Capillary Permeability-surface Area Product Research Articles

A Novel Multi-Model High Spatial Resolution Method for Analysis of DCE MRI Data: Insights from Vestibular Schwannoma Responses to Antiangiogenic Therapy in Type II Neurofibromatosis.

This study aimed to develop and evaluate a new DCE-MRI processing technique that combines LEGATOS, a dual-temporal resolution DCE-MRI technique, with multi-kinetic models. This technique enables high spatial resolution interrogation of flow and permeability effects, which is currently challenging to achieve. Twelve patients with neurofibromatosis type II-related vestibular schwannoma (20 tumours) undergoing bevacizumab therapy were imaged at 1.5 T both before and at 90 days following treatment. Using the new technique, whole-brain, high spatial resolution images of the contrast transfer coefficient (Ktrans), vascular fraction (vp), extravascular extracellular fraction (ve), capillary plasma flow (Fp), and the capillary permeability-surface area product (PS) could be obtained, and their predictive value was examined. Of the five microvascular parameters derived using the new method, baseline PS exhibited the strongest correlation with the baseline tumour volume (p = 0.03). Baseline ve showed the strongest correlation with the change in tumour volume, particularly the percentage tumour volume change at 90 days after treatment (p < 0.001), and PS demonstrated a larger reduction at 90 days after treatment (p = 0.0001) when compared to Ktrans or Fp alone. Both the capillary permeability-surface area product (PS) and the extravascular extracellular fraction (ve) significantly differentiated the 'responder' and 'non-responder' tumour groups at 90 days (p < 0.05 and p < 0.001, respectively). These results highlight that this novel DCE-MRI analysis approach can be used to evaluate tumour microvascular changes during treatment and the need for future larger clinical studies investigating its role in predicting antiangiogenic therapy response.

Critical Review of the Simple Theoretical Models in Dynamic Imaging: Up-Slope Method and Graphical Analysis.

Clinical imaging equipment technological advancements offer insight into the evolution of mathematical techniques used to estimate parameters necessary to characterize the microvasculature and, thus, differentiate normal tissues from abnormal ones. These parameters are blood flow (F), capillary endothelial permeability surface area product (PS), vascular fraction (ve), and extravascular extracellular space size (EES,ve). There are a number of well-established approaches that exist in the literature; however, their analysis is restricted by complexity and is heavily influenced by noise. On the other hand, these characteristics can also be calculated using simpler and straightforward approaches such as Up-Slope Method (USM) and Graphical Analysis (GA). The review looks into the theoretical background and clinical uses of these methodologies, as well as the applicability of these techniques in various sections of the human body.

Assessment of brain tumors by magnetic resonance dynamic susceptibility contrast perfusion-weighted imaging and computed tomography perfusion: a comparison study.

To investigate the association and agreement between magnetic resonance dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) and computed tomography perfusion (CTP) in determining vascularity and permeability of primary and secondary brain tumors. DSC-PWI and CTP studies from 97 patients with high-grade glioma, low-grade glioma and solitary brain metastasis were retrospectively reviewed. Normalized cerebral blood flow (nCBF), cerebral blood volume (nCBV), capillary transfer constant (nK2) and permeability surface area product (nPS) values were obtained. Variables among groups were compared, and correlation and agreement between DSC-PWI and CTP were tested. All DSC-PWI and CTP parameters were higher in high-grade than in low-grade gliomas (p < 0.01 and p < 0.001). Metastases had greater DSC-PWI nCBV (p < 0.05), nCTP-CBF (p < 0.05), nCTP-CBV (p < 0.01) and nCTP-PS (p < 0.0001) than low-grade gliomas and more elevated nCTP-PS (p < 0.01) than high-grade gliomas. The correlation was strong between DSC-PWI nCBF and CTP nCBF (r = 0.79; p < 0.00001) and between DSC-PWI nCBV and CTP nCBV (r = 0.83; p < 0.00001), weaker between DSC-PWI nK2 and CTP nPS (r = 0.29; p < 0.01). Bland-Altman plots indicated that the agreement was strong between DSC-PWI nCBF and CTP nCBF, good between DSC-PWI nCBV and CTP nCBV and poorer between DSC-PWI nK2 and CTP nPS. DSC-PWI and CTP CBF and CBV maps were comparable and interchangeable in the assessment of tumor vascularity, unlike DSC-PWI K2 and CTP PS maps that were more discordant in the analysis of tumor permeability. CTP could be an alternative method to quantify tumor neoangiogenesis when MRI is not available or when the patient does not tolerate it.

Modeling the measurement bias in interstitial glucose concentrations derived from microdialysis in skeletal muscle.

Muscle tissue utilizes glucose as a fuel during exercise and stores glucose in form of glycogen during rest. The associated glucose transport includes delivery of glucose from blood plasma into the interstitial space and subsequent, GLUT‐4 facilitated diffusion into muscle cells. The extent to which the vascular endothelium acts as a barrier to glucose transport, however, remains debated. While accurate measurements of interstitial glucose concentration (IGC) are key to resolve this debate, these are also challenging as removal of interstitial fluid may perturb glucose transport and therefore bias IGC measurements. We developed a three‐compartment model to infer IGC in skeletal muscle from its local metabolism and blood flow. The model predicts that IGC remains within 5% of that of blood plasma during resting conditions but decreases more as metabolism increases. Next, we determined how microdialysis protocols affect IGC. Our model analysis suggests that microdialysis‐based IGC measurements underestimate true values. Notably, reported increases in muscle capillary permeability surface area product (PS) to glucose under the condition of elevated metabolism may owe in part to such measurements bias.Our study demonstrates that microdialysis may be associated with significant measurement bias in the context of muscle IGC assessment. Reappraising literature data with this bias in mind, we find that muscle capillary endothelium may represent less of a barrier to glucose transport in muscle than previously believed. We discuss the impact of glucose removal on the microdialysis relative recovery and means of correcting microdialysis IGC values.

Perfusion Computer Tomography Assessment of the Effect of Angiotensin II On Blood Flow Distribution in Rabbits with Intrarenal VX2 Tumors

Background/Aims: Unlike other organs, which only have one set of capillary network, the renal microvasculature consists of two sets of capillary network series connected by efferent arterioles. Angiotensin II constricts the efferent glomerular artery. Hence, renal tumor blood flow (BF) distribution may be different from tumors in other organs. This study aims to investigate the effects of angiotensin II on the hemodynamics of intrarenal VX2 tumors using perfusion computed tomography(CT). Methods: Twenty-four male New Zealand white rabbits were randomly divided into three groups: groups A (blank controls), group B (negative controls), and group C (angiotensin II-treated animals). Group B and C were established to the model of intrarenal VX2 tumors. Furthermore, perfusion CT of the kidney was performed in each group. Prior to perfusion CT scan in group C, the mean arterial blood was elevated to 150-160 mmHg by angiotensin II. The BF, blood volume (BV), mean transit time (MTT), capillary permeability-surface area product (PS), and relative permeability-surface area product (RPS) of tumors and renal tissues were calculated. Results: Compared with normal renal cortex tissues in group A, the BF, BV and PS values of tumors in group B were significantly lower, MTT was prolonged and RPS increased. Compared with group B, only the RPS of these tumors increased from 83.23 ± 29.17% to 120.94 ± 31.84% by angiotensin II infusion. Angiotensin II significantly increased the RPS value of the renal cortex distant from the tumor (CDT) and the right renal cortex (RRC). Conclusions: Perfusion CT can accurately observe the influence of angiotensin II on normal and tumor BF in kidneys. This clarifies the effect of angiotensin II on intrarenal tumor hemodynamics.

Estimating breast tumor blood flow during neoadjuvant chemotherapy using interleaved high temporal and high spatial resolution MRI.

To evaluate an interleaved MRI sampling strategy that acquires both high temporal resolution (HTR) dynamic contrast-enhanced (DCE) data for quantifying breast tumor blood flow (TBF) and high spatial resolution (HSR) DCE data for clinical reporting, following a single standard injection of contrast agent. A simulation study was used to evaluate the performance of the interleaved technique under different conditions. In a prospective clinical study, 18 patients with primary breast cancer, who were due to undergo neoadjuvant chemotherapy (NACT), were examined using interleaved HTR and HSR DCE-MRI at 1.5 Tesla. Tumor regions of interest were analyzed with a two-compartment tracer kinetic model. Paired parameters (n = 10) from the data acquired before and post-cycle 2 of NACT were compared using the nonparametric Wilcoxon signed-rank test. Simulations demonstrated that TBF was reliably estimated using the proposed strategy. The region of interest analysis revealed significant changes in TBF (0.81-0.43 mL/min/mL; P = 0.002) following two cycles of NACT. The HSR data were reported in the normal way and enabled the assessment of tumor volume, which decreased by 53% following NACT (P = 0.065). TBF can be measured reliably using the proposed strategy without compromising a standard clinical protocol. Furthermore, in our feasibility study, TBF decreased significantly following NACT, whereas capillary permeability surface-area product did not. Magn Reson Med 79:317-326, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Measurement of extracellular volume and transit time heterogeneity using contrast-enhanced myocardial perfusion MRI in patients after acute myocardial infarction.

To assess the ability of dynamic contrast-enhanced myocardial perfusion MRI to measure extracellular volume (ECV) and to investigate the possibility of estimating capillary transit time heterogeneity (CTH) in patients after myocardial infarction and successful revascularization. Twenty-four perfusion data sets were acquired on a 3 Tesla positron emission tomography (PET)/MRI scanner. Three perfusion models of different complexity were implemented in a hierarchical fashion with an Akaike information criterion being used to determine the number of fit parameters supported by the data. Results were compared sector-wise to ECV from an equilibrium T1 mapping method (modified look-locker inversion recovery (MOLLI)). ECV derived from the perfusion analysis correlated well with equilibrium measurements (R² = 0.76). Estimation of CTH was supported in 16% of sectors (mostly remote). Inclusion of a nonzero CTH parameter usually led to lower estimates of first-pass extraction and slightly higher estimates of blood volume and flow. Estimation of the capillary permeability-surface area product was feasible in 81% of sectors. Transit time heterogeneity has a measurable effect on the kinetic analysis of myocardial perfusion MRI data, and Gd-DTPA extravasation in the myocardium is usually not flow-limited in infarct-related pathology. Measurement of myocardial ECV using perfusion imaging could provide a scan-time efficient alternative to methods based on T1 mapping. Magn Reson Med 77:2320-2330, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Possibilities of differentiation of solitary focal liver lesions by computed tomography perfusion.

To evaluate possibilities of computed tomography (CT) perfusion in differentiation of solitary focal liver lesions based on their characteristic vascularization through perfusion parameters analysis. Prospective study was conducted on 50 patients in the period 2009-2012. Patients were divided in two groups: benign and malignant lesions. The following CT perfusion parameters were analyzed: blood flow (BF), blood volume (BV), mean transit time (MTT), capillary permeability surface area product (PS), hepatic arterial fraction (HAF), and impulse residual function (IRF). During the study another perfusion parameter was analyzed: hepatic perfusion index (HPI). All patients were examined on Multidetector 64-slice CT machine (GE) with application of perfusion protocol for liver with i.v. administration of contrast agent. In both groups an increase of vascularization and arterial blood flow was noticed, but there was no significant statistical difference between any of 6 analyzed parameters. Hepatic perfusion index values were increased in all lesions in comparison with normal liver parenchyma. Computed tomography perfusion in our study did not allow differentiation of benign and malignant liver lesions based on analysis of functional perfusion parameters. Hepatic perfusion index should be investigated in further studies as a parameter for detection of possible presence of micro-metastases in visually homogeneous liver in cases with no lesions found during standard CT protocol.

Commentary: Microalbuminuria: Past, present and glorious future

In 1969, Keen and colleagues demonstrated increased urinary albumin excretion (microalbuminuria) during a 50-g glucose load in people with diabetes, compared with those with borderline diabetes and controls, applying a sensitive radioimmunoassay method. The 2-h urinary albumin concentration correlated positively with blood glucose and blood pressure in the diabetic group. This led the authors to suggest: ‘The therapeutic implications of this is that treatment of hypertension associated with diabetes may ameliorate or delay the onset of renal disease’. Increased urinary albumin excretion is the net result of glomerular capillary passage and tubular reabsorption. Increased glomerular albumin passage occurs due to functional and structural abnormalities such as: increased glomerular capillary permeability-surface area product (size and charge selectivity); and elevated glomerular hydraulic pressure. Recently, the importance of the glycocalyx for macromolecular transvascular transport has been documented. Poor glycaemic regulation and diabetes reduce the glycocalyx, leading to increased albuminuria. Studies in diabetic animals and man have demonstrated enhanced size and charge selectivity for large macromolecules and raised measured and estimated glomerular capillary hydraulic pressure. The landmark study by Keen et al. created an avalanche of retroand prospective observational studies demonstrating the predictive power of microalbuminuria for: diabetic nephropathy, end-stage renal disease, fatal and nonfatal cardiovascular events in type 1 and type 2 diabetes, hypertension and in the general population. The mechanisms linking microalbuminuria with fatal and nonfatal cardiovascular disease remain poorly understood. Microalbuminuria has been proposed as a marker of widespread endothelial dysfunction that might predispose to enhanced penetrations in the arterial wall of atherogenic lipoprotein particles (the Steno hypothesis). Secondly, microalbuminuria has been suggested simply as a marker of established cardiovascular disease. Thirdly, microalbuminuria is associated with excess of well-known cardiovascular risk factors such as: elevated blood pressure, dyslipoproteinaemia, increased platelet aggregability, insulin resistance and autonomic neuropathy. It is important to recall that no therapy was available for preventing or treating overt diabetic nephropathy in 1969. My own experience between 1975 and 1980 as a senior registrar at Steno Diabetes Center in Copenhagen, caring for approximately 6000 diabetic patients, can be described as a hospital flooded with young type 1 diabetic patients with end-stage renal disease, waiting to die. No therapy was available, including dialysis/transplantation which were not offered by our nephrologists because our patients frequently suffered from several severe vascular and neurological complications. Two to three decades later, numerous studies have demonstrated a renoprotective effect of improved glycaemic regulation, arterial blood pressure reduction, blockade of the renin-angiotensin system independent of blood pressure and intensified multifactorial intervention—with tight glucose regulation, and the use of renin-angiotensin system blockers, aspirin and lipidlowering agents. Glycaemic regulation has mainly a beneficial effect early in the development of diabetic nephropathy i.e. progression from normoalbuminuria to microalbuminuria. Blood pressure reduction, blockade of the renin-angiotensin system and intensified multifactorial intervention act on every stage of development and progression of diabetic nephropathy and end-stage renal disease. It should also be stressed that the above-mentioned treatment modalities can induce regression of urinary albumin excretion rate, and thereby preserve measured glomerular filtration rate. Those studies suggest that microalbuminuria is a risk factor for diabetic nephropathy [end-stage renal disease (ESRD)]. Recently many new biomarkers have been evaluated as predictors for renal risk in diabetic patients, but apart from urinary proteomics (expensive, timeconsuming and with limited access), none has yet Published by Oxford University Press on behalf of the International Epidemiological Association

Investigation on the optical scan condition for imaging of multi-slice spiral CT liver perfusion in rats

Background Multi-slice CT liver perfusion has been widely used in experimental studies of hemodynamic changes in liver lesions, and is usually performed as an adjunct to a conventional CT examination because of its high temporal and spatial resolution, simple protocol, good reproducibility, and ability to measure hemodynamic changes of liver tissues at the capillary level. Experimental rat models, especially those of induced liver cancer, are often used in studies of hemodynamic changes in liver cancer. Carcinogenesis in rats has a similar pathological progression and characteristics resembling those in human liver cancer; as a result, rat models are often used as ideal animal models in the study of human liver cancer. However, liver perfusion imaging in rats is difficult to perform, because rats' livers are so small that different concentrations, flow rates, and dose of contrast agents during the CT perfusion scanning can influence the quality of liver perfusion images in rats. The purpose of this study, therefore, was to investigate the optimal scan protocol for the imaging of hepatic perfusion using a deconvolution mathematical method in rats by comparing the results of rats in different injection conditions of the contrast agent, including concentration, rate and time. Methods Plain CT scan conditions in eighty 2-month-old male Wistar rats were 5.0 mm slice thickness, 5.0 mm interval, 1.0 pitch, 120 kV tube voltage, 60 mA tube current, 512×512 matrix, and FOV 9.6 cm. Perfusion scanning was carried out with different concentrations of diatrizoate (19%, 38%, 57%, and 76%), different injection rates (0.3 and 0.5 ml/s), and different injection times (1, 2-3, 4-5, and 6 seconds). The above conditions were randomly matched and adjusted to determine the best perfusion scan protocol. Three-phase contrast-enhanced scanning was performed after CT perfusion. Histological examination of the liver tissues with hematoxylin and eosin stains was done after CT scanning. Results When the concentration of the contrast agent was 19% or 38%, no pseudo-color map was created. The viscosity increased when the concentration of the contrast agent was 76%; so it is difficult to inject the contrast agent at such a high concentration. Also no pseudo-color map was generated when the injection time was short (1, 2-3, and 4-5 seconds) or the injection rate was low (0.3 ml/s). The best perfusion images and perfusion parameters were obtained during 50 seconds scanning. Each rat was given an injection of 57% diatrizoate at 0.5 ml/s via the tail vein using a high-pressure syringe for 6 seconds. The perfusion parameters included hepatic blood flow (HBF), hepatic blood volume (HBV), mean transit time (MTT) of the contrast agent, capillary permeability-surface area product (PS), hepatic arterial index (HAI), hepatic artery perfusion (HAP), and hepatic portal perfusion (HPP). All these parameters reflected the perfusion status of liver parenchyma in normal rats. Three phases of enhancement were modified according to the time-density curves (TDCs) of the perfusion imaging: hepatic arterial phase (7 seconds), hepatic portal venous phase (15 seconds), and a delayed phase (23-31 seconds). On examination by microscopy, the liver tissues were pathologically normal. Conclusions The appropriate protocol with multi-slice spiral CT liver perfusion reflected normal liver hemodynamics in rats. This study laid a solid foundation for further investigation of the physiological characteristics of liver cancer in a rat model, and was an important supplement to and reference for conventional contrast-enhanced CT scans.

Increased microvascular proliferation is negatively correlated to tumour blood flow and is associated with unfavourable outcome in endometrial carcinomas

Background:We aimed to study the angiogenic profile based on histomorphological markers in endometrial carcinomas in relation to imaging parameters obtained from preoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) and to explore the potential value of these markers to identify patients with poor outcome.Methods:In fifty-four surgically staged endometrial carcinoma patients, immunohistochemical staining with factor VIII and Ki67 allowed assessment of microvessel density (MVD) and microvascular proliferation reflecting tumour angiogenesis. In the same patients, preoperative pelvic DCE-MRI and DWI allowed the calculation of parameters describing tumour microvasculature and microstructure in vivo.Results:Microvascular proliferation was negatively correlated to tumour blood flow (Fb) (r=−0.36, P=0.008), capillary permeability surface area product (PS) (r=−0.39, P=0.004) and transfer from the blood to extravascular extracellular space (EES) (Ktrans) (r=−0.40, P=0.003), and was positively correlated to tumour volume (r=0.34; P=0.004). High-tumour microvascular proliferation, low Fb and low Ktrans were all significantly associated with reduced progression/recurrence-free survival (P<0.05).Conclusion:Disorganised angiogenesis with coexisting microvascular proliferation and low tumour blood flow is a poor prognostic factor supporting that hypoxia is associated with progression and metastatic spread in endometrial carcinomas.

Dynamic contrast-enhanced MRI in endometrial carcinoma identifies patients at increased risk of recurrence

To study the feasibility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for assessment of tumour microvasculature in endometrial carcinoma patients, and to explore correlations with histological subtype, clinical course and microstructural characteristics based on apparent diffusion coefficient (ADC) values. Diffusion-weighted imaging (DWI) and three-dimensional DCE-MRI (1.5 T) with high temporal resolution (2.49 s) were acquired preoperatively in 55 patients. Quantitative modelling allowed the calculation of four independent parameters describing microvasculature: blood flow (Fb), extraction fraction (E), capillary transit time (Tc) and transfer constant from the extravascular extracellular space [EES] to blood (Kep); and four derived parameters: blood volume (Vb), volume of EES (Ve), capillary permeability surface area product (PS) and transfer from blood to EES (Ktrans). Endometrial carcinoma tissue exhibited reduced Fb, E, Vb, Ve, PS and Ktrans compared with normal myometrium. Non-endometrioid carcinomas (n = 12) had lower Fb, and E than endometrioid carcinomas (n = 43; P < 0.05). Tumour Ve positively correlated with tumour ADC value (r = 0.29, P = 0.03). Reduced survival was observed in patients with low tumour Fb and high tumour Tc (P < 0.05). We demonstrate the feasibility of DCE-MRI in reflecting histological subtype and clinical course in primary endometrial carcinomas. DCE-MRI may potentially provide future biomarkers for preoperative risk stratification in endometrial carcinomas. • Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) offers new information about endometrial carcinoma. • Pelvic DCE-MRI with subsequent quantitative modelling seems feasible in endometrial carcinoma patients. • Low tumour perfusion is a feature of a more aggressive tumour subtype. • DCE-MRI provides potential biomarkers for preoperative risk stratification in endometrial carcinoma patients.

SU‐E‐I‐18: Uncertainty Analysis of Pharmacokinetic Modeling in Dynamic Contrast‐Enhanced MRI Evaluated with MMID4 Simulation

Purpose: Uncertainty analysis including accuracy and precision evaluation is important for the pharmacokinetic modeling in dynamic contrast‐enhanced (DCE) MRI. Few studies had attempted to assess the precision of the commonly used modified Tofts and Kermode (mTK) and the adiabatic approximation to the tissue homogeneity (AATH) models using neutrally simulated data. The study aimed to investigate the precision of these two models using the time curves simulated by multiple path, multiple tracer, indicator dilution, 4 region (MMID4) model, and perform comparisons in patients with nasopharyngeal carcinoma (NPC). Methods: Tissue uptake curves were simulated using the MMID4 model, by adjusting input parameters including blood flow, capillary permeability surface area product, interstitial volume (Ve) and capillary plasma volume(Vp), using literature values representing breast tumor and meningioma. Four levels of Gaussian noise, corresponding to SNRs of 100, 50, 20 and 10, were added to the signal time curves, with 1000 iterations each. A literature‐based arterial input function was applied to the model. For NPC datasets, DCE‐MRI was performed at a 3T clinical scanner using a 3D‐SPGR sequence (TR/TE/FA=4.9ms/1.3ms/30degrees, 60 dynamics, sampling interval=3.9s). Results: Our simulation showed that the AATH provided better accuracy than the mTK model. From the results of the NPC patients, the AATH gave smaller transfer constant (Ktrans) and Ve, and larger Vp values, as compared to mTK model, which agreed with the simulation data. When comparing the coefficient of variance of common parameters by both models, the mTK resulted in superior precision than AATH, and greater CV was found with smaller SNR in all cases. Conclusion: Using the MMID4 model for data simulation, this work found that the AATH model resulted in more accurate but less precise estimates of physiological parameters as compared to the mTK model. Results from the analysis of clinical NPC data were consistent with the computer simulation.

The coronary circulation in exercise training.

Exercise training (EX) induces increases in coronary transport capacity through adaptations in the coronary microcirculation including increased arteriolar diameters and/or densities and changes in the vasomotor reactivity of coronary resistance arteries. In large animals, EX increases capillary exchange capacity through angiogenesis of new capillaries at a rate matched to EX-induced cardiac hypertrophy so that capillary density remains normal. However, after EX coronary capillary exchange area is greater (i.e., capillary permeability surface area product is greater) at any given blood flow because of altered coronary vascular resistance and matching of exchange surface area and blood flow distribution. The improved coronary capillary blood flow distribution appears to be the result of structural changes in the coronary tree and alterations in vasoreactivity of coronary resistance arteries. EX also alters vasomotor reactivity of conduit coronary arteries in that after EX, α-adrenergic receptor responsiveness is blunted. Of interest, α- and β-adrenergic tone appears to be maintained in the coronary microcirculation in the presence of lower circulating catecholamine levels because of increased receptor responsiveness to adrenergic stimulation. EX also alters other vasomotor control processes of coronary resistance vessels. For example, coronary arterioles exhibit increased myogenic tone after EX, likely because of a calcium-dependent PKC signaling-mediated alteration in voltage-gated calcium channel activity in response to stretch. Conversely, EX augments endothelium-dependent vasodilation throughout the coronary arteriolar network and in the conduit arteries in coronary artery disease (CAD). The enhanced endothelium-dependent dilation appears to result from increased nitric oxide bioavailability because of changes in nitric oxide synthase expression/activity and decreased oxidant stress. EX also decreases extravascular compressive forces in the myocardium at rest and at comparable levels of exercise, mainly because of decreases in heart rate and duration of systole. EX does not stimulate growth of coronary collateral vessels in the normal heart. However, if exercise produces ischemia, which would be absent or minimal under resting conditions, there is evidence that collateral growth can be enhanced. While there is evidence that EX can decrease the progression of atherosclerotic lesions or even induce the regression of atherosclerotic lesions in humans, the evidence of this is not strong due to the fact that most prospective trials conducted to date have included other lifestyle changes and treatment strategies by necessity. The literature from large animal models of CAD also presents a cloudy picture concerning whether EX can induce the regression of or slow the progression of atherosclerotic lesions. Thus, while evidence from research using humans with CAD and animal models of CAD indicates that EX increases endothelium-dependent dilation throughout the coronary vascular tree, evidence that EX reverses or slows the progression of lesion development in CAD is not conclusive at this time. This suggests that the beneficial effects of EX in CAD may not be the result of direct effects on the coronary artery wall. If this suggestion is true, it is important to determine the mechanisms involved in these beneficial effects.

Perfusion CT Assessment of Tissue Hemodynamics Following Hepatic Arterial Infusion of Increasing Doses of Angiotensin II in a Rabbit Liver Tumor Model

To investigate the effects of increasing doses of angiotensin II on hepatic hemodynamics in the normal rabbit liver and in hepatic VX2 tumors by using dynamic contrast material-enhanced perfusion computed tomography (CT). This study was approved by the institutional animal care and use committee. Solitary hepatic VX2 tumors were implanted into 12 rabbits. In each animal, perfusion CT of the liver was performed before (at baseline) and after hepatic arterial infusion of varying doses (0.1-50.0 μg/mL) of angiotensin II. Images were acquired continuously for 80 seconds after the start of the intravenous contrast material administration. Blood flow (BF), blood volume (BV), mean transit time (MTT), and capillary permeability-surface area product were calculated for the tumor and the adjacent and distant normal liver tissue. Generalized linear mixed models were used to estimate the effects of angiotensin II dose on outcome measures. Angiotensin II infusion increased contrast enhancement of the tumor and distal liver vessels. Tumor BF increased in a dose-dependent manner after administration of 0.5-25.0 μg/mL angiotensin II, but only the 2.5 μg/mL dose induced a significant increase in tumor BF compared with BF in the adjacent (68.0 vs 26.3 mL/min/100 g, P < .0001) and distant (68.0 vs 28.3 mL/min/100 g, P = .02) normal liver tissue. Tumor BV varied with angiotensin II dose but was greater than the BV of the adjacent and distant liver tissue at only the 2.5 μg/mL (4.8 vs 3.5 mL/100 g for adjacent liver [P < .0001], 4.8 vs 3.3 mL/100 g for distant liver [P = .0006]) and 10.0 μg/mL (4.9 vs 4.4 mL/100 g for adjacent liver [P = .007], 4.9 vs 4.3 mL/100 g for distant liver [P = .04]) doses. Tumor MTT was significantly shorter than the adjacent liver tissue MTT at angiotensin II doses of 2.5 μg/mL (9.7 vs 15.8 sec, P = .001) and 10.0 μg/mL (5.1 vs 13.2 sec, P = .007) and significantly shorter than the distant liver tissue MTT at 2.5 μg/mL only (9.7 vs 15.3 sec, P = .0006). The capillary permeability-surface area product for the tumor was higher than that for the adjacent liver tissue at the 2.5 μg/mL angiotensin II dose only (11.5 vs 8.1 mL/min/100 g, P = .01). Perfusion CT enables a mechanistic understanding of angiotensin II infusion in the liver and derivation of the optimal effective dose. The 2.5 μg/mL angiotensin II dose increases perfusion in hepatic VX2 tumors versus that in adjacent and distant normal liver tissue primarily by constricting normal distal liver vessels and in turn increasing tumor BF and BV.

Dynamic contrast enhanced MRI (DCE MRI) for Phase I anti-angiogenic trial: Comparison of the transfer constant (Ktrans) to blood flow and permeability derived by a distributed parameter model

3514 Background: The distributed parameter (DP) model is a DCE-MRI model that enables derivation of blood flow and capillary permeability-surface area product (PS). We aim to compare the DP model to Ktrans in the assessment of angiogenesis assessment in a Phase I anti- angiogenic trial. Methods: Twenty-seven evaluable patients from a completed phase I trial (ABT-869) with 3 dose escalations formed the study population. All patients underwent DCE-MRI at baseline, Day 3 and Day 15 with temporal resolution of 4 seconds. Gadolinium concentrations were estimated using dual flip angle method. Ktrans, normalized IAUC60, permeability-surface area product derived from DP model (DP-PS), and blood flow derived from DP model, were calculated. Patients demonstrating progressive disease in first 2 evaluations scans (cycle 2 or 4) based on RECIST criteria were considered progressors and all other patients, non-progressors. Receiver operating curve (ROC) analysis was performed. Correlation with area under the curve extrapolated to infinity (AUCinf) was analyzed. Results: There is good correlation between DP-PS and drug exposure above threshold (threshold concentration 80 ng/mL; time threshold 3.5 hours) measured by AUCinf (Spearman's coefficient −0.556, p = 0.007). Although slightly weaker correlation is found with normalized IAUC60 (Spearman's coefficient −0.537, p = 0.01), the difference is not significant. (p = 0.9334) There is poor correlation for Ktrans (Spearman's coefficient −0.128, p = 0.570). ROC analysis for predicting progressors versus non-progressors showed a higher ROC area for DP-PS compared to Ktrans (0.869 versus 0.417, p < 0.001) and normalized IAUC60 (0.869 versus 0.643, p = 0.1543, not significant). Using a 29.45% drop from baseline at Day 15 to predict non-progressors, the sensitivity of DP-PS is 64.3% and the specificity is 100% whereas the sensitivity of Ktrans is 28.6% and the specificity is 66.7%. In 7 cases, DP-PS correctly predicted the eventual outcome whereas Ktrans predicted the direct opposite. Conclusion: Permeability-surface area product derived from DP model shows better correlation with drug exposure and may predict patient outcome better than Ktrans. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories

Effects of Intrabrachial Metacholine Infusion on Muscle Capillary Recruitment and Forearm Glucose Uptake during Physiological Hyperinsulinemia in Obese, Insulin-Resistant Individuals

Impairment of insulin-mediated capillary recruitment in skeletal muscle contributes to a hampered glucose uptake in obesity. The objective of this study was to evaluate whether metacholine (MCh), a nitric oxide vasodilator, potentiates muscle capillary recruitment and forearm glucose uptake (FGU) during physiological hyperinsulinemia. The double-forearm technique [i.e. infused vs. control (Ctrl) forearm] was combined with im microdialysis during an oral glucose tolerance test in 15 nondiabetic, obese subjects divided into a group of insulin-resistant (IR) (n = 7) and insulin-sensitive (n = 8) individuals. After the oral glucose tolerance test, forearm blood flow in the Ctrl forearm was unchanged, whereas it increased about 3-fold (P < 0.0001 vs. baseline) in response to MCh. Capillary permeability surface area product for glucose (PS(glu)) (capillary recruitment), FGU, and interstitial insulin concentrations increased significantly over time (P < 0.001) in both forearms. Compared with insulin-sensitive, the IR subjects exhibited lower PS(glu) (P < 0.001) and FGU (P < 0.01) in the Ctrl arm, whereas this difference was insignificant in the MCh arm despite the blunted forearm blood flow increase. Moreover, in IR individuals MCh significantly (P < 0.05) ameliorated the delayed onset of insulin action, i.e. the FGU response to hyperinsulinemia. Finally, we found PS(glu) to be a strong and independent predictor of FGU response (adjusted R(2) 0.72; P < 0.0001). MCh-induced vasodilation may improve the microvascular and metabolic responses to physiological hyperinsulinemia in obese, IR individuals. Further studies are required to unravel whether stimulation of nitric oxide production in skeletal muscle may represent an attractive therapeutic approach to bypassing cellular resistance to glucose disposal.

Late tissue effects following radiotherapy and neoadjuvant hormone therapy of the prostate measured with quantitative magnetic resonance imaging

Background and Purpose To use quantitative MRI to detect changes in the vascular and MR relaxation characteristics of the prostate gland 1 year after external beam radiotherapy. Materials and methods Twenty-one patients underwent MRI before and after external beam radiotherapy for prostatic adenocarcinoma. Tracer kinetics analysis was applied to data from regions of interest in prostate tumour, normal prostate peripheral zone and muscle to obtain estimates of blood flow, extravascular–extracellular volume, blood volume and capillary permeability surface area product. T 1 and T 2 were also measured in these regions. Results Significant changes ( p < 0.05) after radiotherapy were found in all three tissues examined. Tumour blood flow was 0.34 and 0.14 ml (ml tissue) −1 min −1 before and after treatment, respectively, and T 1 increased from 922 to 1070 ms. In normal peripheral zone, extravascular–extracellular volume increased from 0.21 to 0.52 ml (ml tissue) −1, and T 2 decreased from 126 to 106 ms. In muscle, both permeability surface area product and T 2 rose, from 0.02 to 0.06 ml (ml tissue) −1 min −1 and from 50 to 56 ms, respectively. Conclusions Quantitative MRI can be used to measure significant changes in both vascular and MR relaxation properties of the prostate and nearby muscle following treatment for prostate cancer using external beam radiotherapy.

Stress Perfusion Magnetic Resonance Imaging of the Heart

Extensive research has documented that rapid imaging during the first pass of a magnetic resonance imaging (MRI) contrast agent provides good sensitivity to detect myocardial blood flow deficits caused by coronary disease, cardiomyopathies, or microvascular dysfunction in patients without obstructive lesions in the coronary arteries. The autoregulatory mechanisms of the coronary circulation serve the purpose of maintaining sufficient blood flow at baseline in the presence of flow-obstructing coronary lesions. Stress testing is most commonly used in this setting to determine the hemodynamic effect of coronary lesions in the epicardial arteries when the small-vessel resistance has been minimized by vasodilation. The protocols for perfusion MRI combined with vasodilation have been successfully tested in large patient studies. Besides the absence of any ionizing radiation, MRI offers the advantages of relatively high spatial resolution to detect perfusion defects limited to the inner layer of the heart muscle. Furthermore, MRI can be used for noninvasive quantitative measurements of myocardial blood flow that compare well with invasive measurements with labeled microspheres. Additional useful markers, such as the dynamic distribution volume, the delay in the arrival of the contrast agent in a myocardial region relative to the enhancement in the arterial input, and the capillary permeability-surface area product, may, in the future, further enhance the capabilities to characterize with MRI coronary atherosclerosis, coronary vascular dysfunction, and adaptive mechanisms in the coronary circulation, such as arteriogenesis, that reduce ischemia.

What levels of precision are achievable for quantification of perfusion and capillary permeability surface area product using ASL?

We examine the use of arterial spin labeling (ASL) in normal brains of rats and humans to measure perfusion (F) and capillary permeability surface area product (PS) using a previously described two-compartment model. We investigate the experimental limits on F and PS quantification using simulations and experimental verification in rat brain at 9.4T. A sensitivity analysis on the two-compartment model is presented to estimate optimal experimental inversion times (TIs) for F and PS quantification and indicate how sensitive the model would be to changes in F and PS. We present the expected error on flow-sensitive alternating inversion recovery (FAIR)-based F and PS measurements and quantify the precision with which these parameters could be estimated at various signal-to-noise ratios (SNRs). Perfusion was measured in four rat brains using FAIR ASL, and we conclude that perfusion could be quantified with an acceptable level of precision using this technique. However, we found that to measure PS with even a 100% coefficient of variation (CV) would require an SNR increase of approximately 2 orders of magnitude over our acquired data. We conclude that with current MR capabilities and with the experimental approach used in this study, acceptable levels of precision in the measurement of PS are not possible.