Regional Blood Volume Research Articles

Methodological approaches to quantitative evaluation of microcirculation in tissues with dynamic magnetic resonance tomography

The development of rapid magnetic resonance imaging (MRI) sequences makes it possible to detect the fast kinetics of tissue response after intravenous administration of paramagnetic contrast media (CM), reflecting the status of tissue microcirculation. In this paper, the basic physical and tracer kinetic principles of dynamic relativity and susceptibility contrast MRI techniques are reviewed. The quantitative analysis of the acquired dynamic image data is broken up into an MR specific part, in which the observed signal variations are related to the CM concentration in the tissue, and an MR independent part, in which the computed concentration-time-courses are analyzed by tracer kinetic modeling. The purpose of the applied models is to describe the underlying physiological processes in mathematical terms and thus to enable the estimation of tissue specific parameters from measured dynamic image series. Whereas the capillary permeability can be estimated from dynamic relativity contrast enhanced MRI studies, the regional blood volume as well as the regional blood flow can be determined from dynamic susceptibility contrast enhanced image series. However, since there are no intravascular but only diffusible CM available at present, the application of the susceptibility technique is currently restricted to brain tissues with intact blood brain barrier. The practical realization of both dynamic MRI techniques is demonstrated by case studies.

Quantitative magnetic resonance imaging of capillary water permeability and regional blood volume with an intravascular MR contrast agent.

A novel method is presented to simultaneously measure the permeability surface area product of water (PS), also known as capillary diffusion capacity, and the regional blood volume (RBV). It is based on magnetic resonance imaging of the longitudinal relaxation times of tissue and blood at different concentrations of an intravascular MR contrast agent. PS and RBV were measured in vivo in different regions of the brain and the skeletal muscle of the rat. The average PS values (n = 5) obtained in cerebral cortex, corpus callosum, hippocampus, thalamus, jaw muscle, and tongue muscle were 3.31 +/- 0.20, 1.81 +/- 0.25, 3.37 +/- 0.36, 3.68 +/- 0.44, 10.6 +/- 1.1, and 14.1 +/- 2.51 ml x min(-1) x g(-1), respectively. The corresponding average RBV values were 1.63 +/- 0.18, 1.22 +/- 0.25, 3.30 +/- 0.37, 3.03 +/- 0.36, 1.66 +/- 0.30, and 1.38 +/- 0.33 ml x 100 g(-1). These results are in good agreement with previously reported literature values obtained by means of autoradiography.

Regional perfusion parameters from pulmonary microfocal angiograms.

An indicator-dilution model was developed to describe transport of vascular contrast medium through an organ during acquisition of vascular dynamic contrast images. The model provides the theoretical basis for methods of determining regional blood flow, blood volume, and mean transit time from time-absorbance curves acquired from the images of tissue regions of interest (ROI) distal from the inlet site. The robustness of these methods was evaluated using a computer-simulated vessel network, which simulated the passage of a bolus of contrast medium through arterioles, networks of capillaries, and venules. The network was used to evaluate the reliability of ROI parameter estimation methods when the underlying model assumptions are violated. The shape of the ROI inlet concentration curve and moderate amounts of random noise did not affect the ability of the method to recover accurate parameter estimates. The estimates of ROI flow and transit time were degraded in the presence of significant dispersion of the inlet concentration curve as it traveled through arteries upstream from the microvascular ROI or when the flow was redistributed within the ROI. The estimates of ROI volume were relatively robust. The method was applied to image data of the dog pulmonary vasculature obtained using microfocal X-ray angiography to show that the results obtained from the simulations are consistent with actual data.

Quantification of regional lung density and blood volume with tomographic and blood pool imaging

Quantification of regional lung density and blood volume with tomographic and blood pool imaging

Measurement of liver blood volume using a macromolecular MRI contrast agent at equilibrium

Liver regional blood volume (LRBV) is altered by several disease states and various drugs. Preliminary studies in the rat, using research MR imaging instruments at 2T and vascular contrast agents, have suggested that MRI may be used to measure LRBV. Our goal was to develop a technique for measuring LRBV using a clinical machine at 1.5 T. This study was performed in the rabbit, using CarboxyMethylDextran Gd-DTPA, a macromolecular contrast agent with a molecular weight of 158 kDa. MRI was performed at 1.5 T, in the plane of the inferior vena cava, with and without flow compensation, before contrast injection and in the steady state after injection. Accuracy and stability of LRBV measurement, over 2 h and with various doses (0.01–0.05 mmol/kg), was tested against a standard Evan's Blue dye-indicator technique. LRBV was 28 ± 2 mL/100 g when measured by MRI with flow compensation, which is in good agreement with the literature and with the 26 ± 6 mL/100 g, measured by the Evan's Blue dilution technique. Measurements varied less than 7% over time and less than 9% over the range of doses. LRBV was overestimated using a sequence without flow compensation especially when large doses of contrast agent were injected. This noninvasive MRI technique provides a simple method for measuring liver LRBV and offers new prospects for future physiological and pathological studies.

Improving MR quantification of regional blood volume with intravascular T1 contrast agents: accuracy, precision, and water exchange.

The goal of this work was to develop a comprehensive understanding of the relationship between vascular proton exchange rates and the accuracy and precision of tissue blood volume estimates using intravascular T1 contrast agents. Using computer simulations, the effects of vascular proton exchange and experimental pulse sequence parameters on measurement accuracy were quantified. T1 and signal measurements made in a rat model implanted with R3230 mammary adenocarcinoma tumors demonstrated that the theoretical findings are biologically relevant; data demonstrated that over-simplified exchange models may result in measures of tumor, muscle, and liver blood volume fractions that depend on experimental parameters such as the vascular contrast concentration. As a solution to the measurement of blood volume in tissues with exchange that is unknown, methods that minimize exchange rate dependence were examined. Simulations that estimated both the accuracy and precision of such methods indicated that both the inversion recovery and the transverse-spoiled gradient echo methods using a "no-exchange" model provide the best trade-off between accuracy and precision.

Modeling regional myocardial flows from residue functions of an intravascular indicator.

The purpose of the present study was to determine the accuracy and the sources of error in estimating regional myocardial blood flow and vascular volume from experimental residue functions obtained by external imaging of an intravascular indicator. For the analysis, a spatially distributed mathematical model was used that describes transport through a multiple-pathway vascular system. Reliability of the parameter estimates was tested by using sensitivity function analysis and by analyzing "pseudodata": realistic model solutions to which random noise was added. Increased uncertainty in the estimates of flow in the pseudodata was observed when flow was near maximal physiological values, when dispersion of the vascular input was more than twice the dispersion of the microvascular system for an impulse input, and when the sampling frequency was < 2 samples/s. Estimates of regional blood volume were more reliable than estimates of flow. Failure to account for normal flow heterogeneity caused systematic underestimates of flow. To illustrate the method used for estimating regional flow, magnetic resonance imaging was used to obtain myocardial residue functions after left atrial injections of polylysine-Gd-diethylenetriaminepentaacetic acid, an intravascular contrast agent, in anesthetized chronically instrumental dogs. To test the increase in dispersion of the vascular input after central venous injections, magnetic resonance imaging data obtained in human subjects were compared with left ventricular blood pool curves obtained in dogs. It is concluded that if coronary flow is in the normal range, when the vascular input is a short bolus, and the heart is imaged at least once per cardiac cycle, then regional myocardial blood flow and vascular volume may be reliably estimated by analyzing residue functions of an intravascular indicator, providing a noninvasive approach with potential clinical application.

Magnetic resonance tomography in myocardial ischemia: state of the art

Recent developments in MR imaging have opened up new avenues in the investigation of ischaemic heart disease. Conventional unenhanced spin-echo sequences have been used to detect and quantify myocardial infarction. Along with the technical advances aimed at reducing motion artifacts and imaging time, the advent of contrast media for MR imaging has further strengthened its diagnostic capacities. The applications of MR contrast media are increasing, and they are becoming more specific, to enable differentiation of occlusive and reperfused myocardial infarctions and to discriminate between reversible and irreversible myocardial injury. Previous studies have also indicated that dual administration of both relativity-based and susceptibility-based contrast media can be used to determine whether viable myocardium is present in the reperfused ischaemic area. Magnetic susceptibility MR contrast media have the potential to demonstrate a region of the ischaemically injured myocardium in which myocardial necrosis is present. A cornerstone in the MR assessment of ischaemic heart disease has been achieved with the advent of fast MR imaging techniques. Ultrafast gradient-recalled-echo sequences or echo-planar imaging allow to monitor the first passage of the contrast medium through the heart. With the aid of MR contrast media, these techniques may be useful in estimating regional myocardial perfusion and blood volume. Experimental and clinical perfusion studies indicate that perfusion-sensitive MR imaging, particularly in concert with coronary vasodilators, can detect compromised myocardium. Combining myocardial perfusion imaging with the anatomic and functional information provided by other MR imaging techniques such as cine and velocity-encoded sequences could make MR imaging a comprehensive noninvasive diagnostic tool for the assessment of ischaemic heart disease.

Reduced beta adrenoceptor density in vivo in human lung tumours: a preliminary study with positron emission tomography.

Reduced beta adrenergic receptor density in tumours has been reported in previous in vitro studies. The aim of the present study was to assess whether this occurs in vivo. Pulmonary beta adrenoceptors were imaged and quantified in vivo using positron emission tomography (PET) and the beta antagonist radioligand (S)-[11C]CGP-12177 in five men with lung tumours of mean age 58 years (range 42-68). The histology of the tumours was squamous cell carcinoma in two cases, adenocarcinoma in one, carcinoid tumour in one, and large cell carcinoma in one. The regional blood volume and extravascular tissue density were also measured using PET. Regions of interest were drawn for both non-tumour and tumour lung tissue. The mean (SD) blood volume was 0.142 (0.025) ml/ml in tumour regions and 0.108 (0.010) ml/ml in normal lung regions--a difference of 31%. Mean (SD) extravascular tissue density was 0.653 (0.133) g/ml in tumour regions, substantially higher than in normal lung regions (0.157 (0.021) g/ml). On the contrary, beta receptor density was 5.1 (1.8) pmol/g in tumour regions, lower than the value of 9.9 (1.6) pmol/g found in adjacent normal lung--a difference of 48%. In vivo beta adrenoceptor density is reduced in human lung tumours.

Dynamic susceptibility contrast MRI of regional cerebral blood volume in Alzheimer's disease

The purpose of this study was to investigate the potential effectiveness of dynamic susceptibility contrast magnetic resonance imaging (MRI) to discriminate elderly patients with Alzheimer's disease from normal matched comparison subjects. Images of regional cerebral blood volume (CBV) were generated from echo-planar MRI with the dynamic susceptibility contrast method in 13 Alzheimer's disease patients and 13 comparison subjects group-matched on age and gender. Temporoparietal cerebral blood volume, expressed as a percentage of the cerebellum value, was reduced 17% bilaterally in the patients with Alzheimer's disease. Blood volume in sensorimotor regions was reduced only 8.5% in the patients. Discriminant function analysis based on left and right temporoparietal measures correctly classified 88.5% of the subjects as patients or comparison subjects. Temporoparietal CBV was reduced even in mildly affected Alzheimer's disease patients (Mini-Mental State scores > 24). Dynamic susceptibility contrast MRI of regional CBV is promising as a nonradioactive, potentially lower-cost alternative to other functional neuroimaging methods for evaluating Alzheimer's disease.

Magnetization exchange in capillaries by microcirculation affects diffusion‐controlled spin‐relaxation: A model which describes the effect of perfusion on relaxation enhancement by intravascular contrast agents

The effect of perfusion on relaxation time in tissue has only been considered for first-pass kinetics of NMR-signal after application of contrast agents. The importance of perfusion on relaxation has not yet been studied for steady state conditions, i.e., when the intravascular relaxation rate is constant in time. The aim of this study is to develop a model in which T1 relaxation is derived as a function of perfusion and intracapillary volume fraction (regional blood volume). Tissue is considered to be two-compartment system, which consists of intracapillary and extravascular space. Intracapillary relaxation differs from relaxation in the arterial system due to diffusion-exchange of magnetization from extravascular to intracapillary space. Perfusion tends to attenuate this difference and thus counteracts the effect on intracapillary relaxation. Relaxation in the extravascular and intracapillary magnetization are linked by diffusion. This dependence is presented in analytical form and a generic equation is derived. AT1 experiment is considered in which all spins of tissue and blood are inverted at the beginning. Calculations are performed for the fast exchange model of tissue. Perfusion increases relaxation enhancement of intravascular contrast agents. This effect is considerable in highly perfused tissue like myocardium. The dependence of relaxation on perfusion implies an overestimation of the regional blood volume when the calculation of the latter is based on tissue models that neglect perfusion. The model presented here is applied to predict the effect of perfusion on T1 imaging with FLASH-pulse sequences because this technique has been proven to be a powerful method to obtain T1 maps within a short time interval. For the fast exchange model, two algorithms are suggested that determine perfusion and regional blood volume from T1 imaging in the presence and absence of intravascular contrast agents.

Effect of volume expansion on systemic hemodynamics and central and arterial blood volume in cirrhosis

Background & Aims: Systemic vasodilatation in cirrhosis may lead to hemodynamic alterations with reduced effective blood volume and decreased arterial blood pressure. This study investigates the response of acute volume expansion on hemodynamics and regional blood volumes in patients with cirrhosis and in controls. Methods: Thirty-nine patients with cirrhosis (12 patients with Child-Turcotte class A, 14 with class B, and 13 with class C) and 6 controls were studied. During hepatic vein catheterization, cardiac output, systemic vascular resistance, central and arterial blood volume, noncentral blood volume, and arterial pressure were determined before and during a volume expansion induced by infusion of a hyperosmotic galactose solution. Results: During volume expansion, the central and arterial blood volume increased significantly in patients with class A and controls, whereas no significant change was found in patients with either class B or class C. Conversely, the noncentral blood volume increased in patients with class B and C. In both patients and controls, the cardiac output increased and the systemic vascular resistance decreased, whereas the mean arterial blood pressure did not change significantly. Conclusions: Only in mild cirrhosis is the effective blood volume able to increase in response to volume expansion. Our results are consistent with the peripheral vasodilatation hypothesis and the circulatory hyporeactivity occurring in advanced cirrhosis.

A proposed blood circulation model for Reference Man.

As part of the revision of the Reference Man model of the International Commission on Radiological Protection (ICRP), we have reviewed and reanalyzed available data on blood flow and in previous publications have proposed reference values for total and regional blood volumes, total cardiac output, and the distribution of cardiac output. In this paper we unify these proposed features of the revised Reference Man within the framework of a dynamic blood circulation model and show how the model can be used to predict the distribution of decays of short-lived radionuclides after injection or absorption into blood. The total blood volume is partitioned into the blood contents of 24 separate organs or tissues, right heart chambers, left heart chambers, pulmonary circulation, arterial outflow to the systemic tissues (aorta and large arteries), and venous return from the systemic tissues (large veins). As a compromise between physical reality and computational simplicity, the circulation of blood is viewed as a system of first-order transfers between blood pools, but outflow from any given pool is delayed during the first pass of material through the circulation with the delay time depending on the mean transit time across the pool. The model can be used to predict the movement and gradual dispersal of a bolus of material in the circulation after intravascular injection. In contrast to the treatment of the circulation in ICRP Publication 53, Radiation Dose to Patients from Radiopharmaceuticals, the present model allows consideration of incomplete, tissue-dependent extraction of material during passage through the circulation and return of material from tissues to plasma.

Changes in regional vascular resistance and blood volume after hemorrhage in fed and fasted awake rats

To determine whether fasting alters the response of blood flow to hemorrhage, blood flow was measured by radiolabeled microspheres before and after a 20 ml.kg-1.3 min-1 hemorrhage in fed and fasted chronically cannulated male Sprague-Dawley rats. Restitution of blood volume, as determined by dilution of hematocrit, was attenuated in fasted rats, although the responses of arterial blood pressure, heart rate, cardiac output, and total peripheral resistance were not significantly different. Fasting only affected resting blood flow in the bronchial artery and fat and had no effect on resting vascular resistance in any organ studied. In both fed and fasted rats, hemorrhage led to a significant fall in blood flow to the stomach, small intestine, cecum, colon, spleen, pancreas, kidney, bronchial artery, thymus, and muscle and a rise in blood flow to the adrenals. However, fasting did not significantly alter the response of flow or vascular resistance to these organs. Fasting did alter the blood flow response to hemorrhage in bone, fat, and the hepatic artery. These results demonstrate that 24 h of fasting does not affect the responses of blood flow and vascular resistance to hemorrhage in most organs, even though restitution of blood volume is attenuated.

Quantitative measurement of regional blood flow with gadolinium diethylenetriaminepentaacetate bolus track NMR imaging in cerebral infarcts in rats: validation with the iodo[14C]antipyrine technique.

NMR bolus track measurements were correlated with autoradiographically determined regional cerebral blood flow (rCBF). The NMR method is based on bolus infusion of the contrast agent gadolinium diethylenetriaminepentaacetate and high-speed T*2-sensitive NMR imaging. The first pass of the contrast agent through the image plane causes a transient decrease of the signal intensity. This time course of the signal intensity is transformed into relative concentrations of the contrast agent in each pixel. The mean transit time and relative blood flow and volume are calculated from such indicator dilution curves. We investigated whether this NMR technique correctly expresses the relative rCBF. The relative blood flow data, calculated from NMR bolus track experiments, and the absolute values of iodo[14C]antipyrine autoradiography were compared. A linear relationship was observed, indicating the proportionality of the transient NMR signal change with CBF. Excellent interindividual reproducibility of calibration constants is observed (r = 0.963). For a given NMR protocol, bolus track measurements calibrated with autoradiography after the experiment allow determination of absolute values for rCBF and regional blood volume.

The developing role of magnetic resonance contrast media in the detection of ischemic heart disease.

Recent developments in magnetic resonance (MR) imaging have opened up new avenues in the investigation of cardiovascular physiology. Inherent signal intensity of any tissue on MR images depends largely on proton concentration as well as longitudinal (T1) and transverse (T2) relaxation times. Myocardial contrast can be manipulated by using specific MR pulse sequences which are selectively sensitive to differences in any one of these parameters. Paramagnetic metal complexes are used as contrast media in MR imaging to enhance the inherent contrast. Contrast media in MR imaging are not directly visible but change the magnetic properties of other nuclei in close proximity, such as those of the water hydrogen. The signal of water can be altered by the contrast medium in different ways, either by changing the relaxation times or through bulb susceptibility effects, or both. The role of MR contrast media for quantitative characterization of ischemic heart disease has advanced considerably in the past 10 years. Conventional MR imaging techniques following the administration of contrast media are useful for identifying and sizing myocardial infarctions and for distinguishing between occlusive and reperfused myocardial infarctions as well as reversible (stunned) and irreversible injuries. Recent results suggest that contrast-enhanced MR imaging can also be used to identify dead cells in reperfused ischemically injured myocardium. The recently developed fast MR imaging techniques, with the aid of MR contrast media as a perfusion indicator, may be useful in estimating regional myocardial perfusion and blood volume. The assessment of capillary circulation or myocardial perfusion may be used for evaluating the extent of hypoperfusion and treatment efficacy. Experimental and clinical perfusion studies indicate that perfusion-sensitive MR imaging detects compromised myocardium (area at risk). Combining myocardial perfusion imaging with the anatomic and functional information provided by other MR imaging sequences could make MR imaging a comprehensive noninvasive technique for the evaluation of ischemic heart disease.

Regional myocardial blood volume and flow: first-pass MR imaging with polylysine-Gd-DTPA.

The authors investigated the utility of an intravascular magnetic resonance (MR) contrast agent, poly-L-lysine-gadolinium diethylenetriaminepentaacetic acid (DTPA), for differentiating acutely ischemic from normally perfused myocardium with first-pass MR imaging. Hypoperfused regions, identified with microspheres, on the first-pass images displayed significantly decreased signal intensities compared with normally perfused myocardium (P < .0007). Estimates of regional myocardial blood content, obtained by measuring the ratio of areas under the signal intensity-versus-time curves in tissue regions and the left ventricular chamber, averaged 0.12 mL/g +/- 0.04 (n = 35), compared with a value of 0.11 mL/g +/- 0.05 measured with radiolabeled albumin in the same tissue regions. To obtain MR estimates of regional myocardial blood flow, in situ calibration curves were used to transform first-pass intensity-time curves into content-time curves for analysis with a multiple-pathway, axially distributed model. Flow estimates, obtained by automated parameter optimization, averaged 1.2 mL/min/g +/- 0.5 (n = 29), compared with 1.3 mL/min/g +/- 0.3 obtained with tracer microspheres in the same tissue specimens at the same time. The results represent a combination of T1-weighted first-pass imaging, intravascular relaxation agents, and a spatially distributed perfusion model to obtain absolute regional myocardial blood flow and volume.

Systemic cytokine administration can affect blood-brain barrier permeability in the rat.

The aim of the present study was to clarify the effect of intracarotid injection of interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) on the permeability of the blood-brain barrier (BBB) in the rat. A regional blood-to-brain transfer constant (Ki) for [14C] alpha-aminoisobutyric acid ([14C]AIB) and the cerebral residual blood volume were calculated 10 min following administration of cytokines (CKs; 1000 U/rat). The injection of IL-2 and IL-6 (but not of IL-1 beta) induced a significant enhancement of Ki values for [14C]AIB within several brain areas; conversely, when the rats were given TNF-alpha, a striking decrease in BBB permeability was observed. The cerebral regional blood volumes appeared significantly lower in the rats injected with IL-6 than in the control animals, but markedly increased following TNF-alpha administration. Our findings confirm the ability of some CKs to affect the permeability of the BBB and/or to act, probably indirectly, as vasomodulator agents of the cerebral microvessel endothelium.

Erythrocyte and polymorphonuclear cell transit time and concentration in human pulmonary capillaries

Pulmonary capillary transit times were examined in patients who required lung resection by use of 99mTc-labeled macroaggregates (99Tc-MAA) and chromium-labeled erythrocytes (51Cr-RBC) to measure regional blood flow and volume in the resected lung. Cell flow (cells.ml-1.s-1) to each resected lung sample was determined by multiplying the number of polymorphonuclear leukocytes (PMN) per milliliter of circulating blood by the blood flow to that sample. Capillary blood volume was obtained by multiplying the morphometrically determined fraction of pulmonary blood in capillaries by the total 51Cr-RBC volume in each sample. Cell concentrations (cells/ml) in capillary blood were calculated morphometrically, and capillary transit times were obtained by dividing cell concentration by cell flow. The results show that PMN transit times were 60-100 times longer than the RBC transit times, with a 22% overlap between their distributions. We conclude that PMN are concentrated with respect to RBC in pulmonary capillary blood because of differences in their transit times and that these long transit times provide an opportunity for PMN-endothelial interactions.

Using H215O and C15O in Noninvasive Pulmonary Measurements

Regional pulmonary blood flow (PBF), regional pulmonary extravascular water (PEW), and regional pulmonary blood volume (PBV) were measured quantitatively with positron emission tomography (PET) using H2(15)O and C15O in normal human subjects and patients before and after thoracotomy. The method was based on the Kety's model and a modification of the Mintun's method of measuring regional PBF with H2(15)O. The method consisted of intravenous injection of H2(15)O and dynamic PET scanning of the lung field and the right heart blood pool. Another scan following C15O inhalation was performed to visualize the blood pool, and the influence of the blood pool radioactivity to the H2(15)O image was subtracted. A mathematic model was applied to the data analysis, and the least-square fitting procedure was used with a computer for obtaining the optimal parameters. The mean values of the measured PBF, PEW, and PBV in two normal human subjects were 67.2 +/- 23 ml/min/100 ml, 17 +/- 5 ml/100 ml, and 19 +/- 6 ml/100 ml, respectively. The PBF, PEW, and PBV increased in the direction of gravity in the transverse cross-section image of the lung. Using this method, we studied the condition of patients who underwent lung surgery with thoracotomy. The PEW increased and the PBF decreased in the patients after surgery. This condition lasted for a few days, and the patients then recovered. The well-known phenomenon of pulmonary edema occurring after thoracotomy, which is usually recognized by symptoms and radiologically, was thus confirmed quantitatively by our method.