Autoregulation Of Flow Research Articles

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.

Abstract 34: Diminished Contractile Capability In Cerebral Vascular Smooth Muscle Cells In The TgF344-AD Rat Model Of Alzheimer's Disease

We recently reported that cerebral vascular dysfunction leads to impaired autoregulation of cerebral blood flow (CBF), neurovascular coupling (NVC), and blood-brain barrier (BBB) leakage. The present study examined if cerebral vascular dysfunction precedes cognitive impairment in the TgF344-AD (AD) rat model of Alzheimer's disease. In the present study, we confirmed that the AD rats develop learning and memory deficits beginning at 24-week of age using an eight-arm water maze. AD rats (n = 11) took a longer time to escape and displayed more errors than age-matched wildtype (WT) rats (n = 6). We also completed a longitudinal comparison of the myogenic response (MR) of the middle cerebral artery (MCA) and found that the MR was similar in AD and WT rats at 8- to 12-week of age when perfusion pressure was increased from 40 to 180 mmHg. However, the MR was significantly reduced in 16-week old AD rats (n = 6) as the inner diameter of the MCA only decreased by 8.2 ± 2.4% when perfusion pressure was increased from 40 to 180 mmHg compared with 14.5% ± 2.0% in age-matched WT rats (n = 6). The impaired MR of the MCA was exacerbated in AD rats with aging. Autoregulation of CBF AD rats (n = 4) in vivo was impaired in the surface and deep cortex at 24-week of age compared to age-matched WT rats (n = 4). Furthermore, we found the contractile capability of the cerebral vascular smooth muscle cells (VSMCs) isolated from AD rats (n = 4) was significantly reduced compared with WT rats (n = 4), detected by the reduction in size of 15.7 ± 0.9% vs. 25.4 ± 1.0% using a collagen gel-based assay kit. These results provide evidence that cerebral VSMC dysfunction, impaired MR, and autoregulation of CBF precede the development of memory and learning deficits in the TgF344-AD rat model. However, the underlying mechanisms for the loss of VSMCs contractility in this AD model overexpressing mutant human amyloid precursor protein ( APPsw ) and presenilin 1 ( PS1ΔE9 ) genes remain to be determined. Nevertheless, these results provide novel insight into the vascular contribution to AD.

Microcirculatory bed in reperfused flaps: modern possibilities for the correction of hemodynamic disorders (part III)

The paper presents an analysis of the literature data concerning the autoregulation of tissue blood flow in free axial flaps. Autoregulation of microcirculation is an extremely important physiological phenomenon that ensures the stability of peripheral blood circulation and adequate metabolism in organs and tissues, regardless of fluctuations in systolic blood pressure in the range of 80-160 mm Hg. The types of sludge and their origin are described. Technologies of elimination of erythrocyte aggregates (sludge) by using dextrans of different molecular weights and pentoxifylline are discussed. Controlling the duration of primary ischemia, maintaining adequate perfusion pressure in the replants of the limbs and in free flaps, as well as reducing the peripheral vascular resistance in them, will make it possible to level the disturbances in the autoregulation of microcirculation in the reperfused tissues, ensuring the stability of capillary pressure.

Abstract WP458: Effect of Olmesartan / Azelnidipine Combination Tablets on Ambulatory Blood Pressure and Cognitive Function in the Post-Stroke Patients

Background and aims: In patients with severe hypertension, or history of stroke, the lower limit of cerebral blood flow (CBF) autoregulation is shifted to a higher blood pressure (BP) than in healthy subjects. The aim of this study was to compare the effects of olmesartan/azelnidipine combination (OLM/AZ) vs high-dose of olmesartan on ambulatory blood pressure (ABPM), cognitive function, and rehabilitation outcome in the post-stroke patients with hypertension. Methods: A total of 36 patients, 20 men and 16 women, aged 58-72 years, with sitting diastolic BP >90mmHg and systolic BP >140mmHg were eligible for participation in the present study. We randomly assigned 36 patients to either the OLM/AZ group or high-dose olmesartan group for 12 weeks. At the end of a 2-week wash-out period and after 12 weeks of active treatment, 24-h noninvasive ambulatory BP monitoring (ABPM) was performed, and cognitive function was evaluated through neuropsychological testing. In addition, rehabilitation outcome measurements were also collected during study period. Results: Both treatments significantly reduced ambulatory BP. However, the OLM/AZ produced a greater reduction in 24-h, day-time and night time ABPM values. High-dose olmesartan did not induce significant changes in any of the cognitive function test scores, whereas at 12 weeks OLM/AZ significantly improved the neuropsychological test score (Digid span test, Token test, Digital symbol test, Trail making test part A and B) (p< 0.01). Patients treated with OLM/AZ showed effective rates of improvement in hand (38.9%), upper extremities (55.6%) and lower extremities (72.2%), measured by Brunnstrom stage; these improvements were significantly different from those in high-dose olmesartan group for the total (P< 0.05) scores. Conclusions: These results suggest that in hypertensive post-stroke patients treatment with OLM/AZ produces a slightly greater reduction in ambulatory BP than high-dose olmesartan, and unlike this latter, improves some of the components of cognitive function, particularly psychomotor speed, attention and mentation. Our results suggest that OLM/AZ may improve cognitive function and rehabilitation outcome in hypertensive stroke patients in whom CBF autoregulation is impaired.

1094 A Study of the Characteristics of Hepatic Blood Flow Ex Vivo Using a Cardio-Emulation Arterial Pump Perfusion System

INTRODUCTION: The CAVESWave® organ perfusion system provides cardio-emulated systolic and diastolic pressure waves to the hepatic artery HA, as well as variable pressure to the portal vein PV, replicating in vivo hepatic perfusion conditions. This allows a unique opportunity to study the interaction between HA and PV flow patterns in the autoregulation of hepatic venous HV outflow. The conditions exclude artefacts generated from cardiac pulsations. METHODS: Ten freshly procured porcine livers were perfused on the CAVESWave® system for four hours. At the two-hour midpoint, the temperature of the perfusate was increased from 15°C to 30°C and the flow variation associated with the temperature change documented. Flow rates in the HA, PV and HV were captured using flow sensors in the perfusion circuit. The distribution of perfusate was documented using Infra-red thermography (IRT), which measured surface liver temperature to a depth of 3 mm. RESULTS: Both IRT and the flow sensor measurements demonstrated stable, steady-state values after target perfusate temperatures were reached. Pulsatile waves reflecting cardio-emulated systolic and diastolic pressure waves were present in both HA (Figure 1) and PV (Figure 2). The only possible source of pulsations in the PV was transmission from the HA. Pulsatile waves were significantly attenuated or absent in the HV (Figure 3). The flow at 150 C in the HA (630.1 + 239.9; ml/min M + SD) was significantly greater than in the PV (316.2 + 90; P < 0.004). As expected, flow in the HV (904 + 292.8) approximated the sum of HA and PV flow. Increasing the temperature of the perfusate to 300 C significantly increased flow in all three circuits: HA (761.5 + 220; P < 0.014); PV flow (375.0 + 139.1; P < 0.007) and HV (1016.1 + 302.4; P < 0.007). The flow in the HA increased by 116.75 + 140.9 ml/min; the increase was 56.7 + 80.3 in the PV and 111.8 + 100.8 in the HV. The time for this change was significantly shorter for HA (18.9 + 13.5 mins) than for PV (26.4 + 18.1; P < 0.05). The significance of the delay in the PV flow is unclear. It likely reflects greater capacitance within the venous circuit. PV flow was inversely correlated with HA flow at all temperatures, correlation coefficient, -0.26. This suggests compensation or buffering between the arterial and venous circuits. CONCLUSION: Autoregulation of flow in response to temperature change is maintained in the ex vivo perfused liver. The inverse correlation between HA and PV flow, suggests a Hepatic Artery Buffering Response, HABR in this model.

Abstract P3016: High Glucose Induced Diabetic Dementia is Mediated by Mitochondria Dysfunction

Diabetes is an important risk factor for dementia. We previously reported that cognitive dysfunction is associated with impaired cerebral vascular function in our diabetic rat model. Hyperglycemia contributes to endothelial dysfunction by increasing the production of reactive oxygen species (ROS). However, the role of changes in mitochondrial dynamics in altering autoregulation of cerebral blood flow and the loss of cognitive function in diabetes is unknown. The present study examined the myogenic response of middle cerebral arteries (MCAs), as well as mitochondrial function and fission in primary vascular smooth muscle cells (VSMCs) maintained in normal glucose (NG) or high glucose (HG). ROS production assessed by DHE staining was significantly increased in freshly isolated MCAs of diabetic rats (55.77 ± 11.27 arbitrary unit (a.u.), n=4) vs. Sprague Dawley (SD, 15.46 ± 1.92 a.u. n=4) rats. In addition, HG-treated primary VSMCs from SD rats exhibited more mitochondrial ROS than controls, as detected by MitoSOX. The myogenic response of MCAs was impaired in 3-month old diabetic rats compared to age-matched controls. Treatment with superoxide dismutase (150 U/mL) restored the myogenic response. Mitochondrial respiration was decreased in HG-treated (91.1 ± 7.6 pmol/min/mg/ml, n=6) vs. NG-treated (153.2 ± 6.3 pmol/min/mg/ml, n=9) VSMCs as measured by a Seahorse XF e 24 analyzer. Treatment with HG also caused mitochondrial depolarization as assessed by staining with JC-1. The length of mitochondria in high glucose-treated VSMCs was significantly less than in control VSMCs (HG: 5.66 ± 0.14 μm vs. Control: 11.70 ± 0.23 μm, n=3, 100) as seen by Tomm20 immunostaining. In addition, levels of OPA1 were significantly lower and MFF levels were higher in HG-treated cells compared to controls, indicating an increase in mitochondrial fission and a decrease in fusion in the HG-treated VSMCs. This was associated with decreased levels of p-AMPK in HG-treated vs. control VSMCs. These results demonstrate that the impaired myogenic response in cerebral arteries in diabetes is associated with impaired mitochondrial dysfunction and elevated production of ROS via the p-AMPK/MFF signaling pathway, which may contribute to the loss of cognitive function in diabetes.

Abstract 145: Knockout of Gamma- Adducin Impairs Vascular Function in Renal Arterioles in Association With Htn-Induced Renal Injury

The FHH rat is a genetic model of hypertension that develops proteinuria, glomerulosclerosis, and chronic kidney disease. However, the genetic causes are unknown. We have previously identified an inactivating mutation of Add3 in FHH rats in association with reduced ADD3 expression and impaired myogenic reactivity of the renal arterioles. The vascular impairment and renal dysfunction were restored with knock-in of wild type (WT) Add3 in FHH rats. The present study examined whether knockout (KO) of Add3 in normal WT rats impairs the myogenic response of renal afferent arteriole (Af-art), interlobular arteriole (IA), arcuate arteriole (AA), renal blood flow (RBF) autoregulation, and if the reduction of expression of ADD3 promotes hypertension-induced renal dysfunction. Blood pressure was similar in 24-week old Add3 KO vs. WT rats, and after induction of 3 weeks of DOCA-salt-hypertension in these strains. Proteinuria was significantly higher in both normotensive and hypertensive Add3 KO compared with WT rats. KO of Add3 abolished the myogenic response of Af-art compared with WT rats. Similarly, the diameters of IA and AA increased 46 % (from 55.28 ± 2.95 um to 80.39 ± 0.41 um) and 25 % (from 92.57 ± 9.51 um to 115.49 ± 11.68 um) respectively in Add3 KO rats (n=4), while they remained unchanged in WT (n=5). Moreover, KO of Add3 abolished the RBF autoregulation compared with WT rats. These results indicate that KO of Add3 plays an important role to reduce the myogenic reactivity of renal arterioles and RBF autoregulation, and enhances renal damage after the onset of hypertension.

No effect of the angiotensin receptor blocker candesartan on cerebrovascular autoregulation in rats during very high and low sodium intake.

Autoregulation of cerebral blood flow (CBF) denotes that CBF is constant despite fluctuation of blood pressure within wide limits. Inhibition of the renin–angiotensin system (RAS) is known to decrease the lower and upper limits of CBF autoregulation. We have previously shown that this includes inhibition by the angiotensin receptor blocker (ARB) candesartan. In the present study we investigated the influence of the ARB candesartan on the lower limit of CBF autoregulation in two groups of Sprague-Dawley rats, on high (4.0% Na+) and low (0.004% Na+) sodium diet, respectively. Control animals were given the same diet, but no ARB. CBF was studied with the laser Doppler method. Blood pressure was lowered by controlled bleeding. Results revealed that both high and low sodium diet with low and high renin levels respectively block the influence of candesartan on CBF autoregulation. This was expected in rats on a high salt diet with a low renin level, but unexpected in rats with a low salt intake with a high renin level.

Prostacyclin Affects the Relation Between Brain Interstitial Glycerol and Cerebrovascular Pressure Reactivity in Severe Traumatic Brain Injury

BackgroundCerebral injury may alter the autoregulation of cerebral blood flow. One index for describing cerebrovascular state is the pressure reactivity (PR). Little is known of whether PR is associated with measures of brain metabolism and indicators of ischemia and cell damage. The aim of this investigation was to explore whether increased interstitial levels of glycerol, a marker of cell membrane damage, are associated with PR, and if prostacyclin, a membrane stabilizer and regulator of the microcirculation, may affect this association in a beneficial way.Materials and MethodsPatients suffering severe traumatic brain injury (sTBI) were treated according to an intracranial pressure (ICP)-targeted therapy based on the Lund concept and randomized to an add-on treatment with prostacyclin or placebo. Inclusion criteria were verified blunt head trauma, Glasgow Coma Score ≤ 8, age 15–70 years, and a first measured cerebral perfusion pressure of ≥ 10 mmHg. Multimodal monitoring was applied. A brain microdialysis catheter was placed on the worst affected side, close to the penumbra zone. Mean (glycerolmean) and maximal glycerol (glycerolmax) during the 96-h sampling period were calculated. The mean PR was calculated as the ICP/mean arterial pressure (MAP) regression coefficient based on hourly mean ICP and MAP during the first 96 h.ResultsOf the 48 included patients, 45 had valid glycerol and PR measurements available. PR was higher in the placebo group as compared to the prostacyclin group (p = 0.0164). There was a positive correlation between PR and the glycerolmean (ρ = 0.503, p = 0.01) and glycerolmax (ρ = 0.490, p = 0.015) levels in the placebo group only.ConclusionsPR is correlated to the glycerol level in patients suffering from sTBI, a relationship that is not seen in the group treated with prostacyclin. Glycerol has been associated with membrane degradation and may support glycerol as a biomarker for vascular endothelial breakdown. Such a breakdown may impair the regulation of cerebrovascular PR.

STRATIFICATION OF NEPHROCEREBRAL AND CARDIOVASCULAR RISK IN CHRONIC GLOMERULONEPHRITIS (LITERATURE REVIEW)

This article analyzes the literature data concerning the origin and progression of cerebrovascular and cardiac diseases in renal dysfunction. Cardiovascular diseases and chronic kidney disease have common “traditional” risk factors, while the population growth in patients with renal impairment is currently mainly due to secondary renal damage in socially important diseases such as obesity, hypertension, atherosclerosis, type 2 diabetes, ischemic heart disease and chronic heart failure. The presented data of scientific researches testify to the direct correlation correlation between the decrease of the renal function and the increased risk of cardioand cerebrovascular diseases and death, irrespective of other risk factors. Obesity and associated biological substrates are independent risk factors for persistent impairment of kidney function and an increase in the body mass index causes direct damage to the kidneys, due to the disrupted synthesis of fat cytokines by various cytokines with nephrotoxic action, and also mediated — by inducing the development of diabetes mellitus 2 type and arterial hypertension, which are the most frequent risk factors for chronic kidney disease and cardiovascular diseases. The presented data on the role of endothelial dysfunction in impaired renal function, which contributes to the formation of atherosclerosis, and the increase in the severity of the atherosclerotic process contributes to an increase in the sever ity of renal failure. Literature data on the value of the heart rate are also presented. The increase in the heart rate can lead to atherosclerotic densification of the arteries, which is associated with an increase in the rate of spread of the pulse wave with a violation of the mechanisms of autoregulation of the blood flow in the brain and kidneys.

Abstract 056: Knockout of Dual-Specificity Protein Phosphatase 5 Protects Against Hypertension Induced Chronic Kidney Disease

Dual-specificity protein phosphatase 5 (Dusp5) is a member of serine-threonine phosphatase family that regulates intracellular signal transduction by dephosphorylating ERK1/2. We previously generated Dusp5 zinc-finger knockout (KO) rats and found that KO of Dusp5 enhances myogenic response of middle cerebral artery and autoregulation of cerebral blood flow. This study investigated whether Dusp5 KO also improves renal hemodynamics and protects against hypertension-induced chronic kidney disease (CKD). Renal tissue expression of Dusp5 was decreased and levels of phosphorylated ERK1/2 (p-ERK1/2) and p-PKC enhanced in KO rats. Blood pressure increased similarly to 180 mmHg in both WT and Dusp5 KO rats treated with DOCA/salt. KO of Dusp5 enhanced autoregulation of renal blood flow (RBF increased by 12.1 ± 4.1% vs. 32.7 ± 4.7% when MAP increased from 100 to 180 mmHg, p<0.05) and reduced renal vascular remodeling compared with WT rats (0.64±0.03 vs. 0.94±0.06 wall-to-lumen ratio, p<0.05). Improvement in renal hemodynamics in hypertensive Dusp5 KO vs. WT rats was associated with decreased proteinuria (226.71 ± 23.82 vs. 337.62 ± 30.41 mg/day, p<0.05) and protein cast formation in the renal corticomedullary region (1.01 ± 0.17% vs. 2.4 ± 0.51%, p<0.05). The degree of glomerular injury was reduced (2.22 ± 0.04 vs. 3.12 ± 0.04, p<0.05) and nephrin expression was greater in hypertensive Dusp5 KO rats vs. WT rats. Hypertension-induced renal fibrosis was attenuated in Dusp5 KO rats (5.32 ± 0.6% vs. 9.90 ± 0.7%, p<0.01) in association with decreased MCP-1 expression, reduced ED-1 + macrophage infiltration, down-regulated TGF-β1 expression, and attenuated fibrosis-related epithelial-mesenchymal transition (EMT) in the kidney (decreased expression of α-SMA and vimentin, and increased expression of E-cadherin). In conclusion, these results indicate that KO of Dusp5 protects against hypertension-induced proteinuria and renal fibrosis by enhancing renal hemodynamics and reducing vascular remodeling, glomerular injury, macrophage infiltration, TGF-β1 expression and EMT in the kidney. Thus, targeting Dusp5 may offer a novel approach for treating or preventing hypertension-induced CKD.

Abstract 027: Hyperglycemia and Oxidative Stress Contribute to Impaired CerebralAutoregulation in Association With Dementia in Diabetes

Diabetes mellitus is characterized by hyperglycemia and is well established to associate with oxidative stress. The present study examines whether impaired myogenic response of middle cerebral artery MCA and autoregulation of cerebral blood flow (CBF) in our T2DN diabetic rats is due to hyperglycemia and oxidative stress induced actin cytoskeleton reorganization, and if this contributes to dementia. We identified that both young (4-month) and older (18-month) T2DN diabetic rats exhibit impaired pressure-induced myogenic response in isolated MCAs. Forced dilatation occurred at pressures above 140 mmHg in MCAs isolated from elderly T2DN rats with mild hypertension but not controls. Cortical blood flow measured by laser Doppler flowmetry rose by 137 ± 15% and 36 ± 5%, respectively, in T2DN and SD rats when MAP was increased from 100 to 180 mmHg. Autoregulation of CBF was shifted to lower pressures in elderly T2DN rats and they exhibited breakthrough at pressures above 140 mmHg. The F-Actin distribution area was significantly reduced in the vascular smooth muscle cells (VSMCs) freshly isolated from MCAs of T2DN rats compared with normal Sprague Dawley (SD) rats. The F-actin was disrupted similarly in VSMCs treated with high glucose or H 2 O 2 . Superoxide production is elevated in fresh isolated middle cerebral arteries (MCA) in T2DN diabetic rats compared to normal SD rats. We also found increased production of superoxide in primary VSMCs isolated from normal SD rats cultured in high glucose condition or freshly isolated from diabetic rats. T2DN rats exhibited neurons death in the hippocampus and cortex. Elderly T2DN rats showed memory disabilities. These results indicate that hyperglycemia induced elevated superoxide production causes actin cytoskeleton reorganization in cerebral VSMCs of diabetic T2DN rats, which may contribute to impaired cerebral vascular function, neurodegeneration and cognitive impairment.

Cerebrovascular Regulation and Sleep Apnea

The brain relies on a constant blood flow to match nutrient delivery with the local metabolic demands. Cerebral blood flow (CBF) autoregulation is particularly important under hypoxic conditions such as obstructive sleep apnea (OSA) to prevent brain hypoxia. We aim to give a brief overview of cerebral blood flow regulation and evaluate the current evidence for cerebrovascular sensitivity to hypoxia, the capacity of cerebral arteries to respond to reduced oxygen supply during normal sleep and OSA. In clinical conditions such as intermittent hypoxia as well as untreated OSA, cerebrovascular system becomes less reactive to CO2 and impaired autoregulation, and makes the brain more susceptible to ischemic stroke. Results from studies in patients with OSA indicate worse clinical outcome including higher chance of cerebrovascular events, impaired functional capacity and cognition. Early treatment of OSA with continuous positive airway pressure (CPAP), resulting in reversal of cerebral autoregulation.

Role of Circulatory Hypoxia in the Development of Retinopathy of Prematurity

Purpose: to study the pathogenesis of retinopathy of prematurity.Patients and methods.642 preterm infants born before 30 weeks gestation with the weight less 1500 grams were examined. The study included: indirect ophthalmoscopy; digital retinoscopy; calibrometry of retinal vessels; dopplerography; analysis of partial pressure of oxygen and carbon dioxide in the capillary blood. Results. The first phase of retinopathy of prematurity (ROP) occurred due to the immaturity of the mechanisms of autoregulation of the blood flow and the inadequate reaction of immature retinal vessels to oxygen. It was established: the less gestational age of a child, so there are less mechanisms of autoregulation of hemodynamics. The perverse reaction of autoregulation leads to pronounced arteriospasm, increasing the zone of hypoxia, and triggering pathological angiogenesis. In morphologically immature children, arteriospasm of retina vessels is more often detected, and narrowing degree of vessels is higher. Arteriospasm is defined in 82 % of children born at the age of gestation from 25 to 27 weeks, in 67 % — at a period from 28 to 29 weeks, in 54 % — from 30 to 32 weeks. In children with ROP in the preclinical period of the disease, retinal angiospasm is noted at values of pO2 in capillary blood less then 40 mm Hg or exceeding the upper limit of the norm values of pCO2 (the norm values of pO2 are 40–60 mmHg, pCO2 are 35–45 mm Hg). Autoregulation of blood flow is immature and inadequate. In the group before 30 weeks of post-conceptual gestational age without development of ROP, a spastic reaction of retinal arteries was revealed at the background of subnormal pO2 values in capillary blood. Biochemical autoregulation of blood flow is still immature. But from the 30 week of post-conceptual gestational age arteriospasm of retina is formed at values of pO2 of 45 mm Hg or higher (p < 0.05). The normal caliber of retinal arteries in children without development of ROP is revealed at the background of mean values of pO2 below 45 mm Hg and values of pCO2 below 42 mm Hg before 30 weeks of post-conceptual gestational age, and above 45 mm Hg from the 30th week of post-conceptual gestational age. In children without ROP from 30 weeks of gestational age biochemical autoregulation of blood flow functions. It is important the degree of an angiospasm for the development of ROP. Dopplerographic critical index of blood flow disturbance in the ophthalmic and anterior cerebral arteries has been established — the index of resistance (IR) exceeding 0.8. It is a precursor of the development of ROP and pathological angiogenesis. In the group of children with ROP, the IR of the anterior cerebral artery is 0.84 ± 0.02 (in av.). The IR of the ocular artery was 0.83 ± 0.03. In higher index (up to 0.9–1), the process in the eye was more active.

Effect of Tafluprost and Tafloprost/Timolol on the Optic Nerve Head, Peripapillary and Macular Microcirculation According to OCT-Angiography

Relevance. The ability of antiglaucoma drugs to improve ocular hemoperfusion is an important aspect of their action. Tafluprost is the first prostaglandin analogue (PA) containing no preservatives. The efficacy and safety of tafluprost, as well as tafluprost/timolol fixed combination (FC), was demonstrated in randomized multicenter trials. However, there is no literature on the effect of tafluprost and it’s FC on peripapillary and macular blood flow.Purpose. to assess the effect of tafluprost and tafloprost/timolol on the microcirculation in the optic nerve head, peripapillary area and macula in patients with primary open-angle glaucoma (POAG) according to OCT angiography (OCT-A).Patients and methods. OCT-A was performed in dynamics with an interval of a week in 36 patients (36 eyes) with a newly diagnosed initial stage of POAG, 12 received tafluprost, 12 — tafluprost/timolol FCs, 12 eyes represented control group (no drugs were prescribed). The change in IOP, mean perfusion pressure (PP) of the eye, and vessel density (VD) inside the optic nerve head (ONH) (inside disc), as well as in the peripapillary retina and macula were evaluated by comparing paired repeated observations using the median growth analysis.Results. In the tafluprost group there was a decrease in IOP by 19.4 % and an increase in PP by 8.7 % from the reference level. In the tafluprost/timolol group, these figures were 43 % and 30.1 %, respectively. OCT-A values did not change reliably, except for VD inside Disc: in the tafluprost group, the median growth was –2.28 (p = 0.02), for the tafluprost/ timolol group — –1.82 (p = 0.03). These changes were obtained in 11 patients of 12 in each group under treatment. In patients who did not receive treatment, all indicators remained unchanged.Conclusions. The results of this study showed a decrease in the density of the microcirculatory bed in the ONH in patients with initial glaucoma against the background of the tafluprost and tafluprost/timolol treatment, which can be explained by the restoration of autoregulation of the ocular blood flow in conditions of pronounced hypotensive drugs effect.

Extreme Hyperglycemia Causes Vascular Hypoperfusion at Optic Nerve Head in Diabetic Patients (DM)

Background: OCT angiography (OCTA) and laser speckle flowgraphy (LSFG) are novel and noninvasive imaging modalities which could evaluate fundus blood flow quantitatively. However, the role of OCTA and LSFG as diagnostic tools has not been widely investigated. Previous reports indicated that NO, reduced by hyperglycemia, exerts a key role for the autoregulation of retinal blood flow. We designed this study to evaluate the retinal blood flow by OCTA and LSFG in hyperglycemic DM. Method: 10 patients with extreme hyperglycemia at our outpatient clinic (FPG>250mg/dL, or casual PG>350mg/dL, age 58±5, 7 males, HbA1c 11.1±0.5%) and 32 healthy volunteers (age 48±2, 17 males) were included. Vascular density was calculated using OCTA. LSFG measured relative blood velocity (mean blur rate: MBR) in the optic nerve head (ONH). MBR-A (the mean of all area), MBR-V (the vessel mean) and MBR-T (the tissue mean) were analyzed. Result: OCTA revealed no difference between two groups in the vascular density at macula (47.37±1.14% for DM and 47.44±0.67% for NDM) and a tendency of decrease in the diabetic vascular density at ONH (40.14±3.56% for DM and 42.48±1.25% for NDM) without statistical significance. With LSFG, MBR-A and MBR-T did not exhibit significant differences, while MBR-V significantly decreased in DM compared to the healthy (42.85±2.05% for DM, 49.25±1.34% for NDM, p = 0.025). Discussion: Our results demonstrated that vascular hypoperfusion at ONH was associated with extreme hyperglycemia in DM with tendency to decrease in vascular density. It is generally supposed that the retinal blood flow decreases in DM and acute hyperglycemia. In DM actually presented physiological changes in the retina. Besides, there is a report that autoregulation of blood flow in the ONH is disrupted in diabetic rabbits, as well as in healthy ones with uncoupled gap junctions. It is possible that the similar mechanisms are involved in ONH blood flow decrease observed in this study. Disclosure T. Mitsumatsu: None. F. Yagi: None. Y. Kondo: None. A. Anraku: None. S. Okahata: None. K. Sakamoto: None. G. Tomita: None. T. Shiba: Speaker's Bureau; Self; Shionogi & Co., Ltd., Pfizer Inc., Merck Sharp & Dohme Corp., Kowa Company, Ltd., Daiichi Sankyo Company, Limited.

Abstract TP403: Effect of Hypercapnia on Dynamic Cerebral Autoregulation During Transient Hypotension

Background and Purpose: Hypercapnia leads to increased cerebral blood flow and impaired autoregulation by changing the cerebrovascular resistance (CVR). We studied the effect of hypercapnia on critical closing pressure (CCP) and resistance area product (RAP) which effectively reflects the role of vascular tone and resistance respectively in altering cerebrovascular resistance and maintaining cerebral autoregulation during transient hypotension. Methods: –26 healthy subjects had continuous cerebral blood flow velocity and arterial blood pressure recording. Transient hypotension was induced by sudden release of thigh cuff after suprasystolic inflation for 3 minutes. 3 trials of thigh cuff maneuver were performed with normal breathing, 3% CO 2 breathing and 5% CO 2 breathing. CO 2 inhalation was given for last 45 seconds of thigh cuff maneuver and continued for 90 seconds after release. Autoregulatory Index (ARI) was calculated for each trial with Tieck’s model. CCP and RAP were computed for 10 seconds’ window each at 1 minute after inflation (Baseline), immediately before release (Prerelease) and immediately after release (Release) of inflated thigh cuff. Results: –ARI values decreased significantly (p < 0.0001) from 5.46 ± 1.47 to 2.0 ± 1.35 and 1.63 ± 1.09 during 3% CO 2 and 5% CO 2 trial respectively. No significant changes were observed in CCP value during thigh cuff release with all three trials. RAP significantly dropped from prerelease value after thigh cuff release in all 3 trials. Drop in RAP attenuated during hypercapnia trial and had significant (p < 0.0001) difference between RAP Prerelease – Release ( d RAP) for Normal breathing (0.20 ± 0.12) and 3% and 5 % CO 2 trials (0.089 ± 0.090, 0.081 ± 0.093). d RAP was significantly correlated (Spearmen r = 0.42, p = 0.0004) with the ARI values where higher d RAP had better autoregulation. Conclusion: – Cerebral autoregulation during transient hypotension acts by changing vascular resistance i.e. RAP without any effect on vascular tone i.e. CCP and had been suggested to reflect myogenic component of autoregulation to blood pressure changes. We concluded that hypercapnia leads to impairment of myogenic component of autoregulation during transient arterial blood pressure changes as suggested by attenuated d RAP.

Abstract 153: The Preserve Trial: Intensive Blood Pressure Lowering and Cerebral Blood Flow in Small Vessel Disease

Background and Aims: In patients with severe cerebral small vessel disease (SVD), in whom both cerebral blood flow and cerebral autoregulation are reduced, intensive BP lowering might reduce cerebral blood flow (CBF) and increase the rate of white matter hyperintensity (WMH) progression. In an RCT we determined the effect of intensive BP lowering on CBF in lacunar stroke with confluent WMH. Method: In the PRESERVE trial Perfusion sub-study, patients from 2 sites with MRI confirmed symptomatic lacunar infarct and confluent WMH were randomised to “normal” (systolic=130-140mmHg, N=33) versus “intensive” (systolic=<125mmHg, N=29) BP targets. CBF was determined using arterial spin labelling; the primary end point was change in global CBF between baseline and 3 months. Linear regression was performed comparing change in CBF against change in BP. Analyses controlled for site. Results: Mean(SD) systolic BP reduced by 8(12) and 27(17)mmHg in the standard/intensive groups, respectively (difference between groups p <0.001) with achieved BP of 141(13) and 126(10) mmHg respectively. Baseline global CBF was 32(10) and 31(10)ml/min/100g in the standard/intensive groups. There was no difference in change in global CBF between treatment arms: standard, mean(SD) (ml/min/100g)= -0.46 (9.39); intensive, 0.73 (8.62), p =0.63. No differences were observed when analysis examined grey or white matter only, or was confined to those achieving target BP. Change in CBF did not have a significant association with change in systolic or diastolic BP. Conclusion: Intensive BP lowering did not reduce CBF in severe SVD characterised by lacunar stroke and confluent WMH. This suggests intensive CBF reduction is unlikely to accelerate WMH progression.

Abstract 067: Genetic Complementation Establishes That a K572Q Mutation in Gamma-adducin Plays a Causal Role in Renal Microvascular Dysfunction in FHH and MNS Rats

The Fawn-Hooded hypertensive (FHH) rat is a genetic model of hypertension-induced renal disease. However, the causal genes and pathways involved are unclear. We previously reported that the transfer of a small region in Chr. 1 of Brown-Norway (BN) rats which contains 15 genes, including gamma-Adducin (Add3), into the FHH background restores renal microvascular function and attenuates the development of proteinuria in FHH rats. Our further work identified a K572Q mutation in Add3 in FHH rats as a potential candidate variant in the pathogenesis of renal disease. The present study examined the role of Add3 in the impaired myogenic response of the afferent artery (Af-art) and autoregulation of renal blood flow (RBF) using transgenic and KO rats. RBF increased by 21.5 ± 3.0% in SD. Add3 KO rats (n=7) when mean arterial pressure (MAP) was increased from 100 to 150 mmHg. In contrast, RBF only increased by 3.5 ± 0.9% in wildtype SD rats (n=13). The diameters of the renal Af-art decreased by 12.9 ± 0.8% in SD rats when perfusion pressure was increased from 60 to 120 mmHg, but it increased in SD.Add3 KO rats. The myogenic response of the Af-art in FHH rats was markedly impaired and increased by 8 ± 1.2% when the pressure was increased by from 60 to120 mmHg. The myogenic response was restored, and the diameters of the Af-art decreased by 12 ± 0.7% and 7 ± 1.0% in FHH. 1 BN congenic rats (n=27) and FHH.Add3 transgenic rats that express wt-Add3. RBF increased by 35.1 ± 3.0% when MAP was increased from 100 to 150 mmHg in FHH rats (n=15) versus 7.5 ± 1.7% and 6.0+ 1.3% in FHH.1 BN or a F1 cross of FHH and FHH.1 BN rats (n=8) and FHH.Add3 transgenic rats. The myogenic response of Af-art and autoregulation of RBF were also impaired in MNS rats (n=6) that carry the same K572Q mutation in Add3 as FHH rats. These phenotypes were complemented in a F1 cross of FHH and MNS rats (n=7), but the myogenic response and autoregulation of RBF were restored in an F1 cross of FHH and FHH.1 BN rats with one copy of wt-Add3. These results indicate that the recessive K572Q mutation of Add3 in FHH and MNS rats plays a causal role in renal microvascular dysfunction, which may contribute to the development of chronic kidney disease induced by hypertension in these models.

Phenomenology and Clinical Relevance of the Flammer Syndrome

The Flammer syndrome (FS) describes the phenotype of people with a predisposition for an altered reaction of the blood vessels to stimuli like coldness, emotional stress or high altitude. Frequent symptoms are: cold hands and/or feet, low blood pressure, prolonged sleep onset time, reduced feeling of thirst, increased sensitivity to odour, pain, vibration and certain drugs. SF subjects are often ambitious and successful but also perfectionistic and sometimes brooding. Frequent signs are: altered gene expression, prolonged blood flow cessation in nailfold capillaroscopy after cold provocation, reduced autoregulation of ocular blood flow, and reduced vasodilation after stimulation with flickering light. Retinal venous pressure is on the average higher and retinal astrocytes are more often activated. FS occurs more often in females than in males, in thin than in obese subjects, in young than in old people, in graduates than in blue collar workers, in subjects with indoor than outdoor jobs. Associated diseases are: normal tension glaucoma, occlusion of ocular vessels, retinitis pigmentosa, multiple sclerosis, tinnitus or even sudden hearing loss.