Validation of CT-based ventilation and perfusion biomarkers with histopathology confirms radiation-induced pulmonary changes in a porcine model.
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SUBMITTER: Flakus MJ
PROVIDER: S-EPMC10256800 | biostudies-literature | 2023 Jun
REPOSITORIES: biostudies-literature
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Validation of CT-based ventilation and perfusion biomarkers with histopathology confirms radiation-induced pulmonary changes in a porcine model.
Flakus Mattison J MJ Wuschner Antonia E AE Wallat Eric M EM Graham Melissa M Shao Wei W Shanmuganayagam Dhanansayan D Christensen Gary E GE Reinhardt Joseph M JM Bayouth John E JE
Scientific reports 20230609 1
Imaging biomarkers can assess disease progression or prognoses and are valuable tools to help guide interventions. Particularly in lung imaging, biomarkers present an opportunity to extract regional information that is more robust to the patient's condition prior to intervention than current gold standard pulmonary function tests (PFTs). This regional aspect has particular use in functional avoidance radiation therapy (RT) in which treatment planning is optimized to avoid regions of high functio ...[more]
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Project description:BackgroundTo validate pulmonary computed tomography (CT) perfusion in a porcine model by invasive monitoring of cardiac output (CO) using thermodilution method.MethodsAnimals were studied at a single center, using a Swan-Ganz catheter for invasive CO monitoring as a reference. Fifteen pigs were included. Contrast-enhanced CT perfusion of the descending aorta and right and left pulmonary artery was performed. For variation purposes, a balloon catheter was inserted to block the contralateral pulmonary vascular bed; additionally, two increased CO settings were created by intravenous administration of catecholamines. Finally, stepwise capillary occlusion was performed by intrapulmonary arterial injection of 75-μm microspheres in four stages. A semiautomatic selection of AFs and a recirculation-aware tracer-kinetics model to extract the first-pass of AFs, estimating blood flow with the Stewart-Hamilton method, was implemented. Linear mixed models (LMM) were developed to calibrate blood flow calculations accounting with individual- and cohort-level effects.ResultsNine of 15 pigs had complete datasets. Strong correlations were observed between calibrated pulmonary (0.73, 95% confidence interval [CI] 0.6-0.82) and aortic blood flow measurements (0.82, 95% CI, 0.73-0.88) and the reference as well as agreements (± 2.24 L/min and ± 1.86 L/min, respectively) comparable to the state of the art, on a relatively wide range of right ventricle-CO measurements.ConclusionsCT perfusion validly measures CO using LMMs at both individual and cohort levels, as demonstrated by referencing the invasive CO.Relevance statementPossible clinical applications of CT perfusion for measuring CO could be in acute pulmonary thromboembolism or to assess right ventricular function to show impairment or mismatch to the left ventricle.Key points• CT perfusion measures flow in vessels. • CT perfusion measures cumulative cardiac output in the aorta and pulmonary vessels. • CT perfusion validly measures CO using LMMs at both individual and cohort levels, as demonstrated by using the invasive CO as a reference standard.
| S-EPMC10959917 | biostudies-literature
Project description:To test the accuracy of quantification of myocardial perfusion imaging (MPI) using computed tomography (CT) in ex-vivo porcine models. Five isolated porcine hearts were perfused according to Langendorff. Hearts were perfused using retrograde flow through the aorta and blood flow, blood pressure and heart rate were monitored throughout the experiment. An inflatable cuff was placed around the circumflex (Cx) artery to create stenosis grades which were monitored using a pressure wire, analysing perfusion at several fractional flow reserve values of 1.0, 0.7, 0.5, 0.3, and total occlusion. Second-generation dual-source CT was used to acquire dynamic MPI in shuttle mode with 350 mAs/rot at 100 kVp. CT MPI was performed using VPCT myocardium software, calculating myocardial blood flow (MBF, ml/100 ml/min) for segments perfused by Cx artery and non-Cx myocardial segments. Microspheres were successfully infused at three stenosis grades in three of the five hearts. Heart rate ranged from 75 to 134 beats per minute. Arterial blood flow ranged from 0.5 to 1.4 l min and blood pressure ranged from 54 to 107 mmHg. MBF was determined in 400 myocardial segments of which 115 were classified as 'Cx-territory'. MBF was significantly different between non-Cx and Cx segments at stenosis grades with an FFR ≤0.70 (Mann-Whitney U test, p < 0.05). MBF showed a moderate correlation with microsphere MBF for the three individual hearts (Pearson correlation 0.62-0.76, p < 0.01). CT MPI can be used to determine regional differences in myocardial perfusion parameters, based on severity of coronary stenosis. Significant differences in MBF could be measured between non-ischemic and ischemic segments.
| S-EPMC5682851 | biostudies-literature
Project description:A form of lung function imaging is emerging that uses phase-resolved four-dimensional CT (4DCT or breath-hold CT) images along with image processing techniques to generate lung function maps that provide a surrogate of lung ventilation. CT-based ventilation (referred to as CT-ventilation) research has gained momentum in Radiation Oncology because many lung cancer patients undergo four-dimensional CT simulation as part of the standard treatment planning process. Therefore, generating CT-ventilation images provides functional information without burdening the patient with an extra imaging procedure. CT-ventilation has progressed from an image processing calculation methodology, to validation efforts, to retrospective demonstration of clinical utility in Radiation Oncology. In particular, CT-ventilation has been proposed for two main clinical applications: functional avoidance radiation therapy and thoracic dose-response assessment. The idea of functional avoidance radiation therapy is to preferentially spare functional portions of the lung (as measured by CT-ventilation) during radiation therapy with the hypothesis that reducing dose to functional portions of the lung will lead to reduced rates of radiation-related thoracic toxicity. The idea of imaging-based dose-response assessment is to evaluate pre- to post-treatment CT-ventilation-based imaging changes. The hypothesis is that early, imaging-change-based response can be an early predictor of subsequent thoracic toxicity. Based on the retrospective evidence, the clinical applications of CT-ventilation have progressed from the retrospective setting to on-going prospective clinical trials. This review will cover basic CT-ventilation calculation methodologies, validation efforts, presentation of clinical applications, summarize on-going clinical trials, review potential uncertainties and shortcomings of CT-ventilation, and discuss future directions of CT-ventilation research.
| S-EPMC7592480 | biostudies-literature
Project description:To analyze radiation induced changes in Hounsfield units and determine their correlation with changes in perfusion and ventilation. Additionally, to compare the post-RT changes in human subjects to those measured in a swine model used to quantify perfusion changes and validate their use as a preclinical model. A cohort of 5 Wisconsin Miniature Swine (WMS) were studied. Additionally, 19 human subjects were recruited as part of an IRB approved clinical trial studying functional avoidance radiation therapy for lung cancer and were treated with SBRT. Imaging (a contrast enhanced dynamic perfusion CT in the swine and 4DCT in the humans) was performed prior to and post-RT. Jacobian elasticity maps were calculated on all 4DCT images. Contours were created from the isodose lines to discretize analysis into 10 Gy dose bins. B-spline deformable image registration allowed for voxel-by-voxel comparative analysis in these contours between timepoints. The WMS underwent a research course of 60 Gy in 5 fractions delivered locally to a target in the lung using an MRI-LINAC system. In the WMS subjects, the dose-bin contours were copied onto the contralateral lung, which received < 5 Gy for comparison. Changes in HU and changes in Jacobian were analyzed in these contours. Statistically significant (p < 0.05) changes in the mean HU value post-RT compared to pre-RT were observed in both the human and WMS groups at all timepoints analyzed. The HU increased linearly with dose for both groups. Strong linear correlation was observed between the changes seen in the swine and humans (Pearson coefficient > 0.97, p < 0.05) at all timepoints. Changes seen in the swine closely modeled the changes seen in the humans at 12 months post RT (slope = 0.95). Jacobian analysis showed between 30 and 60% of voxels were damaged post-RT. Perfusion analysis in the swine showed a statistically significant (p < 0.05) reduction in contrast inside the vasculature 3 months post-RT compared to pre-RT. The increases in contrast outside the vasculature was strongly correlated (Pearson Correlation 0.88) with the reduction in HU inside the vasculature but were not correlated with the changes in Jacobians. Radiation induces changes in pulmonary anatomy at 3 months post-RT, with a strong linear correlation with dose. The change in HU seen in the non-vessel lung parenchyma suggests this metric is a potential biomarker for change in perfusion. Finally, this work suggests that the WMS swine model is a promising pre-clinical model for analyzing radiation-induced changes in humans and poses several benefits over conventional swine models.
| S-EPMC8222280 | biostudies-literature
Project description:Purpose: To quantify the impact of image noise on CT-based lung ventilation biomarkers calculated using Jacobian determinant techniques. Methods: Five mechanically ventilated swine were imaged on a multi-row CT scanner with acquisition parameters of 120 kVp and 0.6 mm slice thickness in static and 4-dimensional CT (4DCT) modes with respective pitches of 1 and 0.09. A range of tube current time product (mAs) values were used to vary image dose. On two dates, subjects received two 4DCTs: one with 10 mAs/rotation (low-dose, high-noise) and one with CT simulation standard of care 100 mAs/rotation (high-dose, low-noise). Additionally, 10 intermediate noise level breath-hold (BHCT) scans were acquired with inspiratory and expiratory lung volumes. Images were reconstructed with and without iterative reconstruction (IR) using 1 mm slice thickness. The Jacobian determinant of an estimated transformation from a B-spline deformable image registration was used to create CT-ventilation biomarkers estimating lung tissue expansion. 24 CT-ventilation maps were generated per subject per scan date: four 4DCT ventilation maps (two noise levels each with and without IR) and 20 BHCT ventilation maps (10 noise levels each with and without IR). Biomarkers derived from reduced dose scans were registered to the reference full dose scan for comparison. Evaluation metrics were gamma pass rate (Γ) with 2 mm distance-to-agreement and 6% intensity criterion, voxel-wise Spearman correlation (ρ) and Jacobian ratio coefficient of variation (CoVJR). Results: Comparing biomarkers derived from low (CTDIvol = 6.07 mGy) and high (CTDIvol = 60.7 mGy) dose 4DCT scans, mean Γ, ρ and CoVJR values were 93% ± 3%, 0.88 ± 0.03 and 0.04 ± 0.009, respectively. With IR applied, those values were 93% ± 4%, 0.90 ± 0.04 and 0.03 ± 0.003. Similarly, comparisons between BHCT-based biomarkers with variable dose (CTDIvol = 1.35–7.95 mGy) had mean Γ, ρ and CoVJR of 93% ± 4%, 0.97 ± 0.02 and 0.03 ± 0.006 without IR and 93% ± 4%, 0.97 ± 0.03 and 0.03 ± 0.007 with IR. Applying IR did not significantly change any metrics (p Discussion: This work demonstrated that CT-ventilation, calculated using the Jacobian determinant of an estimated transformation from a B-spline deformable image registration, is invariant to Hounsfield Unit (HU) variation caused by image noise. This advantageous finding may be leveraged clinically with potential applications including dose reduction and/or acquiring repeated low-dose acquisitions for improved ventilation characterization.
| S-EPMC9971492 | biostudies-literature
Project description:IntroductionCurrent treatment with vasodilators for pulmonary hypertension associated with respiratory diseases is limited by their inhibitory effect on hypoxic pulmonary vasoconstriction (HPV) and uncoupling effects on ventilation-perfusion (V'/Q'). Hypoxia is also a well-known modulator of the nitric oxide (NO) pathway, and may therefore differentially affect the responses to phosphodiesterase 5 (PDE5) inhibitors and soluble guanylyl cyclase (sGC) stimulators. So far, the effects of the sGC stimulator riociguat on HPV have been poorly characterized.Materials and methodsContraction was recorded in pulmonary arteries (PA) in a wire myograph. Anesthetized rats were catheterized to record PA pressure. Ventilation and perfusion were analyzed by micro-CT-SPECT images in rats with pulmonary fibrosis induced by bleomycin.ResultsThe PDE5 inhibitor sildenafil and the sGC stimulator riociguat similarly inhibited HPV in vitro and in vivo. Riociguat was more effective as vasodilator in isolated rat and human PA than sildenafil. Riociguat was ≈3-fold more potent under hypoxic conditions and it markedly inhibited HPV in vivo at a dose that barely affected the thromboxane A2 (TXA2) mimetic U46619-induced pressor responses. Pulmonary fibrosis was associated with V'/Q' uncoupling and riociguat did not affect the V'/Q' ratio.ConclusionPDE5 inhibitors and sGC stimulators show a different vasodilator profile. Riociguat was highly effective and potentiated by hypoxia in rat and human PA. In vivo, riociguat preferentially inhibited hypoxic than non-hypoxic vasoconstriction. However, it did not worsen V'/Q' coupling in a rat model of pulmonary fibrosis.
| S-EPMC5783366 | biostudies-literature
Project description:PurposeTo evaluate the accuracy of a low-dose first-pass analysis (FPA) CT pulmonary perfusion technique in comparison to fluorescent microsphere measurement as the reference standard.MethodThe first-pass analysis CT perfusion technique was validated in six swine (41.7 ± 10.2 kg) for a total of 39 successful perfusion measurements. Different perfusion conditions were generated in each animal using serial balloon occlusions in the pulmonary artery. For each occlusion, over 20 contrast-enhanced CT images were acquired within one breath (320 x 0.5mm collimation, 100kVp, 200mA or 400mA, 350ms gantry rotation time). All volume scans were used for maximum slope model (MSM) perfusion measurement, but only two volume scans were used for the FPA measurement. Both MSM and FPA perfusion measurements were then compared to the reference fluorescent microsphere measurements.ResultsThe mean lung perfusion of MSM, FPA, and microsphere measurements were 6.21 ± 3.08 (p = 0.008), 6.59 ± 3.41 (p = 0.44) and 6.68 ± 3.89 ml/min/g, respectively. The MSM (PMSM) and FPA (PFPA) perfusion measurements were related to the corresponding reference microsphere measurement (PMIC) by PMSM = 0.51PMIC + 2.78 (r = 0.64) and PFPA = 0.79PMIC + 1.32 (r = 0.90). The root-mean-square-error for the MSM and FPA techniques were 3.09 and 1.72 ml/min/g, respectively. The root-mean-square-deviation for the MSM and FPA techniques were 2.38 and 1.50 ml/min/g, respectively. The CT dose index for MSM and FPA techniques were 138.7 and 8.4mGy, respectively.ConclusionsThe first-pass analysis technique can accurately measure regional pulmonary perfusion and has the potential to reduce the radiation dose associated with dynamic CT perfusion for assessment of pulmonary disease.
| S-EPMC7015394 | biostudies-literature
Project description:PurposeTo compare measurements of regional pulmonary perfused blood volume (PBV) and pulmonary blood flow (PBF) obtained with computed tomography (CT) in two pig models.Materials and methodsThe institutional animal care and use committee approved all animal studies. CT-derived PBF and PBV were determined in four anesthetized, mechanically ventilated, supine swine by using two methods for creating pulmonary parenchymal perfusion heterogeneity. Two animals were examined after sequentially moving a pulmonary arterial balloon catheter from a distal to a central location, and two others were examined over a range of static airway pressures, which varied the extents of regional PBF. Lung sections were divided into blocks and Pearson correlation coefficients calculated to compare matching regions between the two methods.ResultsCT-derived PBF, CT-derived PBV, and their associated coefficients of variation (CV) were closely correlated on a region-by-region basis in both the balloon occlusion (Pearson R = 0.91 and 0.73 for animals 1 and 2, respectively; Pearson R = 0.98 and 0.87 for comparison of normalized mean and CV for animals 1 and 2, respectively) and lung inflation studies (Pearson R = 0.94 and 0.74 for animals 3 and 4, respectively; Pearson R = 0.94 and 0.69 for normalized mean and CV for animals 3 and 4, respectively). When accounting for region-based effects, correlations remained highly significant at the P < .001 level.ConclusionCT-derived PBV heterogeneity is a suitable surrogate for CT-derived PBF heterogeneity.
| S-EPMC3662901 | biostudies-literature
Project description:RationaleBronchoconstriction in asthma leads to heterogeneous ventilation and the formation of large and contiguous ventilation defects in the lungs. However, the regional adaptations of pulmonary perfusion (Q) to such ventilation defects have not been well studied.MethodsWe used positron emission tomography to assess the intrapulmonary kinetics of intravenously infused tracer nitrogen-13 ((13)NN), and measured the regional distributions of ventilation and perfusion in 11 patients with mild asthma. For each subject, the regional washout kinetics of (13)NN before and during methacholine-induced bronchoconstriction were analyzed. Two regions of interest (ROIs) were defined: one over a spatially contiguous area of high tracer retention (TR) during bronchoconstriction and a second one covering an area of similar size, showing minimal tracer retention (NR).ResultsBoth ROIs demonstrated heterogeneous washout kinetics, which could be described by a two-compartment model with fast and slow washout rates. We found a systematic reduction in regional Q to the TR ROI during bronchoconstriction and a variable and nonsignificant change in relative Q for NR regions. The reduction in regional Q was associated with an increase in regional gas content of the TR ROI, but its magnitude was greater than that anticipated solely by the change in regional lung inflation.ConclusionDuring methacholine-induced bronchoconstriction, perfusion to ventilation defects are systematically reduced by a relative increase in regional pulmonary vascular resistance.
| S-EPMC2648114 | biostudies-literature
Project description:BackgroundBiomarkers estimating local lung ventilation have been derived from computed tomography (CT) imaging using various image acquisition and post-processing techniques. CT-ventilation biomarkers have potential clinical use in functional avoidance radiation therapy (RT), in which RT treatment plans are optimized to reduce dose delivered to highly ventilated lung. Widespread clinical implementation of CT-ventilation biomarkers necessitates understanding of biomarker repeatability. Performing imaging within a highly controlled experimental design enables quantification of error associated with remaining variables.PurposeTo characterize CT-ventilation biomarker repeatability and dependence on image acquisition and post-processing methodology in anesthetized and mechanically ventilated pigs.MethodsFive mechanically ventilated Wisconsin Miniature Swine (WMS) received multiple consecutive four-dimensional CT (4DCT) and maximum inhale and exhale breath-hold CT (BH-CT) scans on five dates to generate CT-ventilation biomarkers. Breathing maneuvers were controlled with an average tidal volume difference <200 cc. As surrogates for ventilation, multiple local expansion ratios (LERs) were calculated from the acquired CT scans using Jacobian-based post-processing techniques. LER2$LER_2$ measured local expansion between an image pair using either inhale and exhale BH-CT images or two 4DCT breathing phase images. LERN$LER_N$ measured the maximum local expansion across the 4DCT breathing phase images. Breathing maneuver consistency, intra- and interday biomarker repeatability, image acquisition and post-processing technique dependence were quantitatively analyzed.ResultsBiomarkers showed strong agreement with voxel-wise Spearman correlation ρ>0.9$\rho > 0.9$ for intraday repeatability and ρ>0.8$\rho > 0.8$ for all other comparisons, including between image acquisition techniques. Intra- and interday repeatability were significantly different (p < 0.01). LER2 and LERN post-processing did not significantly affect intraday repeatability.Conclusions4DCT and BH-CT ventilation biomarkers derived from consecutive scans show strong agreement in controlled experiments with nonhuman subjects.
| S-EPMC10544701 | biostudies-literature