Cerebral Blood Flow Autoregulation Research Articles

Risk of overestimating loss of cerebral autoregulation-author's reply.

Editor—We read with great interest the correspondence from Claudia Niño and colleagues about our paper ‘Impact of impaired cerebral blood flow autoregulation on electroencephalogram signals in adults undergoing propofol anaesthesia: a pilot study’.1 Their main concern is that the number of patients with impaired cerebral autoregulation (CA) may have been overestimated. They point to a possible difference in prevalence of comorbidities between the preserved CA group (CA+, mean flow index, Mxa <0.3) and the impaired CA group (CA−, Mxa ≥0.3).

HYPERTENSIVE ENCEPHALOPATHY: TO BE DIAGNOSED AND TREATED IMMEDIATELY

It is important to have a good understanding of the pat­hogenetic diagnosis and treatment features of the severe complication with high mortality – hypertensive encepha­lopathy (HE) because of the amount of people suffering from chronic arterial hypertension is constantly increa­sing. Thus, this article briefly reviews the mechanism of cerebral blood flow autoregulation, HE pathophysiology, and the main aspects of diagnosis and treatment. An HE episode is caused by a sudden and significant increase in arterial blood pressure, when the autoregulatory mecha­nism of cerebral blood flow becomes ineffective. Along with increased blood pressure, the patient gradually deve­lops neurological symptoms ranging from intense heada­che to vision loss, loss of consciousness, and convulsions. The diagnosis of HE is based on the clinical signs – acute arterial hypertension and the subsequent neurological symptoms. Also, the diagnosis of HE can be determined retrospectively when the neurological symptoms rapi­dly disappear with effective antihypertensive treatment. Computed tomography is important in differentiating HE from intracerebral hemorrhage and ischemic stroke. In management of HE it is recommended to return to the limits of cerebral blood flow autoregulation by immedi­ately reducing mean arterial blood pressure by 20-25%. In order to achieve the maximum rapid antihyperten­sive effect, it is suggested to administer the medication only intravenously. Labetalol and sodium nitroprusside are currently recommended first-line drugs for the treat­ment of HE. Patients with HE should be hospitalized in the intensive care unit for continuous control of decre­asement of arterial blood pressure while observing the cautious dynamics of the neurological condition. The outcome of patients depends on the urgency and effici­ency of treatment in returning arterial blood pressure to the limits of cerebral blood flow autoregulation, as well as on comorbidities, the severity of the condition and possible complications.

Dynamic effects of cholinergic blockade upon cerebral blood flow autoregulation in healthy adults.

Background: Cerebral flow autoregulation (CFA) is a homeostatic mechanism critical for survival. The autonomic nervous system (ANS) plays a key role in maintaining proper CFA function. More quantitative studies of how the ANS influences CFA are desirable. Objective: To discover and quantify the dynamic effects of cholinergic blockade upon CFA in response to changes of arterial blood pressure and blood CO2 tension in healthy adults. Methods: We analyzed time-series data of spontaneous beat-to-beat mean arterial blood pressure (ABP) and cerebral blood flow velocity in the middle cerebral arteries (CFV), as well as breath-to-breath end-tidal CO2 (CO2), collected in 9 adults before and after cholinergic blockade, in order to obtain subject-specific predictive input-output models of the dynamic effects of changes in ABP and CO2 (inputs) upon CFV (output). These models are defined in convolutional form using "kernel" functions (or, equivalently, Transfer Functions in the frequency domain) that are estimated via the robust method of Laguerre expansions. Results: Cholinergic blockade caused statistically significant changes in the obtained kernel estimates (and the corresponding Transfer Functions) that define the linear dynamics of the ABP-to-CFV and CO2-to-CFV causal relations. The kernel changes due to cholinergic blockade reflect the effects of the cholinergic mechanism and exhibited, in the frequency domain, resonant peaks at 0.22 Hz and 0.06Hz for the ABP-to-CFV and CO2-to-CFV dynamics, respectively. Conclusion: Quantitative estimates of the dynamics of the cholinergic component in CFA are found as average changes of the ABP-to-CFV and CO2-to-CFV kernels, and corresponding Transfer Functions, before and after cholinergic blockade.

Does Cardiac Function Affect Cerebral Blood Flow Regulation?

Many previous studies indicate that heart failure (HF) increases the risk of cognitive dysfunction and stroke, showing the logic that several physiological factors associated with cardiac dysfunctions affect homeostasis in the cerebral circulation. In the chronic process of HF patients, it is suggested that reduced cerebral blood flow (CBF) and abnormal auto-regulation might result in impaired perfusion, metabolic insufficiency, and regional or global structural deteriorations in the brain. However, the mechanism underlying HF-induced brain disease remains unclear. Cardiac dysfunction in patients with HF or HF-induced several physiological abnormalities may cause brain dysfunction. Possible physiological factors should be considered for future studies to prevent brain disease as well as cardiovascular dysfunction in patients with HF.

Transcranial Doppler ultrasound: Clinical applications from neurological to cardiological setting.

Transcranial Doppler (TCD) ultrasonography is a rapid, noninvasive, real-time, and low-cost imaging technique. It is performed with a low-frequency (2 MHz) probe in order to evaluate the cerebral blood flow (CBF) and its pathological alterations, through specific acoustic windows. In the recent years, TCD use has been expanded across many clinical settings. Actually, the most widespread indication for TCD exam is represented by the diagnosis of paradoxical embolism, due to patent foramen ovale, in young patients with cryptogenic stroke. In addition, TCD has also found useful applications in neurological care setting, including the following: cerebral vasospasm following acute subarachnoid hemorrhage, brain trauma, cerebrovascular atherosclerosis, and evaluation of CBF and cerebral autoregulation after an ischemic stroke event. The present review aimed to describe the most recent evidences of TCD utilization from neurological to cardiological setting.

Effects of early human immunodeficiency virus infection on cerebral white matter blood flow autoregulation.

Blood flow autoregulation in cerebral white matter was measured before and after acute nicardipine-induced changes in mean arterial pressure of 10-21% in 21 treatment naïve HIV-positive adults and 32 controls. The autoregulatory index (-% cerebral blood flow change/% mean arterial pressure change) was not different at baseline ( P = 0.71) or after 1 year of treatment ( n = 11, P = 0.17). We found no autoregulatory defect to explain the increased stroke risk or the development of cerebral white damage in people with HIV.

Regional impairment of deep gray matter perfusion in neonates with congenital heart disease revealed by arterial spin labeling MRI.

The present study examined deep gray matter perfusion in neonates with congenital heart disease (CHD) with arterial spin labeling magnetic resonance imaging preoperatively. We found that neonates with cyanotic CHD showed lower right thalamus compared with controls and lower right basal ganglia perfusion compared with acyanotic CHD. When the CHD group was assessed as a whole, it showed slightly decreased left thalamus perfusion compared with controls. The results suggest that cardiac physiology plays a crucial part in changes in regional cerebral perfusion. Perfusion with arterial spin labeling may be a useful marker of high risk for impaired cerebral blood flow auto-regulation and cerebral hypoperfusion in neonates with CHD.

Abstract P101: AT1-AA Induced Hypertension During Pregnancy Decreases Maternal Cerebral Blood Flow Autoregulation Postpartum

Preeclampsia (PE), new-onset hypertension during pregnancy, is the leading cause of morbidity and mortality for the mother and is associated with multi-organ dysfunction including the brain. Women with PE have activated B cells producing agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA) which remain elevated in maternal circulation up to 8 years postpartum (PP); therefore, we believe it to play a role in PE pathophysiology and the increased incidents of cardiovascular disorders PP. Although we have shown at AT1-AA infusion into pregnant rats results in elevated mean arterial pressure (MAP), impaired cerebral blood flow (CBF) autoregulation, and reduced pup weight, we don’t know the effects of AT1-AA on MAP and CBF hemodynamics in the PP period. We hypothesize that AT1-AA induced hypertension during pregnancy will cause maternal hypertension and impaired maternal CBF PP. To test this hypothesis, AT1-AA (1:40) was infused on gestational day (GD) 14 via a mini-osmotic pump. Dams were allowed to deliver; pup weights were recorded within 12 hours. PP dams were aged to 9 weeks after birth and one group of AT1-AA PP dams received a second infusion of AT1-AA (1:80), to mimic the levels of AT1-AA seen in PP PE women. At 10 weeks PP, maternal MAP was measured and at 12 weeks PP, CBF autoregulation was measured by laser Doppler flowmeter. At PP week 12, MAP was 118±3 mmHg in NP (n=4), 119±2 mmHg in AT1-AA (n=5), and 126±5 in AT1-AA + AT1-AA (1:80) PP (P&lt;0.05, n=5). CBF increased by 43±8% (P&lt;0.05, n=2) in rats with AT1-AA during pregnancy and by 37±9% (P&lt;0.05, n=4) in rats with AT1-AA during pregnancy and (1:80) PP in response to increased MAP from 100 to 140 mmHg, versus only 6±2% (n=3) in normal pregnant controls. In conclusion, AT1-AA during pregnancy causes sustained changes in CBF hemodynamics PP. Sustained maternal AT1-AA PP also causes increased blood pressures long-term in association with impaired CBF. These data indicate that perinatal and PP AT1-AA cause long-term cardiovascular and cerebrovascular consequences for PE women.

Cerebral Autoregulation in Healthy Term Newborns: Brief Report

Cerebral autoregulation is a homeostatic process that maintains cerebral blood flow (CBF) across a range of mean arterial pressures (MAPs). Cerebral autoregulation can be impaired in pathologic systemic and neurological conditions and can lead to cerebral hypoperfusion or cerebral hyperperfusion from low and high MAPs, respectively. 1 Obrist W.D. Gennarelli T.A. Segawa H. Dolinskas C.A. Langfitt T.W. Relation of cerebral blood flow to neurological status and outcome in head-injured patients. J Neurosurg. 1979; 51: 292-300 Crossref PubMed Scopus (116) Google Scholar Little is known about the maturation of cerebral autoregulation after birth or whether there are sex differences in CBF at birth. One study of 16 term neonates without congenital heart disease tested autoregulation using cerebral oximeter monitoring with tilt testing and reported that cerebral autoregulation was intact between three and 10 days. 2 Tran N.N. Kumar S.R. Hodge F.S. Macey P.M. Cerebral autoregulation in neonates with and without congenital heart disease. Am J Crit Care. 2018; 27: 410-416https://doi.org/10.4037/ajcc2018672 Crossref PubMed Scopus (11) Google Scholar Sex differences in CBF have been observed in older ages. Similar to healthy adolescents aged 10 to 16 years and healthy adults, prepubertal girls between four and eight years have higher middle cerebral and basilar artery flow velocities than age-matched boys. 3 Vavilala M.S. Kincaid M.S. Muangman S.L. Suz P. Rozet I. Lam A.M. Gender differences in cerebral blood flow velocity and autoregulation between the anterior and posterior circulations in healthy children. Pediatr Res. 2005; 58: 574-578 Crossref PubMed Scopus (92) Google Scholar ,4 Tontisirin N. Muangman S.L. Suz P. et al. Early childhood gender differences in anterior and posterior cerebral blood flow velocity and autoregulation. Pediatrics. 2007; 119: e610-e615 Crossref PubMed Scopus (62) Google Scholar Studies report that both healthy boys and girls aged between four and 16 years have intact cerebral autoregulation and children aged two to six years have a lower limit of autoregulation (LLA) similar to adolescents and adults. 3 Vavilala M.S. Kincaid M.S. Muangman S.L. Suz P. Rozet I. Lam A.M. Gender differences in cerebral blood flow velocity and autoregulation between the anterior and posterior circulations in healthy children. Pediatr Res. 2005; 58: 574-578 Crossref PubMed Scopus (92) Google Scholar , 4 Tontisirin N. Muangman S.L. Suz P. et al. Early childhood gender differences in anterior and posterior cerebral blood flow velocity and autoregulation. Pediatrics. 2007; 119: e610-e615 Crossref PubMed Scopus (62) Google Scholar , 5 Vavilala M.S. Lee L.A. Lam A.M. The lower limit of cerebral autoregulation in children during sevoflurane anesthesia. J Neurosurg Anesthesiol. 2003; 15: 307-312 Crossref PubMed Scopus (78) Google Scholar This finding means that infants and young children have less cerebral autoregulatory reserve (difference between MAP and LLA) than older children. 5 Vavilala M.S. Lee L.A. Lam A.M. The lower limit of cerebral autoregulation in children during sevoflurane anesthesia. J Neurosurg Anesthesiol. 2003; 15: 307-312 Crossref PubMed Scopus (78) Google Scholar However, girls aged four to 16 years have higher normative autoregulatory indices of the basilar artery compared with age-matched boys and healthy boys aged four to 16 years have higher normative autoregulatory indices of the middle cerebral artery (MCA) compared with healthy girls; the reasons for these differences are not well understood. 3 Vavilala M.S. Kincaid M.S. Muangman S.L. Suz P. Rozet I. Lam A.M. Gender differences in cerebral blood flow velocity and autoregulation between the anterior and posterior circulations in healthy children. Pediatr Res. 2005; 58: 574-578 Crossref PubMed Scopus (92) Google Scholar ,4 Tontisirin N. Muangman S.L. Suz P. et al. Early childhood gender differences in anterior and posterior cerebral blood flow velocity and autoregulation. Pediatrics. 2007; 119: e610-e615 Crossref PubMed Scopus (62) Google Scholar In clinical practice, hypotension is commonly defined in relation to gestational age (GA), and hypotension is common in critically ill neonates. 6 Dilli D. Soylu H. Tekin N. Neonatal hemodynamics and management of hypotension in newborns. Turk Pediatri Ars. 2018; 53: S65-S75 Crossref PubMed Scopus (10) Google Scholar Obtaining normative data for female and male newborns is a requisite for further understanding CBF and cerebral autoregulation and optimizing cerebral perfusion in critically ill neonates. We explored CBF velocity and cerebral autoregulation of the anterior cerebral circulation among healthy term newborns.

Is there a role of proinflammatory cytokines on degenerin-mediated cerebrovascular function in preeclampsia?

Preeclampsia (PE) is associated with adverse cerebrovascular effects during and following parturition including stroke, small vessel disease, and vascular dementia. A potential contributing factor to the cerebrovascular dysfunction is the loss of cerebral blood flow (CBF) autoregulation. Autoregulation is the maintenance of CBF to meet local demands with changes in perfusion pressure. When perfusion pressure rises, vasoconstriction of cerebral arteries and arterioles maintains flow and prevents the transfer of higher systemic pressure to downstream microvasculature. In the face of concurrent hypertension, loss of autoregulatory control exposes small delicate microvessels to injury from elevated systemic blood pressure. While placental ischemia is considered the initiating event in the preeclamptic cascade, the factor(s) mediating cerebrovascular dysfunction are poorly understood. Elevated plasma proinflammatory cytokines, such as tumor necrosis factor α (TNF‐α) and interleukin‐17 (IL‐17), are potential mediators of autoregulatory loss. Impaired CBF responses to increases in systemic pressure are attributed to the impaired pressure‐induced (myogenic) constriction of small cerebral arteries and arterioles in PE. Myogenic vasoconstriction is initiated by pressure‐induced vascular smooth muscle cell (VSMC) stretch. Recent studies from our laboratory group indicate that proinflammatory cytokines impair the myogenic mechanism of CBF autoregulation via inhibition of vascular degenerin proteins, putative mediators of myogenic constriction in VSMCs. This brief review links studies showing the effect of proinflammatory cytokines on degenerin expression and CBF autoregulation to the pathological cerebral consequences of preeclampsia.

Dynamics of the cerebral autoregulatory response to paced hyperventilation assessed using subcomponent and time-varying analyses.

Cerebral blood flow (CBF) can be altered by a change in partial pressure of arterial CO2 (Pco2), being reduced during hyperventilation (HPV). Critical closing pressure (CrCP) and resistance area product (RAP) are parameters that can be studied to understand this change, but their dynamic response has not been investigated during paced HPV (PHPV). Seventy-five participants had recordings at rest and during PHPV. Blood pressure (BP) (Finometer), bilateral CBF velocity (CBFV) (transcranial Doppler), end-tidal CO2 (capnography), and heart rate (HR) were recorded continuously. Subcomponent analysis (SCA) and time-varying CrCP, RAP, and dynamic cerebral autoregulation (autoregulation index, ARI) were estimated by comparing PHPV with poikilocapnia. PHPV caused a change in CBFV (P < 0.01), EtCO2, (P < 0.01), HR (P < 0.001), and RAP (P < 0.01). SCA demonstrated RAP was the main parameter explaining the changes in CBFV due to PHPV. The time-varying step responses for CBFV and RAP during PHPV demonstrated considerable nonstationarity compared with poikilocapnia (P < 0.00001). Although time-varying ARI was temporarily depressed, after 60 s of PHPV it was significantly higher (6.81 ± 1.88) (P < 0.0001) than in poikilocapnia (5.08 ± 1.86). The mean plateau of the RAP step response was -98.3 ± 58.8% 60 s after the onset of PHPV but -71.7 ± 45.0% for poikilocapnia (P = 0.0026), with no corresponding changes in CrCP (P = 0.6). Further work is needed to assess the role of sex and aging in our findings, and the potential for using RAP and CrCP to improve the sensitivity and specificity of CO2 reactivity studies in cerebrovascular conditions.NEW & NOTEWORTHY The dynamic response of critical closing pressure (CrCP) and resistance-area product (RAP) of the cerebral circulation to a step change in mean arterial pressure can shed light on the nonstationary changes induced by paced hyperventilation and the effects of hypocapnia on the autoregulation of cerebral blood flow. Contrary to hypercapnia, where the response is dominated by CrCP, hypocapnia shows an initial depression of cerebral autoregulation, followed by improvements controlled by changes in RAP.

Modeling of Cerebral Blood Flow Autoregulation Using Mathematical Control Theory

A mathematical model of cerebral blood flow in the form of a dynamical system is studied. The cerebral blood flow autoregulation modeling problem is treated as a nonlinear control problem and the potential and applicability of the nonlinear control theory techniques are analyzed in this respect. It is shown that the cerebral hemodynamics model in question is differentially flat. Then, the integrator backstepping approach combined with barrier Lyapunov functions is applied to construct the control laws that recover the cerebral autoregulation performance of a healthy human. Simulation results confirm the good performance and flexibility of the suggested cerebral blood flow autoregulation design. The conducted research should enrich our understanding of the mathematics behind the cerebral blood flow autoregulation mechanisms and medical treatments to compensate for impaired cerebral autoregulation, e.g., in preterm infants.

Autoregulation of Cerebral Blood Flow During 3-h Continuous Cardiopulmonary Resuscitation at 27°C.

Introduction: Victims of accidental hypothermia in hypothermic cardiac arrest (HCA) may survive with favorable neurologic outcome if early and continuous prehospital cardiopulmonary resuscitation (CPR) is started and continued during evacuation and transport. The efficacy of cerebral autoregulation during hypothermic CPR is largely unknown and is aim of the present experiment. Methods: Anesthetized pigs (n = 8) were surface cooled to HCA at 27°C before 3 h continuous CPR. Central hemodynamics, cerebral O2 delivery (DO2) and uptake (VO2), cerebral blood flow (CBF), and cerebral perfusion pressure (CPP) were determined before cooling, at 32°C and at 27°C, then at 15 min after the start of CPR, and hourly thereafter. To estimate cerebral autoregulation, the static autoregulatory index (sARI), and the CBF/VO2 ratio were determined. Results: After the initial 15-min period of CPR at 27°C, cardiac output (CO) and mean arterial pressure (MAP) were reduced significantly when compared to corresponding values during spontaneous circulation at 27°C (−66.7% and −44.4%, respectively), and remained reduced during the subsequent 3-h period of CPR. During the first 2-h period of CPR at 27°C, blood flow in five different brain areas remained unchanged when compared to the level during spontaneous circulation at 27°C, but after 3 h of CPR blood flow in 2 of the 5 areas was significantly reduced. Cooling to 27°C reduced cerebral DO2 by 67.3% and VO2 by 84.4%. Cerebral VO2 was significantly reduced first after 3 h of CPR. Cerebral DO2 remained unaltered compared to corresponding levels measured during spontaneous circulation at 27°C. Cerebral autoregulation was preserved (sARI > 0.4), at least during the first 2 h of CPR. Interestingly, the CBF/VO2 ratio during spontaneous circulation at 27°C indicated the presence of an affluent cerebral DO2, whereas after CPR, the CBF/VO2 ratio returned to the level of spontaneous circulation at 38°C. Conclusion: Despite a reduced CO, continuous CPR for 3 h at 27°C provided sufficient cerebral DO2 to maintain aerobic metabolism and to preserve cerebral autoregulation during the first 2-h period of CPR. This new information supports early start and continued CPR in accidental hypothermia patients during rescue and transportation for in hospital rewarming.

Cerebral Blood Flow Autoregulation in Offspring From Experimentally Preeclamptic Rats and the Effect of Age.

Preeclampsia is a hypertensive disorder of pregnancy that causes significant, long term cardiovascular effects for both the mother and offspring. A previous study demonstrated that middle cerebral arteries in offspring from an experimental rat model of preeclampsia were smaller, stiffer, and did not enlarge over the course of maturation, suggesting potential hemodynamic alterations in these offspring. Here we investigated the effect of experimental preeclampsia on cerebral blood flow autoregulation in juvenile and adult offspring that were born from normal pregnant or experimentally preeclamptic rats. Relative cerebral blood flow was measured using laser Doppler flowmetry, and cerebral blood flow autoregulation curves were constructed by raising blood pressure and controlled hemorrhage to lower blood pressure. Immunohistochemistry was used to assess middle cerebral artery size. Heart rate and blood pressure were measured in awake adult offspring using implanted radiotelemetry. Serum epinephrine was measured using enzyme-linked immunosorbent assay. Offspring from both groups showed maturation of cerebral blood flow autoregulation as offspring aged from juvenile to adulthood as demonstrated by the wider autoregulatory plateau. Experimental preeclampsia did not affect cerebral blood flow autoregulation in juvenile offspring, and it had no effect on cerebral blood flow autoregulation in adult offspring over the lower range of blood pressures. However, experimental preeclampsia caused a right shift in the upper range of blood pressures in adult offspring (compared to normal pregnant). Structurally, middle cerebral arteries from normal pregnant offspring demonstrated growth with aging, while middle cerebral arteries from experimentally preeclamptic offspring did not, and by adulthood normal pregnant offspring had significantly larger middle cerebral arteries. Middle cerebral artery lumen diameters did not significantly change as offspring aged. Serum epinephrine was elevated in juvenile experimentally preeclamptic offspring, and a greater degree of hemorrhage was required to induce hypotension, suggesting increased sympathetic activity. Finally, despite no evidence of increased sympathetic activity, adult experimentally preeclamptic offspring were found to have persistently higher heart rate. These results demonstrate a significant effect of experimental preeclampsia on the upper range of autoregulation and cerebrovascular structure in juvenile and adult offspring that could have an important influence on brain perfusion under conditions of hypo and/or hypertension.

THE EFFECT OF RENAL DENERVATION ON CEREBRAL BLOOD FLOW IN DIABETIC PATIENTS WITH RESISTANT HYPERTENSION

Objective: Long-term and persistent increase in blood pressure (BP) leads to vascular remodeling, which deteriorates cerebral blood flow. The combination of hypertension (HTN) with diabetes mellitus (DM) accelerates the vascular damage and impairs the cerebral blood flow autoregulation, which may be accompanied by an uncompensated decrease in cerebral perfusion in response to a decrease in BP. Renal denervation (RDN) leads to a rapid and sustained decrease in BP, therefore the aim of this study was to assess of changes in cerebral blood flow in patients with resistant HTN (RHTN) and type 2 DM at 6 month after the intervention. Design and method: Evaluation of cerebral blood flow was performed in 21 patients with RHTN and type 2 DM, who were included in single-arm prospective interventional studies (protocol numbers NCT01499810 and NCT02667912 on ClinicalTrials.gov) (mean age 61.4 ± 7.6 years, mean office (systolic/diastolic) BP (SBP/DBP) 167.1 ± 19.4/85.6 ± 15.9 mmHg, HbA1c 7.1 ± 1.3%, 8 men (32%), 19 pts (91%) had atherosclerosis of internal carotid arteries (ICA) with mean values of stenosis 22.2 ± 9.7%). All patients were undergone to ambulatory 24-hour BP, Doppler high-resolution ultrasound of ICA and middle cerebral arteries (MCA) at baseline and 6 month follow-up. The patients were instructed not to change their medication regimen during the study. Results: There was a significant decrease in mean 24-hour BP (systolic/diastolic) (-12.6/-7.3 mmHg, p &lt; 0.05). At the same time, there was no deterioration in blood flow of ICA and MCA at 6 months after RDN. Conclusions: Our data indicate that the significant decrease in BP after RDN does not lead to deterioration of cerebral blood flow and therefore indicates the safety of this procedure for the brain in patients with RHTN with type 2 DM.

Sex differences in cerebrovascular dysfunction and hypertension in offspring of hypertensive pregnant rats

BACKGROUNDOffspring from preeclamptic women have a greater risk of hypertension and cerebrovascular dysfunction later in life. One of the major contributors of cerebrovascular dysfunction is impaired cerebral blood flow (CBF) autoregulation. In the USA, 1 in 25 pregnancies are preeclamptic. Preeclampsia, as defined as new‐onset hypertension during pregnancy, is an inflammatory condition characterized by elevated interleukin 17 (IL‐17), mitochondrial reactive oxygen species (mtROS), mitochondrial dysfunction (mt‐Dys), and intrauterine growth restriction (IUGR). Preliminary work from our laboratory demonstrates that offspring from preeclamptic rats have sex differences. Males have hypertension and a greater impairment of CBF autoregulation, while females have no change in blood pressure with impaired CBF autoregulation. The exact mechanisms for the sex differences in cerebrovascular dysfunction and hypertension is unknown and is the focus of this study. We hypothesize that changes in cerebral mt‐Dys, cerebral mtROS, and circulating IL‐17 contributes to the sex differences in hypertension and cerebrovascular dysfunction in male and female offspring from preeclamptic rats.METHODSIn this study, we compared male and female offspring from normal pregnant and preeclamptic Sprague Dawley rats. All offspring were divided into controls (CON) and IUGR by sex. Hypertensive male and non‐hypertensive female offspring’s with impaired CBF autoregulation were examined at 17 weeks of age for changes in cerebral mitochondrial electron transport chain (ETC) protein complexes, cerebral manganese superoxide dismutase (MnSOD), and circulating IL‐17.RESULTSFemale CON (151±5% IU/Protein/male CON) and IUGR (149±8 %IU/Protein/male CON) offspring have increased MnSOD compared to CON (100±7 %IU/Protein/male CON) and IUGR (122±4 %IU/Protein/male CON) males (p&lt;0.05). No changes in female ETC protein complexes between IUGR and CON. Male IUGR have a decrease in complex II (71±5 vs. 100±8 %IU/Protein/male CON, p&lt;0.05) and V (57±2 vs. 100±10 %IU/Protein/male CON, p&lt;0.05) ETC proteins, and elevated IL‐17 (944±370 vs. 412±115 pg/mL, ns) compared to CON males.CONCLUSIONMale IUGR offspring have mt‐Dys and elevated IL‐17, which may contribute to hypertension and a greater impairment in CBF autoregulation. Female IUGR offspring may be protected due to an increase in mitochondrial antioxidants. In summary, studying the dimorphic sex differences in the mechanisms of hypertension and cerebrovascular dysfunction in offspring of preeclamptic women, may improve the offspring’s risk of hypertension, cardiovascular disease, stroke, and cognitive dysfunction later in life.

Impaired mechanotransduction of small cerebral arteries after traumatic brain injury. Role of arachidonic acid pathway dysfunction

BackgroundHealthy functioning of the brain requires a precise autoregulation of cerebral blood flow, which in part is achieved by the pressure and flow sensitive vasomotor mechanisms. Traumatic brain injury (TBI) frequently occurs worldwide, resulting in brain diseases with high morbidity and mortality. Here, we hypothesized that TBI impairs the autoregulatory mechanisms, namely the pressure‐ and flow‐induced constrictions of isolated rat middle cerebral arteries (MCAs).MethodsTBI was induced in anaesthetized rats by weight drop model, and then MCAs were isolated and transferred into a pressure‐flow chamber. Changes in internal diameter in response to hemodynamic forces and vasoactive drugs were measured by a video‐microscopy.ResultsIn MCAs from intact rats, increases in pressure‐, flow‐ and pressure + flow elicited constrictions (max.: ‐26 ± 1.7; ‐26 ± 1.9; and ‐52 ± 2.8 µm, p &lt; 0.05). Flow‐induced constrictions were significantly reduced by HET0016, an inhibitor of cytochrome P450 4A (CYP450 4A) or in the presence of thromboxane‐prostanoid (TP receptor) antagonist SQ 29,548. Both responses were significantly reduced after TBI. Arachidonic acid, (AA, 10−7 M), and CYP450 4A metabolite 20‐hydroxyeicosatetraenoic acid (20‐HETE) elicited constrictions of intact MCA (‐26 ± 2.3% and ‐31 ± 3.6%), which were significantly reduced after TBI (to ‐11 ± 1.3% and ‐16 ±2.5%). The TP receptor agonist U46619 (10−7 M) elicited substantial constrictions of MCA from intact rats (‐21 ± 3.3%), which were also significantly reduced, after TBI (to ‐16 ± 2.4%).ConclusionsBoth pressure and flow‐induced constrictions of MCA were impaired by traumatic brain injury, likely due to the reduced ability of cytochrome P450 4A to convert arachidonic acid to constrictor prostaglandins (cPGs) and the mitigated sensitivity of thromboxane‐prostanoid receptors to cPGs. We propose that the impairment of autoregulatory vasomotor mechanisms contribute to the TBI‐induced human brain diseases, such as headache, disruption of blood brain barrier, brain edema, Alzheimer‐type diseases and vascular dementia.

Effect of Hyperinsulinemia on Cerebral Autoregulation and Myogenic Control of Cerebral Blood Flow in Healthy Young Adults

ObjectiveHyperinsulinemia has marked vasodilatory effects within the skeletal muscle vasculature in healthy young adults; however, the magnitude of insulin‐stimulated cerebrovascular vasodilation is less clear. Differences between circulations may be due to a greater importance of the cerebral circulation to maintain a constant level of blood flow (i.e., cerebral autoregulation) during hyperinsulinemia. We hypothesized cerebral autoregulation would increase during hyperinsulinemia. Autoregulatory mechanisms, such as myogenic control, play important roles in mediating cerebral vasomotor responses. Thus, we further sought to examine the contribution of the myogenic mechanism to the control of cerebral blood flow during hyperinsulinemia.MethodsMiddle cerebral artery blood velocity (MCAv) and femoral artery blood velocity (FAV) were measured with Doppler ultrasound and femoral artery blood flow (FBF) was calculated in 17 healthy adults (11M/6F, 28±2 yrs, 24±1 kg/m2) at baseline and following a hyperinsulinemic (40 mU/m2body surface area/min), euglycemic infusion. Finger plethysmography was used to assess mean blood pressure (MBP). Normalized transfer function gain between changes in MBP and MCAv were estimated in the 0.02‐0.07 Hz (very low frequency, VLF) and 0.07–0.20 Hz (low frequency, LF) ranges using the Welch method. Interactions between MBP and MCAv or FAV were determined using cross‐correlation analyses.ResultsIntravenous insulin infusion increased plasma insulin concentrations (6±1 to 50±3 μIU/mL, p&lt;0.01) with blood glucose maintained at baseline levels (p=0.33). There was a significant increase in FBF (121±15 to 151±19 mL/min, p=0.03) during hyperinsulinemia, with no change in MCAv (61±4 to 59±4 cm/s, p=0.28) or MBP (86±2 to 89±2 mmHg, p=0.10). There was no effect of hyperinsulinemia on normalized transfer function gain in the VLF (p=0.25) or LF ranges (p=0.46). Hyperinsulinemia had no effect on the association between MBP and MCAv (p=0.15) or FAV (p=0.82).ConclusionsHyperinsulinemia in healthy young adults elicits peripheral vasodilation, but no change in MCAv. Contrary to our hypothesis, the sensitivity of the cerebrovascular circulation to changes in MBP (i.e., cerebral autoregulation) is not altered during systemic hyperinsulinemia in healthy adults. Furthermore, the contribution of the myogenic mechanism to the control of blood flow in the peripheral and cerebral circulations is unaffected by hyperinsulinemia. Whether these results translate to disease states (e.g., diabetes) and the implications for cerebrovascular health warrant further exploration.

Contribution of Beta‐amyloid Accumulation to Cerebral Hypoperfusion in Alzheimer's Disease

Alzheimer’s Disease (AD) is an emerging global health care crisis. However, underlying mechanisms are not understood well enough to translate to precision medicine. There is increasing evidence suggesting that AD is associated with brain hypoperfusion. However, it is unclear whether amyloid‐beta (Aβ) accumulation is a cause or consequence of AD, and how it contributes to cerebral hypoperfusion. The present study examined if Aβ accumulation induces cerebral hypoperfusion in AD by affecting cerebral vascular function via both anterograde (arteriole‐to‐capillary) and retrograde (capillary‐to‐arteriole) pathways in the TgF344‐AD rat model of Alzheimer's disease. We first confirmed that AD rats displayed hippocampal‐based cognitive dysfunction at 6 months of age using an eight‐arm water maze. We then found that AD rats exhibited impaired myogenic response (MR) of middle cerebral arteries (MCAs) and penetrating and parenchymal arterioles (PAs) two months earlier than the onset of cognitive deficits using a Living System pressure myograph. AD rats displayed poor surface and deep cortical cerebral blood flow (CBF) autoregulation recorded by laser Doppler flowmetry, and reduced functional hyperemic response induced by whisker stimulation. Moreover, cell contractile capabilities, detected by collagen gel based‐cell contraction kit, were reduced in Aβ‐treated cerebral VSMCs isolated from F344 rats, similar as seen in VSMCs isolated from AD rats. Furthermore, we found that the productions of reactive oxygen species (ROS) and mitochondrial superoxide in cerebral VSMCs isolated from AD rats were elevated using DHE staining and MitoSOX staining. Moreover, AD cells exhibited reduced mitochondrial respiration and ATP production detected by the Seahorse Cell Mito Stress Test kit. AD cerebral VSMCs also exhibited disrupted actin cytoskeleton and contractile units utilizing immunohistochemistry. Oxidative stress, mitochondrial dysfunction, and actin cytoskeleton disorganization are all factors that are associated with the reduced contractile capabilities of cerebral VSMCs mediated MR and CBF autoregulation. In other studies, we found that capillary endothelial cell‐derived inward rectifier potassium (Kir2.1) activity, which is responsible for retrograde CBF regulation, was reduced in the brain of AD rats using Western blot. PAs with capillaries isolated from AD rats dilated to a lesser degree than WT rats in response to moderately elevated extracellular K+ (10 mM) applied to capillaries. Inhibition of Kir2.1 channels with ML133 diminished the vasodilatory response to a greater extent in WT rats. These findings indicate that Aβ accumulation is associated with cerebral hypoperfusion in AD by affecting cerebral vascular function via both anterograde and retrograde pathways and provide novel insight into the vascular contribution to AD.

Machine Learning Models and Statistical Complexity to Analyze the Effects of Posture on Cerebral Hemodynamics.

The mechanism of cerebral blood flow autoregulation can be of great importance in diagnosing and controlling a diversity of cerebrovascular pathologies such as vascular dementia, brain injury, and neurodegenerative diseases. To assess it, there are several methods that use changing postures, such as sit-stand or squat-stand maneuvers. However, the evaluation of the dynamic cerebral blood flow autoregulation (dCA) in these postures has not been adequately studied using more complex models, such as non-linear ones. Moreover, dCA can be considered part of a more complex mechanism called cerebral hemodynamics, where others (CO2 reactivity and neurovascular-coupling) that affect cerebral blood flow (BF) are included. In this work, we analyzed postural influences using non-linear machine learning models of dCA and studied characteristics of cerebral hemodynamics under statistical complexity using eighteen young adult subjects, aged 27 ± 6.29 years, who took the systemic or arterial blood pressure (BP) and cerebral blood flow velocity (BFV) for five minutes in three different postures: stand, sit, and lay. With models of a Support Vector Machine (SVM) through time, we used an AutoRegulatory Index (ARI) to compare the dCA in different postures. Using wavelet entropy, we estimated the statistical complexity of BFV for three postures. Repeated measures ANOVA showed that only the complexity of lay-sit had significant differences.