Glyoxalase-1 overexpression partially prevents diabetes-induced impaired arteriogenesis in a rat hindlimb ligation model.

We hypothesize that diabetes-induced impaired collateral formation after a hindlimb ligation in rats is in part caused by intracellular glycation and that overexpression of glyoxalase-I (GLO-I), i.e. the major detoxifying enzyme for advanced-glycation-endproduct (AGE) precursors, can prevent this. Wild-type and GLO-I transgenic rats with or without diabetes (induced by 55 mg/kg streptozotocin) were subjected to ligation of the right femoral artery. Laser Doppler perfusion imaging showed a significantly decreased blood perfusion recovery after 6 days in the diabetic animals compared with control animals, without any effect of Glo1 overexpression. In vivo time-of-flight magnetic resonance angiography at 7-Tesla showed a significant decrease in the number and volume of collaterals in the wild-type diabetic animals compared with the control animals. Glo1 overexpression partially prevented this decrease in the diabetic animals. Diabetes-induced impairment of arteriogenic adaptation can be partially rescued by overexpressing of GLO-I, indicating a role of AGEs in diabetes-induced impaired collateral formation.

Semi-automated quantitative intravoxel incoherent motion analysis and its implementation in breast diffusion-weighted imaging.

BACKGROUND: To optimize and validate intravoxel incoherent motion (IVIM) modeled diffusion-weighted imaging (DWI) compared with the apparent diffusion coefficient (ADC) for semi-automated analysis of breast lesions using a multi-reader setup. MATERIALS AND METHODS: Patients (n = 176) with breast lesions (≥1 cm) and known pathology were prospectively examined (1.5 Tesla) with DWI (b = 0, 50, 200, 500, 800, 1000 s/mm(2) ) between November 2008 and July 2014 and grouped into a training and test set. Three independent readers applied a semi-automated procedure for setting regions-of-interest for each lesion and recorded ADC and IVIM parameters: molecular diffusion (Dslow ), microperfusion (Dfast ), and the fraction of Dfast (ffast ). In the training set (24 lesions, 12 benign), a semi-automated method was optimized to yield maximum true negatives (TN) with minimal false negatives (FN): only the optimal fraction (Fo) of voxels in the lesions was used and optimal thresholds were determined. The optimal Fo and thresholds were then applied to a consecutive test set (139 lesions, 23 benign) to obtain specificity and sensitivity. RESULTS: In the training set, optimal thresholds were 1.44 × 10(-3) mm(2) /s (Dslow ), 18.55 × 10(-3) mm(2) /s (Dfast ), 0.247 (ffast ) and 2.00 × 10(-3) mm(2) /s (ADC) with Fo set to 0.61, 0.85, 1.0, and 1.0, respectively, this resulted in TN = 5 (IVIM) and TN = 1 (ADC), with FN = 0. In the test set, sensitivity and specificity among the readers were 90.5-93.1% and 43.5-52.2%, respectively, for IVIM, and 94.8-95.7% and 13.0-21.7% for ADC (P ≤ 0.0034) without inter-reader differences (P = 1.000). CONCLUSION: The presented semi-automated method for breast lesion evaluation is reader independent and yields significantly higher specificity for IVIM compared with the ADC.

Impact of right ventricular endocardial trabeculae on volumes and function assessed by CMR in patients with tetralogy of Fallot.

The objective of this study was to assess the impact of right ventricular (RV) trabeculae and papillary muscles on measured volumes and function assessed by cardiovascular magnetic resonance imaging in patients with repaired tetralogy of Fallot. Sixty-five patients with repaired tetralogy of Fallot underwent routine cardiovascular magnetic resonance imaging. Endocardial and epicardial contours were drawn manually and included trabeculae and papillary muscles in the blood volume. Semi-automatic threshold-based segmentation software excluded these structures. Both methods were compared in terms of end-diastolic, end-systolic and stroke volume, ejection fraction and mass. Observer agreement was determined for all measures. Exclusion of trabeculae and papillary muscle in the RV blood volume decreased measured RV end-diastolic volume by 15 % (from 140 ± 35 to 120 ± 32 ml/m(2)) compared to inclusion, end-systolic volume by 21 % (from 74 ± 23 to 59 ± 20 ml/m(2)), stroke volume by 9 % (from 66 ± 16 to 60 ± 16 ml/m(2)) and relatively increased ejection fraction by 7 % (from 48 ± 7 to 51 ± 8 %) and end-diastolic mass by 79 % (from 28 ± 7 to 51 ± 10 g/m(2)), p < .01. Excluding trabeculae and papillary muscle resulted in an improved interobserver agreement of RV mass compared to including these structures (coefficient of agreement of 87 versus 78 %, p < .01). Trabeculae and papillary muscle significantly affect measured RV volumes, function and mass. Semi-automatic threshold-based segmentation software can reliably exclude trabeculae and papillary muscles from the RV blood volume.

Dynamic contrast-enhanced MR imaging of carotid atherosclerotic plaque: model selection, reproducibility, and validation.

PURPOSE: To compare four known pharmacokinetic models for their ability to describe dynamic contrast material-enhanced magnetic resonance (MR) imaging of carotid atherosclerotic plaques, to determine reproducibility, and to validate the results with histologic findings. MATERIALS AND METHODS: The study was approved by the institutional medical ethics committee. Written informed consent was obtained from all patients. Forty-five patients with 30%-99% carotid stenosis underwent dynamic contrast-enhanced MR imaging. Plaque enhancement was measured at 16 time points at approximately 25-second image intervals by using a gadolinium-based contrast material. Pharmacokinetic parameters (volume transfer constant, K(trans); extracellular extravascular volume fraction, v(e); and blood plasma fraction, v(p)) were determined by fitting a two-compartment model to plaque and blood gadolinium concentration curves. The relative fit errors and parameter uncertainties were determined to find the most suitable model. Sixteen patients underwent imaging twice to determine reproducibility. Carotid endarterectomy specimens from 16 patients who were scheduled for surgery were collected for histologic validation. Parameter uncertainties were compared with the Wilcoxon signed rank test. Reproducibility was assessed by using the coefficient of variation. Correlation with histologic findings was evaluated with the Pearson correlation coefficient. RESULTS: The mean relative fit uncertainty (±standard error) for K(trans) was 10% ± 1 with the Patlak model, which was significantly lower than that with the Tofts (20% ± 1), extended Tofts (33% ± 3), and extended graphical (29% ± 3) models (P < .001). The relative uncertainty for v(p) was 20% ± 2 with the Patlak model and was significantly higher with the extended Tofts (46% ± 9) and extended graphical (35% ± 5) models (P < .001). The reproducibility (coefficient of variation) for the Patlak model was 16% for K(trans) and 26% for v(p). Significant positive correlations were found between K(trans) and the endothelial microvessel content determined on histologic slices (Pearson ρ = 0.72, P = .005). CONCLUSION: The Patlak model is most suited for describing carotid plaque enhancement. Correlation with histologic findings validated K(trans) as an indicator of plaque microvasculature, and the reproducibility of K(trans) was good.

Improving the reproducibility of MR-derived left ventricular volume and function measurements with a semi-automatic threshold-based segmentation algorithm.

To validate a novel semi-automatic segmentation algorithm for MR-derived volume and function measurements by comparing it with the standard method of manual contour tracing. The new algorithms excludes papillary muscles and trabeculae from the blood pool, while the manual approach includes these objects in the blood pool. An epicardial contour served as input for both methods. Multiphase 2D steady-state free precession short axis images were acquired in 12 subjects with normal heart function and in a dynamic anthropomorphic heart phantom on a 1.5 T MR system. In the heart phantom, manually and semi-automatically measured cardiac parameters were compared to the true end-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction (EF). In the subjects, the semi-automatic method was compared to manual contouring in terms of difference in measured EDV, ESV, EF and myocardial volume (MV). For all measures, intra- and inter-observer agreement was determined. In the heart phantom, EDV and ESV were underestimated for both the semi-automatic. As the papillary muscles were excluded from the blood pool with the semi-automatic method, EDV and ESV were approximately 20 ml lower in the patients, whereas EF was approximately 16 % higher. Intra- and inter-observer agreement was overall improved with the semi-automatic method compared to the manual method. Correlation between manual and semi-automatic measurements was high (EDV: R = 0.99, ESV: R = 0.96; EF: R = 0.80, MV: R = 0.99). The semi-automatic method could exclude endoluminal muscular structures from the blood volume with significantly improved intra- and inter-observer variabilities in cardiac function measurements compared to the conventional, manual method, which includes endoluminal structures in the blood volume.

Automated multiscale vessel analysis for the quantification of MR angiography of peripheral arteriogenesis.

PURPOSE: To automatically analyze the time course of collateralization in a rat hindlimb ischemia model based on signal intensity distribution (SID). MATERIALS AND METHODS: Time-of-flight magnetic resonance angiograms (TOF-MRA) were acquired in eight rats at 2, 7, and 21 days after unilateral femoral artery ligation. Analysis was performed on maximum intensity projections filtered with multiscale vessel enhancement filter. Differences in SID between ligated limb and a reference region were monitored over time and compared to manual collateral artery identification. RESULTS: The differences in SID correlated well with the number of collateral arteries found with manual quantification. The time courses of ultrasmall (diameter ≪0.5 mm) and small (diameter ≈0.5 mm) collateral artery development could be differentiated, revealing that maturation of the collaterals and enlargement of their feeding arteries occurred mainly after the first week postligation. CONCLUSION: SID analysis performed on axial maximum intensity projections is easy to implement, fast, and objective and provides more insight in the time course of arteriogenesis than manual identification.

MR angiography of collateral arteries in a hind limb ischemia model: comparison between blood pool agent Gadomer and small contrast agent Gd-DTPA.

The objective of this study was to compare the blood pool agent Gadomer with a small contrast agent for the visualization of ultra-small, collateral arteries (diameter<1 mm) with high resolution steady-state MR angiography (SS-MRA) in a rabbit hind limb ischemia model. Ten rabbits underwent unilateral femoral artery ligation. On days 14 and 21, high resolution SS-MRA (voxel size 0.49×0.49×0.50 mm(3)) was performed on a 3 Tesla clinical system after administration of either Gadomer (dose: 0.10 mmol/kg) or a small contrast agent (gadopentetate dimeglumine (Gd-DTPA), dose: 0.20 mmol/kg). All animals received both contrast agents on separate days. Selective intra-arterial x-ray angiograms (XRAs) were obtained in the ligated limb as a reference. The number of collaterals was counted by two independent observers. Image quality was evaluated with the contrast-to-noise ratio (CNR) in the femoral artery and collateral arteries. CNR for Gadomer was higher in both the femoral artery (Gadomer: 73±5 (mean ± SE); Gd-DTPA: 40±3; p<0.01) and collateral arteries (Gadomer: 18±4; Gd-DTPA: 9±1; p = 0.04). Neither day of acquisition nor contrast agent used influenced the number of identified collateral arteries (p = 0.30 and p = 0.14, respectively). An average of 4.5±1.0 (day 14, mean ± SD) and 5.3±1.2 (day 21) collaterals was found, which was comparable to XRA (5.6±1.7, averaged over days 14 and 21; p>0.10). Inter-observer variation was 24% and 18% for Gadomer and Gd-DTPA, respectively. In conclusion, blood pool agent Gadomer improved vessel conspicuity compared to Gd-DTPA. Steady-state MRA can be considered as an excellent non-invasive alternative to intra-arterial XRA for the visualization of ultra-small collateral arteries.

Magnetic resonance imaging in peripheral arterial disease: reproducibility of the assessment of morphological and functional vascular status.

OBJECTIVES: The aim of the current study was to test the reproducibility of different quantitative magnetic resonance imaging (MRI) methods to assess the morphologic and functional peripheral vascular status and vascular adaptations over time in patients with peripheral arterial disease (PAD). MATERIALS AND METHODS: Ten patients with proven PAD (intermittent claudication) and arterial collateral formation within the upper leg and 10 healthy volunteers were included. All subjects underwent 2 identical MR examinations of the lower extremities on a clinical 1.5-T MR system, with a time interval of at least 3 days. The MR protocol consisted of 3D contrast-enhanced MR angiography to quantify the number of arteries and artery diameters of the upper leg, 2D cine MR phase contrast angiography flow measurements in the popliteal artery, dynamic contrast-enhanced (DCE) perfusion imaging to determine the influx constant and area under the curve, and dynamic blood oxygen level-dependent (BOLD) imaging in calf muscle to measure maximal relative T2* changes and time-to-peak. Data were analyzed by 2 independent MRI readers. Interscan and inter-reader reproducibility were determined as outcome measures and expressed as the coefficient of variation (CV). RESULTS: Quantification of the number of arteries, artery diameter, and blood flow proved highly reproducible in patients (CV = 2.6%, 4.5%, and 15.8% at interscan level and 9.0%, 8.2%, and 7.0% at interreader level, respectively). Reproducibility of DCE and BOLD MRI was poor in patients with a CV up to 50.9%. CONCLUSIONS: Quantification of the morphologic vascular status by contrast-enhanced MR angiography, as well as phase contrast angiography MRI to assess macrovascular blood flow proved highly reproducible in both PAD patients and healthy volunteers and might therefore be helpful in studying the development of collateral arteries in PAD patients and in unraveling the mechanisms underlying this process. Functional assessment of the microvascular status using DCE and BOLD, MRI did not prove reproducible at 1.5 T and is therefore currently not suitable for (clinical) application in PAD.

Optimized pharmacokinetic modeling for the detection of perfusion differences in skeletal muscle with DCE-MRI: effect of contrast agent size.

PURPOSE: The goal of this study was to optimize dynamic contrast-enhanced (DCE)-MRI analysis for differently sized contrast agents and to evaluate the sensitivity for microvascular differences in skeletal muscle. METHODS: In rabbits, pathophysiological perfusion differences between hind limbs were induced by unilateral femoral artery ligation. On days 14 and 21, DCE-MRI was performed using a medium-sized contrast agent (MCA) (Gadomer) or a small contrast agent (SCA) (Gd-DTPA). Acquisition protocols were adapted to the pharmacokinetic properties of the contrast agent. Model-based data analysis was optimized by selecting the optimal model, considering fit error, estimation uncertainty, and parameter interdependency from three two-compartment pharmacokinetic models (normal and extended generalized kinetic models and Patlak model). Model-based parameters were compared to the model-free parameter area-under-curve (AUC). Finally, the sensitivity of transfer constant Krans and AUC for physiological and pathophysiological microvascular differences was evaluated. RESULTS: For the MCA, the optimal model included Ktrans and plasma fraction nu(p). For the SCA, Ktrans and interstitial fraction nu(e) should be incorporated. For the MCA, Ktrans were (4.8 +/- 0.2) x 10(-3) min(-1) (mean standard error) and (3.6 +/- 0.1) x 10(-3) min(-1) for the red soleus and white tibialis muscle, respectively, p < 0.01. With the SCA, Ktrans were (81 +/- 5) x 10(-3) min(-1) (soleus) and (66 +/- 5) x 10(-3) min(-1) (tibialis) p < 0.01. In the ischemic limb, Ktrans was significantly decreased relative to the control limb (soleus: 15%-20%; tibialis: 5%-10%). Similar differences in AUC were found for both contrast agents. CONCLUSIONS: For optimal estimation of microvascular parameters, both model-based and model-free analysis should be adapted to the pharmacokinetic properties of the contrast agent. The detection of microvascular differences based on both Ktrans and AUC was most sensitive when the analysis strategy was tailored to the contrast agent used. The MCA was equally sensitive for microvascular differences as the SCA, with the advantage of improved spatial resolution.

Reliability of pharmacokinetic parameters: small vs. medium-sized contrast agents.

Current clinical applications of dynamic contrast-enhanced MRI (DCE-MRI) are based on the extravasation of relatively small contrast agents (SCAs). SCAs are considered disadvantageous, as they require high image sampling rates. Medium-sized contrast agents (MCAs) leak more slowly into tissue and allow longer dynamic acquisition times, enabling improved image quality. The influence of molecular size on the reliability of pharmacokinetic parameters, including the transfer constant K(trans), was investigated. Computer simulations were performed, with in vivo measured arterial input functions (AIFs), to determine the bias and variance of pharmacokinetic parameters as a function of contrast agent size, sampling frequency, noise level, and acquisition time. Better reliability of all parameters was obtained for the MCA compared to the SCA. To obtain similar variance (10%) in K(trans), the sampling frequency for the SCA (28 min(-1)) had to be 20 times faster than for the MCA (1.3 min(-1)). Optimal reliability in parameter estimation required longer acquisition times for MCAs (13 min for the fraction of the extravascular extracellular space into which the contrast agent distributes (v(e)) and 5 min for K(trans)) than for SCAs (1.7 min for K(trans) and v(e)). Reliable estimation of the fractional blood plasma volume (v(p)) was only achieved with MCAs. In conclusion, MCAs provided superior reliability for pharmacokinetic parameter estimation compared to SCAs.

Differentiation of spinal cord arteries and veins by time-resolved MR angiography.

PURPOSE: To dynamically resolve the inlet arteries and outlet veins of the spinal cord, particularly the Adamkiewicz artery (AKA) and great anterior radiculomedullary vein (GARV), using MR angiography (MRA). MATERIALS AND METHODS: First, conventional two-phase angiography (acquisition time = 38-55 seconds) utilizing elliptic centric k-space ordering was applied to aortic-aneurysm patients. Changes of vessel intensity were compared between two subsequent dynamic phases. Computer modeling of bolus enhancement and k-space sampling was performed to demonstrate the relation between vessel enhancement, acquisition time, and vessel diameter. Second, time-resolved (TR, or "keyhole") angiography using a reduced number of phase-encoding steps was explored in healthy volunteers and aortic-aneurysm patients using acquisition times (range = 6-8.5 seconds) shorter than the spinal cord circulation time. RESULTS: Using two-phase angiography the AKA and GARV were covisualized in the early phase, and contrast decreased for the AKA and increased for the GARV in most (70%) but not all cases. Computer modeling showed that the arteriovenous contrast strongly depended on vessel diameter, and complete separation was only obtained with short acquisition times. Using TR MR angiography (TR-MRA), complete temporal separation of the AKA and GARV was realized in all cases (100%). CONCLUSION: The AKA and GARV can be completely separated by TR-MRA.

Comparison of magnetic resonance with computed tomography angiography for preoperative localization of the Adamkiewicz artery in thoracoabdominal aortic aneurysm patients.

OBJECTIVE: Preoperative localization of the Adamkiewicz artery and its segmental supplier in advance of thoracic aortic aneurysm (TAA) and thoracoabdominal aortic aneurysm (TAAA) repair is proposed to be useful to prevent postoperative paraplegia. The diagnostic potential of magnetic resonance angiography (MRA) and computed tomography angiography (CTA) was evaluated for the preoperative localization of the Adamkiewicz artery in white TAAA patients. METHODS: Thirty-nine consecutive patients with a TAA(A) scheduled for elective open surgical aortic repair preoperatively underwent MRA and CTA. Objective image quality was assessed by measuring the signal-to-noise ratio and contrast-to-noise ratio of the Adamkiewicz artery and was related to patient thickness. Two independent observers scored the location of the Adamkiewicz artery and the subjective image quality of vessel-background contrast of the Adamkiewicz artery, image noise, spinal cord tissue enhancement, epidural venous enhancement, and overall image quality. RESULTS: Average detection rate for Adamkiewicz artery localization was 71% (67% to 74%) for CTA and 97% (94% to 100%) for MRA. Interobserver agreement was 82% for CTA and 94% for MRA. Signal-to-noise ratio was significantly higher (P < .001) and contrast-to-noise ratio was significantly (P < .001) lower for CTA than for MRA. Contrast of the Adamkiewicz artery (P < .001) and overall image quality (P < .004) were judged to be significantly better for MRA. Spinal cord tissue enhancement was judged stronger at CTA (P < .03), with significantly less epidural venous enhancement (P < .001). No significant difference was found in image noise. Signal-to-noise and contrast-to-noise decreased significantly (P < .001) with increasing patient thickness for CTA but not for MRA. CONCLUSIONS: Localization of the Adamkiewicz artery in white TAAA patients is possible with both CTA and MRA. Compared with CTA, MRA is more favorable because of the higher Adamkiewicz artery detection rate, the higher contrast-to-noise ratio, and its independence of patient thickness.