messenger with antioxidant properties, is produced from heme via the heme oxygenase (HO)‐catalyzed reaction. We tested the hypothesis that CO, either produced by the brain, or delivered systemically by the donor molecule CORM‐A1, has a cerebrovascular protective role during neonatal asphyxia. We developed a novel survival model of prolonged asphyxia (50 – 60 min) in newborn pigs that combines insults of severe hypoxia (PaO2, 20–30 mm Hg), hypercapnia (PaCO2, 70–80 mm Hg), and acidosis (pH, 6.9–7.0) while avoiding extreme systemic hypotension and cerebral ischemia. During the asphyxia conditions, we observed immediate and sustained activation of brain HO as detected by an elevated CO concentration in the cortical periarachnoid fluid. Cortical astrocytes are among the main sources of brain CO production in normal and asphyxiated brains. Asphyxia followed by a 60‐min reventilation with room air caused excessive formation of reactive oxygen species (ROS) in the neonatal brain. Brain oxidative stress was potentiated by the HO inhibitor tin protoporphyrin, suggesting that activation of astrocytic HO/CO during asphyxia has antioxidant effects. Administered 30 min before asphyxia, CORM‐A1 (2 mg/kg i.p.) prevented excessive ROS formation in the brain during reventilation. We tested the effects of prolonged neonatal asphyxia on cerebral vascular dilator functions after 24 and 48 h of recovery using the cranial window technique. Endothelium‐dependent vasodilatory responses to hypercapnia and bradykinin were not negatively affected by prolonged asphyxia. In contrast, astrocyte‐dependent cerebral vasodilatory responses to adenosine diphosphate (ADP) and glutamate were compromised, indicating that astrocytes are selectively injured by prolonged asphyxia. Endothelium‐ and astrocyte‐independent cerebral vascular smooth muscle functions tested by vasodilations to isoproterenol and sodium nitroprusside remained intact in post‐asphyxic newborn pigs. In CORM‐A1‐pretreated animals, prolonged asphyxia did not produce any cerebral vascular incapacities, suggesting that CO therapy protects astrocytes from asphyxia/reventilation injury. Overall, prolonged neonatal asphyxia without systemic hypotension or cerebral ischemia injures cortical astrocytes via an oxidative stress‐mediated mechanism that can be partially counteracted by activation of the endogenous HO/CO‐based antioxidant system in the brain or by CO/CORM‐A1 therapy. We propose that gaseous CO and CO donor molecules can be used as novel efficient therapeutic approaches to prevention of neonatal brain injury caused by prolonged asphyxia.Support or Funding InformationR01 NS 101717; R01 HL 034059; R01 HL 042851This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A New Technique for the Assessment of Cerebral Vasodilatory Capacity as Part of Catheter-Based Cerebral Angiography

Previous studies have demonstrated the value of cerebral vasodilatory capacity assessment for risk stratification in patients with extracranial arterial stenosis or occlusion. We describe a new method that assesses cerebral vasodilatory capacity as part of catheter-based cerebral angiography. We assessed regional cerebral blood volume (rCBV) in the arterial distribution of interest using a controlled contrast injection through a diagnostic catheter placed in the common carotid or the subclavian artery. rCBV maps were created using predefined algorithm based on contrast distribution in the venous phase (voxel size 0.466 mm3) into high, intermediate, low, and no detectable rCBV regions. rCBV maps were acquired again after the administration of intra-arterial nicardipine (1.5-2.5 mg), and percentage increases of the area of various grades of rCBV were calculated. Three patients with internal carotid artery stenosis (32% - 64% in severity) and 1 patient with extracranial vertebral artery stenosis (46% in severity) were assessed. There was a variable but consistent increase in the area of high rCBV in the ipsilateral hemisphere in 3 patients with internal carotid artery flow (5.5%-24.5%) and the cerebellum (9.6%) in 1 patient with vertebral artery flow assessments. The increase in high rCBV was most prominent in the patient who received 2.5 mg (24.5%) and least prominent in a patient who received 1.5 mg (5.5%) of intra-arterial nicardipine. There was a concurrent reduction in areas of intermediate and low rCBV (shift) in 3 patients, and there was an increase in all areas of rCBV grades (addition) in 1 patient. Selective assessment of cerebral vasodilatory response in the affected arterial distribution is feasible during catheter-based cerebral angiography.

Impaired cerebrovascular reactivity in obstructive sleep apnea: a case-control study

ObjectiveObstructive sleep apnea (OSA) is an independent risk factor for stroke. Little is known about the cerebrovascular hemodynamic changes during apnea. Hypercapnia occurs in apneas and hypopneas, and a reduced cerebral vasodilatory response to CO2 could compromise the cerebral blood flow (CBF). Therefore, we aimed to evaluate whether the apnea–hypopnea index (AHI) affected the cerebrovascular response to CO2. MethodsA total of 11 patients with OSA were compared to 16 controls. We assessed the cerebrovascular responses with arterial spin labeling (ASL) and blood oxygen level-dependent (BOLD) magnetic resonance imaging during hypercapnia or breath-holding tasks. ResultsThe CBF response to CO2 was impaired with increasing AHI (average CBF: p = 0.018; gray matter: p = 0.038; white matter: p = 0.045), that is, increased OSA severity. When comparing the OSA patients to the control subjects, the OSA patients had a significantly reduced CO2 response of the white matter CBF (p = 0.04). However, the BOLD response to CO2 and the breath-holding task did not show any significant differences between OSA patients and control subjects. ConclusionThe cerebrovascular CO2 reactivity, measured by the CBF, was impaired with increasing AHI, that is, OSA severity. These findings may add to the understanding of the increased stroke risk found in OSA patients.