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PURPOSE - To evaluate how flow territory asymmetry and/or the distribution of blood through collateral pathways may adversely affect the brain's ability to respond to age-related changes in brain function. These patterns have been investigated in cerebrovascular disease; however, here we evaluated how flow-territory asymmetry related to memory generally in older adults.
MATERIALS AND METHODS - A multi-faceted MRI protocol, including vessel-encoded arterial spin labeling capable of flow territory mapping, was applied to assess how flow territory asymmetry; memory performance (CERAD-Immediate Recall); cortical cerebral blood flow (CBF), white matter lesion (WML) count, and cortical gray matter volume were related in older healthy control volunteers (HC; n = 15; age = 64.5 ± 7 years) and age-matched mild cognitive impairment volunteers (MCI; n = 7; age = 62.7 ± 3.7 years).
RESULTS - An inverse relationship was found between memory performance and flow territory asymmetry in HC volunteers (P = 0.04), which reversed in MCI volunteers (P = 0.04). No relationship was found between memory performance and cortical tissue volume in either group (P > 0.05). Group-level differences for HC volunteers performing above versus below average on CERAD-I were observed for flow territory asymmetry (P < 0.02) and cortical volume (P < 0.05) only.
CONCLUSION - Findings suggest that flow territory asymmetry may correlate more sensitively with memory performance than CBF, atrophy and WML count in older adults.
Copyright © 2013 Wiley Periodicals, Inc.
RATIONALE - The spatial distribution of blood flow in the hearts of genetically modified mice is a phenotype of interest because derangements in blood flow may precede detectable changes in organ function. However, quantifying the regional distribution of blood flow within organs of mice is challenging because of the small organ volume and the high resolution required to observe spatial differences in flow. Traditional microsphere methods in which the numbers of microspheres per region are indirectly estimated from radioactive counts or extracted fluorescence have been limited to larger organs for 2 reasons; to ensure statistical confidence in the measured flow per region and to be able to physically dissect the organ to acquire spatial information.
OBJECTIVE - To develop methods to quantify and statistically compare the spatial distribution of blood flow within organs of mice.
METHODS AND RESULTS - We developed and validated statistical methods to compare blood flow between regions and with the same regions over time using 15-µm fluorescent microspheres. We then tested this approach by injecting fluorescent microspheres into isolated perfused mice hearts, determining the spatial location of every microsphere in the hearts, and then visualizing regional flow patterns. We demonstrated application of these statistical and visualizing methods in a coronary artery ligation model in mice.
CONCLUSIONS - These new methods provide tools to investigate the spatial and temporal changes in blood flow within organs of mice at a much higher spatial resolution than currently available by other methods.
Crustacean cardioactive peptide (CCAP) is a highly conserved arthropod neurohormone that is involved in ecdysis, hormone release and the modulation of muscle contractions. Here, we determined the CCAP gene structure in the malaria mosquito Anopheles gambiae, assessed the developmental expression of CCAP and its receptor and determined the role that CCAP plays in regulating mosquito cardiac function. RACE sequencing revealed that the A. gambiae CCAP gene encodes a neuropeptide that shares 100% amino acid identity with all sequenced CCAP peptides, with the exception of Daphnia pulex. Quantitative RT-PCR showed that expression of CCAP and the CCAP receptor displays a bimodal distribution, with peak mRNA levels in second instar larvae and pupae. Injection of CCAP revealed that augmenting hemocoelic CCAP levels in adult mosquitoes increases the anterograde and retrograde heart contraction rates by up to 28%, and increases intracardiac hemolymph flow velocities by up to 33%. Partial CCAP knockdown by RNAi had the opposite effect, decreasing the mosquito heart rate by 6%. Quantitative RT-PCR experiments showed that CCAP mRNA is enriched in the head region, and immunohistochemical experiments in newly eclosed mosquitoes detected CCAP in abdominal neurons and projections, some of which innervated the heart, but failed to detect CCAP in the abdomens of older mosquitoes. Instead, in older mosquitoes CCAP was detected in the pars lateralis, the subesophageal ganglion and the corpora cardiaca. In conclusion, CCAP has a potent effect on mosquito circulatory physiology, and thus heart physiology in this dipteran insect is under partial neuronal control.
INTRODUCTION - Women with fibromyalgia (FM) have symptoms of increased muscular fatigue and reduced exercise tolerance, which may be associated with alterations in muscle microcirculation and oxygen metabolism. This study used near-infrared diffuse optical spectroscopies to noninvasively evaluate muscle blood flow, blood oxygenation and oxygen metabolism during leg fatiguing exercise and during arm arterial cuff occlusion in post-menopausal women with and without FM.
METHODS - Fourteen women with FM and twenty-three well-matched healthy controls participated in this study. For the fatiguing exercise protocol, the subject was instructed to perform 6 sets of 12 isometric contractions of knee extensor muscles with intensity steadily increasing from 20 to 70% maximal voluntary isometric contraction (MVIC). For the cuff occlusion protocol, forearm arterial blood flow was occluded via a tourniquet on the upper arm for 3 minutes. Leg or arm muscle hemodynamics, including relative blood flow (rBF), oxy- and deoxy-hemoglobin concentration ([HbO2] and [Hb]), total hemoglobin concentration (THC) and blood oxygen saturation (StO2), were continuously monitored throughout protocols using a custom-built hybrid diffuse optical instrument that combined a commercial near-infrared oximeter for tissue oxygenation measurements and a custom-designed diffuse correlation spectroscopy (DCS) flowmeter for tissue blood flow measurements. Relative oxygen extraction fraction (rOEF) and oxygen consumption rate (rVO2) were calculated from the measured blood flow and oxygenation data. Post-manipulation (fatiguing exercise or cuff occlusion) recovery in muscle hemodynamics was characterized by the recovery half-time, a time interval from the end of manipulation to the time that tissue hemodynamics reached a half-maximal value.
RESULTS - Subjects with FM had similar hemodynamic and metabolic response/recovery patterns as healthy controls during exercise and during arterial occlusion. However, tissue rOEF during exercise in subjects with FM was significantly lower than in healthy controls, and the half-times of oxygenation recovery (Δ[HbO2] and Δ[Hb]) were significantly longer following fatiguing exercise and cuff occlusion.
CONCLUSIONS - Our results suggest an alteration of muscle oxygen utilization in the FM population. This study demonstrates the potential of using combined diffuse optical spectroscopies (i.e., NIRS/DCS) to comprehensively evaluate tissue oxygen and flow kinetics in skeletal muscle.
Techniques for measuring cerebral perfusion require accurate longitudinal relaxation (T1) of blood, an MRI parameter that is field dependent. T1 of arterial and venous human blood was measured at 7T using three different sources - pathology laboratory, blood bank and in vivo. The T1 of venous blood was measured from sealed samples from a pathology lab and in vivo. Samples from a blood bank were oxygenated and mixed to obtain different physiological concentrations of hematocrit and oxygenation. T1 relaxation times were estimated using a three-point fit to a simple inversion recovery equation. At 37°C, the T1 of blood at arterial pO2 was 2.29±0.1s and 2.07±0.12 at venous pO2. The in vivo T1 of venous blood, in three subjects, was slightly longer at 2.45±0.11s. T1 of arterial and venous blood at 7T was measured and found to be significantly different. The T1 values were longer in vivo than in vitro. While the exact cause for the discrepancy is unknown, the additives in the blood samples, degradation during experiment, oxygenation differences, and the non-stagnant nature of blood in vivo could be potential contributors to the lower values of T1 in the venous samples.
Copyright © 2013 Elsevier Inc. All rights reserved.
Despite the importance of blood flow on brainstem control of respiratory and autonomic function, little is known about regional cerebral blood flow (CBF) during changes in arterial blood gases.We quantified: (1) anterior and posterior CBF and reactivity through a wide range of steady-state changes in the partial pressures of CO2 (PaCO2) and O2 (PaO2) in arterial blood, and (2) determined if the internal carotid artery (ICA) and vertebral artery (VA) change diameter through the same range.We used near-concurrent vascular ultrasound measures of flow through the ICA and VA, and blood velocity in their downstream arteries (the middle (MCA) and posterior (PCA) cerebral arteries). Part A (n =16) examined iso-oxic changes in PaCO2, consisting of three hypocapnic stages (PaCO2 =∼15, ∼20 and ∼30 mmHg) and four hypercapnic stages (PaCO2 =∼50, ∼55, ∼60 and ∼65 mmHg). In Part B (n =10), during isocapnia, PaO2 was decreased to ∼60, ∼44, and ∼35 mmHg and increased to ∼320 mmHg and ∼430 mmHg. Stages lasted ∼15 min. Intra-arterial pressure was measured continuously; arterial blood gases were sampled at the end of each stage. There were three principal findings. (1) Regional reactivity: the VA reactivity to hypocapnia was larger than the ICA, MCA and PCA; hypercapnic reactivity was similar.With profound hypoxia (35 mmHg) the relative increase in VA flow was 50% greater than the other vessels. (2) Neck vessel diameters: changes in diameter (∼25%) of the ICA was positively related to changes in PaCO2 (R2, 0.63±0.26; P<0.05); VA diameter was unaltered in response to changed PaCO2 but yielded a diameter increase of +9% with severe hypoxia. (3) Intra- vs. extra-cerebral measures: MCA and PCA blood velocities yielded smaller reactivities and estimates of flow than VA and ICA flow. The findings respectively indicate: (1) disparate blood flow regulation to the brainstem and cortex; (2) cerebrovascular resistance is not solely modulated at the level of the arteriolar pial vessels; and (3) transcranial Doppler ultrasound may underestimate measurements of CBF during extreme hypoxia and/or hypercapnia.
Mean and pulsatile components of hemodynamic load are related to cardiovascular disease. Vascular growth factors play a fundamental role in vascular remodeling. The links between growth factors and hemodynamic load components are not well described. In 3496 participants from the Framingham Heart Study third generation cohort (mean age: 40±9 years; 52% women), we related 4 tonometry-derived measures of central arterial load (carotid femoral pulse wave velocity and forward pressure wave, mean arterial pressure, and the global reflection coefficient) to circulating concentrations of angiopoietin 2, its soluble receptor; vascular endothelial growth factor, its soluble receptor; hepatocyte growth factor; insulin-like growth factor 1; and its binding protein 3. Using multivariable linear regression models, adjusted for standard cardiovascular risk factors, serum insulin-like growth factor 1 concentrations were negatively associated with carotid femoral pulse wave velocity, mean arterial pressure, and reflection coefficient (P≤0.01 for all), whereas serum vascular endothelial growth factor levels were positively associated with carotid femoral pulse wave velocity and mean arterial pressure (P<0.04). Serum insulin-like growth factor binding protein 3 and soluble angiopoietin 2 receptor levels were positively related to mean arterial pressure and to forward pressure wave, respectively (P<0.05). In our cross-sectional study of a large community-based sample, circulating vascular growth factor levels were related to measures of mean and pulsatile hemodynamic load in a pattern consistent with the known physiological effects of insulin-like growth factor 1 and vascular endothelial growth factor.
Previous studies show that transient increases in both blood flow and magnetic resonance image signal intensity (SI) occur in human muscle after brief, single contractions, and that the SI increases are threefold larger in physically active compared with sedentary subjects. This study examined the relationship between these transient changes by measuring anterior tibial artery flow (Doppler ultrasound), anterior muscle SI (3T, one-shot echo-planar images, TR/TE = 1,000/35), and muscle blood volume and hemoglobin saturation [near-infrared spectroscopy (NIRS)] in the same subjects after 1-s-duration maximum isometric ankle dorsiflexion contractions. Arterial flow increased to a peak 5.9 ± 0.7-fold above rest (SE, n = 11, range 2.6-10.2) within 7 s and muscle SI increased to a peak 2.7 ± 0.6% (range 0.0-6.0%) above rest within 12 s after the contractions. The peak postcontractile SI change was significantly correlated with both peak postcontractile flow (r = 0.61, n = 11) and with subject activity level (r = 0.63, n = 10) estimated from 7-day accelerometer recordings. In a subset of 7 subjects in which NIRS data acquisition was successful, the peak magnitude of the postcontractile SI change agreed well with SI calculated from the NIRS blood volume and saturation changes (r = 0.80, slope = 1.02, intercept = 0.16), confirming the blood-oxygenation-level-dependent (BOLD) mechanism underlying the SI change. The magnitudes of postcontractile changes in blood saturation and SI were reproduced by a simple one-compartment muscle vascular model that incorporated the observed pattern of postcontractile flow, and which assumed muscle O(2) consumption peaks within 2 s after a brief contraction. The results show that muscle postcontractile BOLD SI changes depend critically on the balance between O(2) delivery and O(2) consumption, both of which can be altered by chronic physical activity.
BIIB 513 and EMD 85131 are selective inhibitors of the Na+/H+ exchanger-1 (NHE-1) that are benzoylguanidine derivatives of the clinically employed diuretic amiloride. Prior studies have suggested a role for NHE-1 activity in platelet activation and aggregation using amiloride or its non- benzoylguanidines derivatives. However, the concentrations employed in these prior studies were at levels known to exert effects on other ion transport systems besides the NHE-1. Therefore, the purpose of this study was to examine the effects of more selective NHE-1 inhibitors, BIIB 513 and EMD 85131, on platelet aggregation and in vivo cyclic flow following arterial injury. BIIB 513 and EMD 85131 effects on ex vivo canine and human platelet aggregation in response to various agents was monitored via platelet aggregation. For analysis of in vivo thrombus formation, a femoral artery crush injury model was employed and a flow meter was used to monitor the effect of BIIB 513 on cyclic blood flow. Treatment of either canine or human platelets with up to 1 mM of BIIB 513 had no effect on aggregation induced by platelet activating factor (PAF), thrombin receptor activator peptide (TRAP), or adenosine diphosphate (ADP). Additionally, the structurally related compound EMD 85131 at up to 1 mM failed to inhibit TRAP induced platelet aggregation. In vivo administration of up to 9 mg/kg of BIIB 513 intravenously failed to affect cyclic flow in a canine model of femoral artery injury. These data demonstrate that the specific and selective NHE-1 inhibitors BIIB 513 or EMD 85131 have no effect on ex vivo platelet aggregation or in vivo cyclic flow following arterial injury.
The relative oxygen saturation of hemoglobin and the rate of perfusion are important physiological quantities, particularly in organs such as skeletal muscle, in which oxygen delivery and use are tightly coupled. The purpose of this study was to demonstrate the image-based calculation of the relative oxygen saturation of hemoglobin and quantification of perfusion in skeletal muscle during isometric contractions. This was accomplished by establishing an empirical relationship between the rate of radiofrequency-reversible dephasing and near-infrared spectroscopy-observed oxyhemoglobin saturation (relative oxygen saturation of hemoglobin) under conditions of arterial occlusion and constant blood volume. A calibration curve was generated and used to calculate the relative oxygen saturation of hemoglobin from radiofrequency-reversible dephasing changes measured during contraction. Twelve young healthy subjects underwent 300 s of arterial occlusion and performed isometric contractions of the dorsiflexors at 30% of maximal contraction for 120 s. Muscle perfusion was quantified during contraction by arterial spin labeling and measures of muscle T(1). Comparisons between the relative oxygen saturation of hemoglobin values predicted from radiofrequency-reversible dephasing and that measured by near-infrared spectroscopy revealed no differences between methods (P = 0.760). Muscle perfusion reached a value of 34.7 mL 100 g(-1) min(-1) during contraction. These measurements hold future promise in measuring muscle oxygen consumption in healthy and diseased skeletal muscle.
2010 Wiley-Liss, Inc.