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First-pass measurements of regional blood flow with external detectors
Abstract
A powerful, simple model has been developed for measuring regional blood flow using first-pass tracer kinetics with external detectors such as fast positron emission tomographs (PET). Its derivation is based on the hypothesis that during the first transit of a bolus of activity through an organ there exists a period during which the tracer has not left the region of interest, so that the venous concentration of the tracer is zero. Provided that this condition is met, measurement of blood flow can be obtained in any organ with any radiotracer since there are no requirements in the derivation of the model for diffusion or extraction characteristics of the tracer. The general model has been demonstrated for a special case in the heart using intravenous bolus injections of rubidium-82 with regional positron detectors (beta probes) and validated by comparison with independently determined for by labeled microspheres over a wide range of flow values from zero to five times normal resting coronary blood flow.
... MI and SHAM mice were injected intravenously with 4.0-4.3 MBq (109-117 mCi) of FDG, and 2-min dynamic PET scans were obtained using an Inveon microPET scanner (Siemens) [86][87][88] . The body temperature of mice was maintained at 37 °C. ...
Cognitive dysfunction (CD) in heart failure (HF) adversely affects treatment compliance and quality of life. Although ryanodine receptor type 2 (RyR2) has been linked to cardiac muscle dysfunction, its role in CD in HF remains unclear. Here, we show in hippocampal neurons from individuals and mice with HF that the RyR2/intracellular Ca²⁺ release channels were subjected to post-translational modification (PTM) and were leaky. RyR2 PTM included protein kinase A phosphorylation, oxidation, nitrosylation and depletion of the stabilizing subunit calstabin2. RyR2 PTM was caused by hyper-adrenergic signaling and activation of the transforming growth factor-beta pathway. HF mice treated with a RyR2 stabilizer drug (S107), beta blocker (propranolol) or transforming growth factor-beta inhibitor (SD-208), or genetically engineered mice resistant to RyR2 Ca²⁺ leak (RyR2-p.Ser2808Ala), were protected against HF-induced CD. Taken together, we propose that HF is a systemic illness driven by intracellular Ca²⁺ leak that includes cardiogenic dementia.
... The maximum-slope method presented by Mullani et al. [20,21] was used to calculate the required blood flow parameters [22]. The model assumes that when the tracer first passes through the tissue, the venous exit of the tracer is delayed for a period of time, which is a function of the volume of distribution of the tracer in the target tissue and the blood vessel density [23]. ...
Background:
Kinetic estimation provides fitted parameters related to blood flow perfusion and fluorine-18-fluorodeoxyglucose (18F-FDG) transport and intracellular metabolism to characterize hepatocellular carcinoma (HCC) but usually requires 60 min or more for dynamic PET, which is time-consuming and impractical in a busy clinical setting and has poor patient tolerance.
Methods:
This study preliminarily evaluated the equivalence of liver kinetic estimation between short-term (5-min dynamic data supplemented with 1-min static data at 60 min postinjection) and fully 60-min dynamic protocols and whether short-term 18F-FDG PET-derived kinetic parameters using a three-compartment model can be used to discriminate HCC from the background liver tissue. Then, we proposed a combined model, a combination of the maximum-slope method and a three-compartment model, to improve kinetic estimation.
Results:
There is a strong correlation between the kinetic parameters K1 ~ k3, HPI and [Formula: see text] in the short-term and fully dynamic protocols. With the three-compartment model, HCCs were found to have higher k2, HPI and k3 values than background liver tissues, while K1, k4 and [Formula: see text] values were not significantly different between HCCs and background liver tissues. With the combined model, HCCs were found to have higher HPI, K1 and k2, k3 and [Formula: see text] values than background liver tissues; however, the k4 value was not significantly different between HCCs and the background liver tissues.
Conclusions:
Short-term PET is closely equivalent to fully dynamic PET for liver kinetic estimation. Short-term PET-derived kinetic parameters can be used to distinguish HCC from background liver tissue, and the combined model improves the kinetic estimation.
Clinical relevance statement:
Short-term PET could be used for hepatic kinetic parameter estimation. The combined model could improve the estimation of liver kinetic parameters.
... Кривые динамической оценки доставки трейсера к миокарду позволяют раздельно оценивать кровоток в каждой из коронарных артерий [25]. Подобно изотопам калия, 82 Rb эффективно концентрируется в миокарде с экстракцией около 50-70 % при первом прохождении в состоянии покоя и около 30 % на пике нагрузки [26,27]. Такая нелинейная зависимость с выраженным снижением экстракции трейсера при повышении миокардиаль ного кровотока (MBF, myocardial blood flow) получила название roll-off-феномена [28] (рис. ...
This review considers literature sources on myocardial perfusion studies using positron emission tomography with rubidium-82. The history of the development of the method, the protocols of the study, the dissymmetric data are analyzed, and comparisons are made with other positron emitters that are used in clinical practice and research to study myocardial blood supply. The use of PET/CT with rubidium-82 makes it possible to obtain valuable diagnostic information and it allows to measure myocardial blood directly and make a separate assessment of the coronary arteries function. Due to the fact that the production of rubidium-82 does not require an on-site cyclotron and a radiochemical laboratory, this method of imaging is more accessible than other positron emitters used for the same purpose. Also, the study is not associated with significant discomfort for the patient, since the full stress/rest imaging protocol requires less than half an hour. However, the use of rubidium-82 has a number of drawbacks, including the relatively low sharpness of the resulting image due to the high energy of the emitting positrons. Also there is a necessity for a mathematical correction of the roll-off phenomenon, which is a decrease in radiopharmaceutical extraction with an increase in myocardial blood flow. Due to the short half-life period, the provision of stress tests with ergometers is difficult. It needed to use pharmacological stress tests. In addition, usage of rubidium-82 is characterized by a high cost both due to the expensive production of the parent isotope, strontium-82, and the need for frequent replacement of generators – on average, 11 to 13 times a year.
Renal physiology underpins renal nuclear medicine, both academic and clinical. Clearance, an important concept in renal physiology, comprises tissue uptake rate of tracer (tissue clearance), disappearance rate from plasma (plasma clearance), appearance rate in urine (urinary clearance) and disappearance rate from tissue. In clinical research, steady-state plasma clearances of para-amino-hippurate and inulin have been widely used to measure renal blood flow (RBF) and glomerular filtration rate (GFR), respectively. Routinely, GFR is measured at non-steady state as plasma clearance of a filtration agent, such as technetium-99m diethylenetriaminepentaacetic acid. Scaled to three-dimensional whole body metrics rather than body surface area, GFR in women is higher than in men but declines faster with age. Age-related decline is predominantly from nephron loss. Tubular function determines parenchymal transit time, which is important in renography, and the route of uptake of technetium-99m dimercaptosuccinic acid, which is via filtration. Resistance to flow is defined according to the pressure-flow relationship but in renography, only transit time can be measured, which, being equal to urine flow divided by collecting system volume, introduces further uncertainty because the volume is also unmeasurable. Tubuloglomerular feedback governs RBF and GFR, is regulated by the macula densa, mediated by adenosine and renin, and can be manipulated with proximal tubular sodium–glucose cotransporter-2 inhibitors. Other determinants of renal haemodynamics include prostaglandins, nitric oxide and dopamine, while protein meal and amino acid infusion are used to measure renal functional reserve. In conclusion, for measuring renal responses to exogenous agents, steady-state para-amino-hippurate and inulin clearances should be replaced with rubidium-82 and gallium-68 EDTA for measuring RBF and GFR.
Imaging glucose metabolism with [ ¹⁸ F]fluorodeoxyglucose positron emission tomography has transformed the diagnostic and treatment algorithms of numerous malignancies in clinical practice. The cancer phenotype, though, extends beyond dysregulation of this single pathway. Reprogramming of other pathways of metabolism, as well as altered perfusion and hypoxia, also typifies malignancy. These features provide other opportunities for imaging that have been developed and advanced into humans. In this review, we discuss imaging metabolism, perfusion, and hypoxia in cancer, focusing on the underlying biology to provide context. We conclude by highlighting the ability to image multiple facets of biology to better characterize cancer and guide targeted treatment.
Objective
The aim of this study is to develop a noninvasive technique for measuring tissue tracer extraction efficiency ( E ) and illustrate it for Tc-99m-mercaptoacetyltriglycine (MAG3) and kidney.
Methods
E was measured in 10 patients with normal MAG3 renography. E is the ratio of tissue clearance-to-blood flow ( Ki/F ). For single-photon tracers, attenuation constants are unknown, so Ki and F cannot be separately measured. However, by deriving attenuation-uncorrected Ki’ and F’ from the same regions of interests (ROIs), these constants cancel out, giving E . Using a lung ROI for blood activity, F was measured from first-pass and Ki’ from Gjedde–Patlak–Rutland (GPR) analysis up to 130 s. Because of interference from right ventricle, a left ventricular ROI (LV) is unsuitable for F’ but was used in GPR analysis, making an adjustment for the ratio of respective blood pool signals arising from lung and LV ROIs in early frames (60–90 s).
Results
A lung ROI underestimates F’ by 4% at normal LV function. Chest wall interstitial activity ( I ), which does not affect F’ , amounted to 53 and 30% of the lung and LV signals at 20 min, and 12 and 6% at 130 s, resulting in underestimations of Ki of 4 and 2%, respectively. Ignoring these opposing errors, E based on lung ROI for left and right kidneys was 43.5 (SD 8)% and 47.3 (9)%, and based on LV ROI for GPR analysis was 44.5 (10.9)% and 48.3 (10.6)%.
Conclusion
E can be measured by combining blood flow from first-pass with clearance from GPR analysis, and has potential value both clinically and in clinical research.
Acute respiratory distress syndrome (ARDS) is characterized by a redistribution of regional lung perfusion that impairs gas exchange. While speculative, experimental evidence suggests that perfusion redistribution may contribute to regional inflammation and modify disease progression. Unfortunately, tools to visualize and quantify lung perfusion in patients with ARDS are lacking. This review explores recent advances in perfusion imaging techniques that aim to understand the pulmonary circulation in ARDS. Dynamic contrast-enhanced computed tomography captures first-pass kinetics of intravenously injected dye during continuous scan acquisitions. Different contrast characteristics and kinetic modeling have improved its topographic measurement of pulmonary perfusion with high spatial and temporal resolution. Dual-energy computed tomography can map the pulmonary blood volume of the whole lung with limited radiation exposure, enabling its application in clinical research. Electrical impedance tomography can obtain serial topographic assessments of perfusion at the bedside in response to treatments such as inhaled nitric oxide and prone position. Ongoing technological improvements and emerging techniques will enhance lung perfusion imaging and aid its incorporation into the care of patients with ARDS.
Introduction: Pulmonary perfusion has been poorly characterized in acute respiratory distress syndrome(ARDS). Optimizing protocols to measure pulmonary blood flow(PBF) via dynamic contrast-enhanced(DCE) computed tomography(CT) could improve understanding of how ARDS alters pulmonary perfusion. In this study, comparative evaluations of injection protocols and tracer-kinetic analysis models were performed based on DCE-CT data measured in ventilated pigs with and without lung injury. Materials and Methods: 10 Yorkshire pigs were anesthetized, intubated, and mechanically ventilated; lung injury was induced by bronchial hydrochloric acid instillation. Each DCE-CT scan was obtained during 30-second end-expiratory breath-hold. Reproducibility of PBF measurements was evaluated in 3 pigs. In 8 pigs, undiluted and diluted Isovue-370 were separately injected to evaluate the effect of contrast viscosity on estimated PBF values. PBF was estimated with the peak-enhancement and the steepest-slope approach. Total-lung PBF was estimated in 2 healthy pigs to compare with cardiac output measured invasively by thermodilution in the pulmonary artery. Results: Repeated measurements in the same animals yielded a good reproducibility of computed PBF maps. Injecting diluted isovue-370 resulted in smaller contrast-time curves in the pulmonary artery(p<0.01) and vein(p<0.01) without substantially diminishing peak signal intensity(p=0.46 in the pulmonary artery) compared to the pure contrast agent since its viscosity is closer to that of blood. As compared to the peak-enhancement model, PBF values estimated by the steepest-slope model with diluted contrast were much closer to the cardiac output(R2=0.82) as compared to the peak-enhancement model. Conclusion: DCE-CT using the steepest-slope model and diluted contrast agent provided reliable quantitative estimates of PBF.
Purpose:
Assessment of tumour blood flow (BF) heterogeneity using first-pass FDG PET/CT and textural feature (TF) analysis is an innovative concept. We aim to explore the relationship between BF heterogeneity measured with different TFs calculation methods and the response to neoadjuvant chemotherapy (NAC) in patients with newly diagnosed breast cancer (BC).
Methods:
One hundred and twenty-five patients were enrolled. Dynamic first-pass and delayed FDG PET/CT scans were performed before NAC. Nine TFs were calculated from perfusion and metabolic PET images using relative (RR) or absolute (AR) rescaling strategies with two textural matrix calculation methods. Patients were classified according to presence or absence of a pathologic complete response (pCR) after NAC. The relationship between BF texture features and conventional features were analysed using spearman correlations. The TFs' differences between pCR and non-pCR groups were evaluated using Mann-Whitney tests and descriptive factorial discriminant analysis (FDA).
Results:
Relation between tumour BF-based TFs and global BF parameters were globally similar to those observed for tumour metabolism. None of the TFs was significantly different between pCR and non-pCR groups in the Mann-Whitney analysis, after Benjamini-Hochberg correction. Using a RR led to better discriminations between responders and non-responders in the FDA analysis. The best results were obtained by combining all the PET features, including BF ones.
Conclusion:
A better differentiation of patients reaching a pCR was observed using a RR. Moreover, BF heterogeneity might bring a useful information when combined with metabolic PET parameters to predict the pCR after neoadjuvant chemotherapy.
Experiments were undertaken using /sup 82/Rb and position tomography to examine the relation between myocardial perfusion and cation uptake during acute ischemia. /sup 82/Rb was repeatedly eluted from a /sup 82/Sr-/sup 82/Rb generator. In six dogs emission tomograms were used to measure the delivered arterial and myocardial concentrations at rest and after coronary stenosis, stress and ischemia. There was a poor overall relation between regional myocardial uptake and flow measured by microspheres and a large individual variability. Extraction of /sup 82/Rb was inversely related to flow. Significant regional reduction of cation uptake was detected in the tomograms when regional flow decreased by more than 35 percent. This reduction was significantly greater when ischemia was present. A small but significantly greater when ischemia was present. A small but significant decrease (33.0 +/- 9.1 percent, mean +/- standard deviation) in the myocardial uptake of /sup 82/Rb was detected only when flow was increased by more than 120 percent in relation to a control area after administration of dypiridamole. The technique using /sup 82/Rb and tomography was applied in five volunteers and five patients with angina pectoris and coronary artery disease. Myocardial tomograms recorded at rest and after exercise in the volunteers showed homogeneous uptake of cation in reproducible and repeatable scans. In contrast, the patients with coronary artery disease showed an absolute mean decrease of 36 +/- 14 percent in regional myocardial uptake of /sup 82/Rb after exercise. These abnormalities persisted in serial tomograms for more than 20 minutes after the symptoms and electrocardiographic signs of ischemia.
More than 50% of tracer rubidium entering the coronary circulation is actively taken up by the heart muscle cells during a single passage. Rubidium ions must traverse the capillary wall, the interstitial space, and the muscle cell membrane to enter the very large potential rubidium pool within the cells. The aim of this investigation was to determine which, if any, of these steps are rate limiting. The anterior descending branch of the left common coronary artery was perfused at its origin. Pulse injections containing 86Rb+ , 22Na+ or 14C-sucrose, and 125I-albumin were made into the perfusion line and timed serial samples of coronary sinus blood were collected and analyzed. A model was designed which incorporates rate constants describing both the exchange of 80Rb+ at the capillary wall and its entry at the muscle cell membrane. Labeled sucrose or 22Na+ was used to determine flow per interstitial fluid volume, a parameter necessary for the application of the model. It was assumed that the interstitial fluid volume available for labeled sucrose or 22Na+ was identical to that available for 86Rb+ . The rate constant describing exchange at the capillary wall (the permeability surface product per unit accessible interstitial fluid volume) increased with perfusion, whereas that for uptake by the myocardial cells was relatively constant and independent of flow.
Blood-tissue transport of 42 K, 8a Rb, and 22 Na was studied in perfused gracilis muscles of dogs to ascertain the influence of capillary wall, interstitial space, and muscle cell membranes on overall transport kinetics. Single-injection and continuous-infusion techniques were used, with T-1824 or 51 Cr-hemoglobin as nondiffusible references. Results were as follows: (1) Extraction (E) of the diffusible solutes was incomplete even in the earliest samples of venous outflow. (2) ERb equaled EK in the first few samples, but later, as both declined, the ratio of ERb to EK became less than one; stable ratios between 0.6 and 0.8 were established in different experiments. (3) ENa was initially slightly less than ERb or EK but declined much more sharply in successive samples. (4) Steady- state ERb and EK decreased with increasing blood flow but maintained a constant ratio. Vasomotion sometimes changed ERb and EK but had little effect on their ratio. Local anesthetics (procaine or cocaine) brought the ratio of ERb to EK closer to one. Analysis in terms of capillary and interstitial barriers, which do not discriminate between K, Rb, or Na, in series with a muscle cell membrane barrier, which does, leads to the following conclusions. (1) For K, the nondiscriminating barrier (mainly capillary wall) offeis about 70% of the total resistance to transport and the discriminating barrier (cell membrane) about 30%. (2) For Rb, each barrier offers half the total resistance. (3) The resting muscle cell membrane is 2.5 times more permeable to K than to Rb. Local anesthetics reduce cell permeability to both ions and decrease this ratio. (4) For Na, resistance at the capillary wall is about 1.3 times that for K or Rb. Resistance at the cell membrane is, of course, very much greater.
To facilitate characterization of regional myocardial kinetics of positron-emitting tracers in vivo without distortion by activity outside the region of interest, a probe was developed and evaluated for monitoring radioactivity by detection of positrons themselves. These particles (beta particles) have a maximal range in tissue of only few millimeters rather than the larger range of gamma photons emitted as a result of positron annihiliation. Regional myocardial time-activity curves were determined in open-chest dogs after intracoronary injection of 0.5-1.5 mCi [15O]H2O, a tracer used for measurement of myocardial blood flow, or 6.0-8.0 mCi [11C]palmitate, a tracer used for noninvasive assessment of myocardial metabolism. Time-activity curves after [11C]palmitate injection clearly delineated specific components of myocardial tracer clearance previously identified in vitro in isolated perfused hearts. Myocardial washout of [15O]H2O was monoexponential for more than 2 min without distortion induced by recirculating tracer in ventricular blood. Reproducibility of measured tracer clearance rates during monoexponential clearance was high based on duplicate determinations for both tracers. The beta-detector probe developed overcomes several intrinsic limitations of gamma-probe systems or well counting of serial myocardial biopsies for studies of positron-emitting tracers in vivo and should facilitate assessment of factors of influencing tracer kinetics in vivo relevant to positron-emission tomography.
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