Heterogeneity Of Blood Flow Research Articles

Hepatic blood flow distribution: consideration of gravity, liver surface, and norepinephrine on regional heterogeneity

Blood flow distribution within the livers of cats and dogs was assessed using 15-microns microspheres injected into the hepatic artery and portal vein. Representative vertical core samples (n = 11-18) were taken from the thickest part of each liver. Heterogeneity was assessed in several ways. The difference in total flow to different lobes was greater in dogs than in cats, and in dogs, those lobes with highest portal venous flow had lowest hepatic arterial flow. Overall flow variance was very high in both species, with adjacent surface samples in a single lobe showing variance of 15-22% for both vessels. The ratio of highest to lowest flow within core samples averaged 2.1-3.4 for both vessels in both species. The hepatic arterial flow was highest to the surface 2 mm of the liver. Portal flow most often (31% of all samples) showed a pattern of highest flow to the top, graduating down to lowest flow to the bottom (dorsal side) of the vertical cores. However, this pattern appeared much more frequently in the most ventral liver lobes and very seldom in the lobes lying beneath the liver mass. Norepinephrine reduced heterogeneity. Hepatic arterial occlusion for 10 min produced minor and inconsistent reduction of heterogeneity. Rotating cats from back to front and again to back disrupted patterns of distribution but not in a way that could be interpreted as due to effects of gravity. Flow patterns changed with time. The heterogeneity of perfusion appears to be under dynamic and multiple interacting forces.

Effect of flow reduction on coronary blood flow heterogeneity.

The purpose of this study was to test the hypothesis that under reduced flow conditions, spatial heterogeneity (segment-to-segment variability) of myocardial blood flow would be inversely proportional to the rate of perfusion and that vasoconstriction would alter this relationship in anesthetized open-chest dogs. A carotid-left circumflex coronary artery shunt was created. Coronary blood flow determinations employed the radioactive microsphere technique. Fifty tissue samples were obtained from the affected left ventricle, including subepicardial and subendocardial samples. The coefficient of variation (CV = 100 x SD/mean), an index of spatial heterogeneity, was computed. Flows were obtained under three separate conditions: control, a 50% flow reduction in the circumflex artery, and vasopressin infusion, in which the administered dose reduced circumflex artery flow by 50%. The within-animal CV increased from a control of 18 +/- 9 to 45 +/- 25 with partial occlusion and 46 +/- 18 with vasopressin. No significant differences in CV were found between the two reduced flow conditions. A significant linear relationship between CV and mean coronary flow was found (r = 0.51, P < 0.001) over the entire range of flows studied (CV = -0.34*flow + 50.91) for control, 50% occlusion, and vasopressin treatment. The correlation was significantly improved (r = 0.69) using the equation CV = (1319.06/flow) + 4.44. Thus, the relative heterogeneity of coronary blood flow increased with reductions in coronary blood flow, regardless of the means of flow reduction.

Effect of adenosine on coronary blood flow and its use as a diagnostic test for coronary artery disease

Myocardial perfusion imaging during adenosine induced coronary hyperaemia is a highly sensitive method for diagnosing coronary artery disease. Most perfusion defects reflect heterogeneity in coronary blood flow in the territories of normal and diseased coronary arteries. Myocardial ischaemia can occur, however, due to subendocardial hypoperfusion and coronary artery steal. Evidence for myocardial ischaemia is more difficult to document in clinical than in experimental studies, and includes abnormalities in the ST segment, wall motion, haemodynamic variables, metabolism, and coronary blood flow responses. Using these indices, myocardial ischaemia may occur in some patients with coronary artery disease but it is not a prerequisite for the development of perfusion abnormalities and for the diagnosis of coronary artery during adenosine stress testing.

Gas exchange and regional redistribution of pulmonary blood flow during resuscitation of acute pulmonary bead embolization

Acute pulmonary embolism (PE) was induced by injecting polystyrene beads into the right atrium of 18 anaesthetized dogs. The animals were resuscitated for 45 min with either Ringer's Lactate (RL), norepinephrine (NE) or isoproterenol (IP). The multiple inert gas elimination technique (MIGET) was used to estimate the distributions of ventilation ( V dot ) and blood flow ( Q dot ) to different V dot Q dot regions. Measurements were made prior to embolism, 10 min after PE and during the resuscitative phase. Microspheres with three different radioactive labels were also used to mark blood flow distribution to different lung regions in these three phases. The data show that cardiac output decreases after PE, while perfusion to shunt and low V dot Q dot regions increases. Pulmonary blood flow heterogeneity, estimated from the MIGET data, is also increased after PE. Resuscitation by RL or NE consistently increases cardiac output but IP does so inconsistently and is associated with systemic hypotension. All three methods of resuscitation cause increases in perfusion to the shunt and low V dot Q dot regions but no change in perfusion heterogeneity in the remaining V dot Q dot units. Increases in regional blood flow during resuscitation occur preferentially in the less embolized areas. The concomitant increase in perfusion to shunt and low V dot Q dot units suggests that increased perfusion to these less embolized regions results in further hypoxemia despite improvement in cardiac output.

Methodological error and spatial variability of organ blood flow measurements using radiolabeled microspheres

The quantitative analysis of the spatial variability of organ blood flow by means of radiolabeled microspheres (MS) requires that the methodological variability ("error") of the technique (RDmeth.) is known in each individual organ. Therefore, RDmeth. was quantified (eight to nine nuclides) in 6941 tissue samples from 13 organs of three anesthetized dogs, and the relative importance of errors originating from both the stochastic nature of MS distribution (RDtheo.) and the process of quantitation of MS radioactivity (RDcounting) was assessed under varying conditions (high/low specific MS activity (SAMS); inaccurate separation of gamma spectra; large sample size). At "minimized" methodological error (experiment 2), RDmeth. of samples trapping approximately 375 MS/nuclide was 5.8% and only slightly exceeded RDtheo. (5%). RDmeth. varied in the range 2.7-7.8% in individual organs and contributed little (3.5%) to the organs' observed spatial variability of flow. In contrast, RDmeth.--due to increased RDcounting--considerably exceeded RDtheo. when SAMS was low (experiment 3), overlap of two nuclides' main photopeaks was critical (experiment 1), or counting geometry was inappropriate (pulmonary tissue samples). At the same time, the contribution of RDmeth. to spatial flow variability rose to 7.9% (experiment 3), 26.9% (experiment 1), and 15-23% (lungs). Completely artifactual measurements, as indicated by an extremely high RDmeth. of sample flow, were rarely observed (less than 0.1%). In general, our data suggest that blood flow can be measured reproducibly and with low methodological error using up to 8 nuclides, RDmeth. does not essentially contribute to the observed spatial variability of organ blood flow, and, hence, organ flow variability may be accurately quantified using the MS technique. However, if sources of error as indicated above are present, the practice of using RDtheo. as a measure of RDmeth. (thereby neglecting RDcounting) may notably underestimate true MS error and result in an overestimation of spatial heterogeneity of organ blood flow. RDmeth., therefore, should be quantified separately in each region of interest prior to the onset of a new study.

Regional distributions of blood flow and tissue uptake rates of vitamin B12 and albumin within single rabbit skeletal muscles

The mechanism underlying the marked regional variations in blood flow within single skeletal muscles has not been identified. The present investigation was prompted by previous data pointing to a regional distribution of the number of perfused vessels as one possible determinant for the heterogeneous perfusion pattern. We examined this possibility by assessing the regional tissue uptake rates of vitamin B12 and albumin assuming that these are related to the number of perfused vessels. This is the first study that has included simultaneous measurements of regional blood flow and of regional tissue uptake rates of vitamin B12 and albumin within single skeletal muscles in the intact animal. The microsphere method was adopted to measure regional blood flow in 0.25 g muscle regions in awake and in anaesthetized rabbits. Various tracers were used to assess the regional distributions of tissue uptake rates and of vascular and interstitial volumes. Albeit displaying a marked regional heterogeneity, neither the tissue uptake rate of vitamin B12 nor that of albumin were correlated to regional blood flow (P less than 0.05) at rest (awake or anaesthetized rabbits) or during exercise hyperaemia (anaesthetized). At rest, but not during exercise, the distributions of regional tissue uptake rates of the two tracers showed a striking bimodal pattern. Vascular and interstitial volumes showed minimal interregional variations. The lack of correlation between regional blood flow and tissue uptake rates and the minute interregional variation in vascular volume, argue against variations in the number of perfused vessels as the explanation for the regional heterogeneity in blood flow.

Local blood flow and glucose uptake within resting and exercising rabbit skeletal muscle

A marked regional heterogeneity in blood flow at the level of large arterioles or small arteries is present within single skeletal muscles both in the dog and in the rabbit. A corresponding regional heterogeneity in metabolic activity could explain this phenomenon. We studied the correlation between regional blood flow and regional uptake of glucose within single muscles. Blood flow and glucose uptake were measured using the microsphere technique and the deoxyglucose method, respectively. Blood flow and glucose uptake were determined in 0.25-g regions from resting and stimulated muscles in anesthetized rabbits. Under resting conditions, no correlation between regional blood flow and regional glucose uptake (P greater than 0.05, 12 muscles) was observed. During stimulation, regional blood flow was positively correlated (0.4 less than r less than 0.6, P less than 0.05, 12 muscles) with regional glucose uptake. The coefficients of variation for regional blood flow and regional glucose uptake averaged approximately 0.35 and 0.23, respectively, both at rest and during stimulation. Specific fiber type distributions could not explain either the regional heterogeneity in blood flow or in glucose uptake. We conclude that regional blood flow within single skeletal muscles is not strongly linked to regional uptake of glucose. Both variables show considerable heterogeneity.

The relationship between regional blood flow and contractile function in normal, ischemic, and reperfused myocardium

The prevailing paradigm of coronary physiology and pathophysiology is that a balance between blood flow (i.e., supply) and function (i.e., demand) exists under normal conditions and that an imbalance between supply and demand occurs during ischemia. However, this paradigm is derived largely from studies relating changes in total coronary inflow to global ventricular function. The present article examines the relationship between myocardial blood flow and function on a regional level and proposes that a change may be needed in the current paradigm of coronary pathophysiology. In normal myocardium, considerable heterogeneity of regional blood flow exists, indicating either similar heterogeneity of metabolic demand and function or questioning the precision of metabolic coupling between flow and function. After the onset of ischemia, a transient imbalance between the reduced blood flow and function may exist. However, myocardial function rapidly declines and during early steady-state ischemia regional myocardial blood flow and function are once again evenly matched. Such supply-demand balance may persist over prolonged periods of ischemia enabling the myocardium to remain viable through reduction of energy expenditure for contractile function, i.e., to "hibernate". Whereas in "hibernating" ischemic myocardium, regional myocardial blood flow and function are both reduced but appropriately matched to one another, flow and function appear to be largely uncoupled in reperfused "stunned" myocardium. The clinical identification of viable but ischemic (hibernating) and postischemic (stunned) myocardium is of utmost importance in patients undergoing reperfusion procedures. A new paradigm of coronary and myocardial pathophysiology, encompassing a regional as well as a global view of perfusion and function, will have to include explanations for phenomena such as myocardial hibernation and myocardial stunning.

Relative volume-average murine tumor blood flow measurement via deuterium nuclear magnetic resonance spectroscopy.

A deuterium NMR spectroscopic method to determine relative tumor blood flow (TBF) by measuring the increase in tumor HOD concentration after intravenous injection of 100 microliters D2O (0.9% NaCl) is presented. An integration approach analogous to that validated for positron emission tomographic measurement of cerebral blood flow was implemented. Computer simulations indicated that integration from 30 to 120 s minimizes the sensitivity of the uptake integral to the shape of the arterial input function, which cannot be assessed in each mouse, while maintaining both a nearly linear relationship between TBF and the integral and high NMR signal-to-noise. A strong positive linear correlation was observed between the uptake integral and TBF measured by D2O clearance in both untreated tumors (n = 19; P less than 0.001) and tumors after hyperthermia (n = 16; P less than 0.001). This method can measure relative TBF in tumors with heterogeneous blood flow and is ideally suited to concurrent or interleaved measurement of TBF and metabolism via multinuclear NMR spectroscopy.

Computed myocardial PO2 histograms: effects of various geometrical and functional conditions

A model of myocardial oxygenation was developed that allows calculation of Po2 histograms under varying conditions. The model consists of parallel tissue cylinders with varying radii, simulating the heterogeneity of capillary spacing, in agreement with our previous experimental results. The facilitated diffusion of O2 by myoglobin, an additional resistance to diffusion at the capillary level, and the Michaelis-Menten type of O2 consumption were also incorporated. The shape of the histograms depends on input data. When no additional barrier to O2 transport is included, the histograms resemble those obtained with Po2 surface electrodes, and they are strongly dependent on heterogeneity in capillary spacing and capillary blood flow. On the other hand, an inclusion of an additional capillary barrier combined with the Michaelis-Menten type of O2 consumption can generate Po2 histograms similar to those derived from myoglobin cryospectroscopy. In this case, the Po2 histograms are relatively independent of heterogeneity of capillary spacing and blood flow. The facilitation of O2 diffusion by myoglobin has only a modest effect on the form of the histograms in all situations considered.

Heterogeneity of blood flow in tibial cortical bone: An experimental investigation using microspheres

The distribution of tibial blood flow was measured by injecting approximately (600-1000) x 10(3) 15 mu microspheres, labelled with either tin-113 (113Sn) or cobalt-57 (57Co) into femoral arteries of five mature greyhounds. The diaphyseal cortex, stripped of periosteum and devoid of marrow, was sawn into 40 pieces (10 transverse sections x 4 anatomical quarters/section). Relative deposition densities of the 113Sn microspheres in 40 pieces of cortex were found. These values, together with their associated masses, proved, from a statistical point of view, that flow rate heterogeneity was substantial in the diaphysis. In particular, for the diaphyseal cortex, distribution of relative deposition densities (flow rates) in six bones was found to be positively-skewed with a relative dispersion ((SD/mean) x 100) of approximately 40%.

Fractal modeling of pulmonary blood flow heterogeneity

The heterogeneity of pulmonary blood flow is not adequately described by gravitational forces alone. We investigated the flow distributions predicted by two fractally branching vascular models to determine how well such networks could explain the observed heterogeneity. The distribution of flow was modeled with a dichotomously branching tree in which the fraction of blood flow from the parent to the daughter branches was gamma and 1-gamma repeatedly at each generation. In one model gamma was held constant throughout the network, and in the other model gamma varied about a mean of 0.5 with a standard deviation of sigma. Both gamma and sigma were optimized in each model for the best fit to pulmonary blood flow data from experimental animals. The predicted relative dispersion of flow from the two model fractal networks produced an excellent fit to the observed data. These fractally branching models relate structure and function of the pulmonary vascular tree and provide a mechanism to describe the spatially correlated distribution of flow and the gravity-independent heterogeneity of blood flow.

Maldistribution of heterogeneous coronary blood flow during canine endotoxin shock

STUDY OBJECTIVE - The aim was to investigate whether heterogeneous coronary blood flow is maldistributed during endotoxin shock. DESIGN - Variables were studied before (t = 0) and at t = 90 and t = 120 min after bolus injection of saline (n = 6) or endotoxin (n = 6). SUBJECTS - 12 anaesthetised mongrel dogs, weight 20-27 kg, were used. MEASUREMENTS AND MAIN RESULTS - We studied myocardial blood flows in small tissue sections (of about 1 g in left and 2 g in right ventricle) with radioactive microspheres, together with haemodynamic variables and global myocardial metabolism. At t = 0 min in controls, regional flows per 100 g were heterogeneous and ranged from a factor 0.2 to 2.7 and 0.6 to 1.6 of mean flow per 100 g to the left and right ventricle respectively; heterogeneity was unchanged at t = 90 and t = 120 min. Between t = 0, t = 90, and t = 120 min regional flows correlated: r = 0.78(SD 0.14), n = 18, for left ventricle, and r = 0.70(0.17) for right ventricle. In the endotoxin group, cardiac output and mean arterial pressure decreased by 44(7) and 48(11)% respectively, and lactate increased by 3.2(0.6) mmol.litre-1 at t = 120 min. Global left ventricle blood flow and delivery and metabolism of O2 were unchanged; lactate extraction and external work fell. The ratio between global right ventricular O2 delivery and external work also rose. Regional blood flows ranged from a factor 0.2 to 2.7 and 0.1 to 1.8 of mean flow to left and right ventricles respectively; heterogeneity did not differ from controls and did not change with time. Flow correlations with time were reduced: 0.45(0.24) for left ventricle and 0.45(0.26) for right ventricle (both n = 18, p less than 0.005 v controls). The left ventricular endocardial to epicardial flow ratio fell; flow was redistributed to both layers. CONCLUSIONS - Heterogeneous blood flow is redistributed throughout the heart during canine endotoxin shock so that, at unchanged global blood flow and flow heterogeneity, flow decreases in some but increases in other areas. Flow maldistribution may be associated with focal ischaemia, which may be masked by a rise in O2 uptake for a given workload (contractile inefficiency) in overperfused areas, and may thereby contribute to a fall in global myocardial external work for a given O2 delivery.

The distribution of blood flow and glucose uptake within single skeletal muscles in the awake rabbit

We have previously described a substantial regional heterogeneity both in blood flow and in glucose uptake within single skeletal muscles in anaesthetized rabbits. These heterogeneities could be related to effects of anaesthesia. The main goal of the present study was therefore to study regional muscle blood flow and muscle glucose uptake in awake rabbits. We used the microsphere method and the deoxyglucose technique for assessment of regional blood flow and regional glucose uptake respectively. The measurements were performed in 0.25-g regions from hind leg muscles. Some rabbits were first studied while awake and then during anaesthesia. Others were studied while either awake or anaesthetized. The degree of regional heterogeneity in blood flow and in glucose uptake was similar in awake and anaesthetized rabbits. Both temporal and spatial heterogeneity in blood flow were present. Evidence was found for vasomotion with a cycle time exceeding 45 min in awake rabbits. This perfusion pattern was similar in rabbits in which either the motor or sympathetic vasomotor nerves or both had been blocked. We conclude that regional perfusion and glucose uptake within single muscles are also markedly heterogeneous in awake rabbits. Regional, non-synchronized fluctuations in blood flow with a long cycle time seem to be an important part of this perfusion heterogeneity.

Fractal properties of pulmonary blood flow: characterization of spatial heterogeneity

The heterogeneity of pulmonary blood flow was examined using a fractal analytic procedure, and the results were compared with the traditional gravitational model of flow distribution. 99mTc-labeled macroaggregate was injected intravenously at functional residual capacity in six supine anesthetized dogs. The lungs were fixed in situ and sliced in transverse sections. The slices were imaged on a planar gamma camera, and a three-dimensional array of blood flow measurements was reconstructed for each lung. Fractal analysis was used to examine the spatial heterogeneity or RDs (relative dispersion = SD/mean) as a function of the number of pieces into which the flow array was subdivided. RDs was fractal and could be characterized by a fractal dimension (Ds) of 1.09 +/- 0.02, where a Ds of 1.0 reflects homogeneous flow and 1.5 indicates a random flow distribution. The data fit the fractal model exceptionally well with an average r = 0.98. RDs was examined in gravitational and isogravitational planes and as expected was greatest in the gravitational direction. However, the difference was small, suggesting that gravitation plays a secondary role to an underlying process producing heterogeneity. Within the limits of resolution attained by this study (piece volumes greater than 0.25 cm3), the heterogeneity of pulmonary blood flow is well characterized by a fractal model.

Hyperthermia catheter implantation and therapy in the brain

For the treatment of malignant gliomas, a technique for implanting hyperthermia catheters was developed that utilized a stereotactic template and head-stabilization frame mounted on a computerized tomography (CT) scanner. Computerized tomography scans were used to measure tumor dimensions and to determine the number, implantation depths, and active heating lengths of the catheters, which were implanted through twist-drill holes while the patient was in the CT room. Heat was subsequently delivered via implanted catheters using a computer-controlled hyperthermia system, which partially compensates for heterogeneous and time-varying tumor blood flow.

Heterogeneity of myocardial blood flow under normal conditions and its dependence on arterial PO2

We studied the heterogeneity of myocardial blood flow in nine anesthetized closed-chest dogs using an indicator-dilution technique that allows the stochastic description of transport characteristics for three inert gases (helium, argon, and xenon) from the coronary inflow to outflow. The results show that under normal conditions the transcoronary transport of the tracers is spatially heterogeneous. Heterogeneity is strongly dependent on the arterial oxygen tension over a range of 40-200 Torr. This could be similarly observed with each tracer gas despite different physicochemical properties and was largely independent from the magnitude of coronary blood flow. The results are interpreted to mean that the arteriolar or intratissue PO2 influences myocardial blood flow over a broad range and possibly acts as an important integrating factor in the local regulation of coronary blood flow and flow reserve.

Regulation of capillary blood flow and oxygen supply in skeletal muscle in dogs during hypoxaemia.

1. Multiwire surface electrodes were used to measure local hydrogen clearance curves and tissue PO2 in vivo. Evaluation of the initial slopes of the hydrogen clearance curves enabled the measurement of capillary blood flow and its distribution. 2. Capillary blood flow and tissue PO2 frequency distribution histograms were measured in the m. sartorius of anaesthetized, relaxed mongrel dogs under conditions of normoxic (Fi, O2 = 0.3) and hypoxic (Fi, O2 = 0.15 and 0.1) artificial ventilation. 3. Stepwise hypoxaemia (hypoxic hypoxia) induced an increasing discrepancy between capillary blood flow and arterial blood flow. The former decreased by 6% whereas the latter increased by 86%. 4. PO2 histograms provided no evidence of cellular anoxia even at Fi,O2 = 0.1. Capillary blood flow histograms suggested a redistribution of the local pattern of flow. 5. A 34.7% reduction of O2 consumption was observed as the result of severe hypoxaemia. 6. The concept of heterogeneity of capillary blood flow as a functional O2 reserve is presented, together with evidence for oxygen-dependent regulation of capillary blood flow and oxygen consumption.

A compartmental model to quantitate in vivo glucose transport in the human forearm.

Glucose transport is a critical step in the control of glucose disposal that, until presently, has not been quantitated in vivo in humans. We have employed the perfused forearm and euglycemic insulin-clamp techniques in combination with a dual-tracer injection to measure basal and insulin-mediated glucose transport in six normal subjects. L-[3H]glucose, which is not transported, was used to trace extracellular glucose kinetics; 3-O-[14C]-methyl-D-glucose, transportable but not metabolizable, was used to monitor glucose movement across the cell membrane. After bolus intra-arterial injection of the two tracers, plasma samples were obtained every 15-30 s for 10 min from a deep forearm vein to determine the washout curves. A linear compartmental model was developed that accounts for blood flow heterogeneity. It consists of three parallel, two-compartment chains merging into the sampling compartment to which cellular compartments are appended. A priori identifiability analysis was performed. The uniquely identifiable parameterization includes the transport rate constants of glucose into and out of the cell. The model was identified using nonlinear least-squares parameter estimation. Transport parameters are estimated with very good precision, and their reproducibility is satisfactory. The model also allows the estimation of the mean arteriovenous transit times of both the extracellular and the transported tracer. The compartmental model provides a novel approach to investigate glucose transport in vivo in humans.

Metabolic consequences of coronary stenosis. Transmurally heterogeneous myocardial ischemia studied by spatially localized 31P NMR spectroscopy.

Coronary stenosis results in transmurally non-uniform blood flow with the inner layers of the left ventricular wall typically suffering a more severe hypoperfusion relative to the outer layers. Coupled with numerous other transmural non-uniformities such as systolic tension development and oxygen needs, the heterogeneous blood flow distribution in the presence of coronary stenosis is expected to result in transmurally heterogeneous ischemia. All previous NMR spectroscopy studies of myocardial metabolism and bioenergetics under normal and ischemic conditions treated the organ as a homogeneous tissue. We have utilized spatially localized 31P NMR spectroscopy together with non-NMR measurements of regional blood flow to study the myocardium with transmural spatial differentiation under normal and flow-restricted conditions. 31P NMR and blood flow data obtained concurrently on each heart revealed that sustained coronary artery stenosis resulted in transmurally non-uniform ischemia which largely paralleled the hypoperfusion pattern. The reduction in creatine phosphate content (with consequent elevation of Pi) and hypoperfusion was tightly correlated in the subendocardium for flow rates less than approximately 0.7 mL/min per g wet myocardium. The high energy phosphate and Pi content of the epicardium, however, was responsive not only to the flow to this region but also to the extent of ischemia in the subendocardial layers. These results document the utility of localized NMR spectroscopy in physiologic research and suggest potential biomedical applications due to the tight correlation noted between alterations in blood flow and changes in the phosphorylated metabolite levels detected by 31P NMR.