Estimating ventilation correlation coefficients in the lungs using PREFUL-MRI in chronic obstructive pulmonary disease patients and healthy adults.

PURPOSE: Various parameters of regional lung ventilation can be estimated using phase-resolved functional lung (PREFUL)-MRI. The parameter "ventilation correlation coefficient (Vent-CC)" was shown advantageous because it assesses the dynamics of regional air flow. Calculating Vent-CC depends on a voxel-wise comparison to a healthy reference flow curve. This work examines the effect of placing a reference region of interest (ROI) in various lung quadrants or in different coronal slices. Furthermore, algorithms for automated ROI selection are presented and compared in terms of test-retest repeatability. METHODS: Twenty-eight healthy subjects and 32 chronic obstructive pulmonary disease (COPD) patients were scanned twice using PREFUL-MRI. Retrospective analyses examined the homogeneity of air flow curves of various reference ROIs using cross-correlation. Vent-CC and ventilation defect percentage (VDP) calculated using various reference ROIs were compared using one-way analysis of variance (ANOVA). The coefficient of variation was calculated for Vent-CC and VDP when using different reference selection algorithms. RESULTS: Flow-volume curves were highly correlated between ROIs placed at various lung quadrants in the same coronal slice (r > 0.97) with no differences in Vent-CC and VDP (ANOVA: p > 0.5). However, ROIs placed at different coronal slices showed lower correlation coefficients and resulted in significantly different Vent-CC and VDP values (ANOVA: p < 0.001). Vent-CC and VDP showed higher repeatability when calculated using the presented new algorithm. CONCLUSION: In COPD and healthy cohorts, assessing regional ventilation dynamics using PREFUL-MRI in terms of the Vent-CC metric showed higher repeatability using a new algorithm for selecting a homogenous reference ROI from the same slice.

Phase-Resolved Functional Lung (PREFUL) MRI May Reveal Distinct Pulmonary Perfusion Defects in Postacute COVID-19 Syndrome: Sex, Hospitalization, and Dyspnea Heterogeneity.

BACKGROUND: Pulmonary perfusion defects have been observed in patients with coronavirus disease 2019 (COVID-19). Currently, there is a need for further data on non-contrast-enhanced MRI in COVID patients. The early identification of heterogeneity in pulmonary perfusion defects among COVID-19 patients is beneficial for their timely clinical intervention and management. PURPOSE: To investigate the utility of phase-resolved functional lung (PREFUL) MRI in detecting pulmonary perfusion disturbances in individuals with postacute COVID-19 syndrome (PACS). STUDY TYPE: Prospective. SUBJECTS: Forty-four participants (19 females, mean age 64.1 years) with PACS and 44 healthy subjects (19 females, mean age 59.5 years). Moreover, among the 44 patients, there were 19 inpatients and 25 outpatients; 19 were female and 25 were male; 18 with non-dyspnea and 26 with dyspnea. FIELD STRENGTH/SEQUENCE: 3-T, two-dimensional (2D) spoiled gradient-echo sequence. ASSESSMENT: Ventilation and perfusion-weighted maps were extracted from five coronal slices using PREFUL analysis. Subsequently, perfusion defect percentage (QDP), ventilation defect percentage (VDP), and ventilation-perfusion match healthy (VQM) were calculated based on segmented lung parenchyma ventilation and perfusion-weighted maps. Additionally, clinical features, including demographic data (such as sex and age) and serum biomarkers (such as D-dimer levels), were evaluated. STATISTICAL TESTS: Spearman correlation coefficients to explore relationships between clinical features and QDP, VDP, and VQM. Propensity score matching analysis to reduce the confounding bias between patients with PACS and healthy controls. The Mann-Whitney U tests and Chi-squared tests to detect differences between groups. Multivariable linear regression analyses to identify factors related to QDP, VDP, and VQM. A P-value <0.05 was considered statistically significant. RESULTS: QDP significantly exceeded that of healthy controls in individuals with PACS (39.8% ± 15.0% vs. 11.0% ± 4.9%) and was significantly higher in inpatients than in outpatients (46.8% ± 17.0% vs. 34.5% ± 10.8%). Moreover, males exhibited pulmonary perfusion defects significantly more frequently than females (43.9% ± 16.8% vs. 34.4% ± 10.2%), and dyspneic participants displayed significantly higher perfusion defects than non-dyspneic patients (44.8% ± 15.8% vs. 32.6% ± 10.3%). QDP showed a significant positive relationship with age (ß = 0.50) and D-dimer level (ß = 0.72). DATA CONCLUSION: PREFUL MRI may show pulmonary perfusion defects in patients with PACS. Furthermore, perfusion impairments may be more pronounced in males, inpatients, and dyspneic patients. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Comparison of Free-Breathing 3D Phase-Resolved Functional Lung (PREFUL) MRI With Dynamic 19 F Ventilation MRI in Patients With Obstructive Lung Disease and Healthy Volunteers.

BACKGROUND: Non-contrast-enhanced 1 H magnetic resonance imaging (MRI) with full lung coverage shows promise for assessment of regional lung ventilation but a comparison with direct ventilation measurement using 19 F MRI is lacking. PURPOSE: To compare ventilation parameters calculated using 3D phase-resolved functional lung (PREFUL) MRI with 19 F MRI. STUDY TYPE: Prospective. POPULATION: Fifteen patients with asthma, 14 patients with chronic obstructive lung disease, and 13 healthy volunteers. FIELD STRENGTH/SEQUENCE: A 3D gradient-echo pulse sequence with golden-angle increment and stack-of-stars encoding at 1.5 T. ASSESSMENT: All participants underwent 3D PREFUL MRI and 19 F MRI. For 3D PREFUL, static regional ventilation (RVent) and dynamic flow-volume cross-correlation metric (FVL-CM) were calculated. For both parameters, ventilation defect percentage (VDP) values and ventilation defect (VD) maps (including a combination of both parameters [VDPCombined ]) were determined. For 19 F MRI, images from eight consecutive breaths under volume-controlled inhalation of perfluoropropane were acquired. Time-to-fill (TTF) and wash-in (WI) parameters were extracted. For all 19 F parameters, a VD map was generated and the corresponding VDP values were calculated. STATISTICAL TESTS: For all parameters, the relationship between the two techniques was assessed using a Spearman correlation (r). Differences between VDP values were compared using Bland-Altman analysis. For regional comparison of VD maps, spatial overlap and Sørensen-Dice coefficients were computed. RESULTS: 3D PREFUL VDP values were significantly correlated to VDP measures by 19 F (r range: 0.59-0.70). For VDPRVent , no significant bias was observed with VDP of the third and fourth breath (bias range = -6.8:7.7%, P range = 0.25:0.30). For VDPFVL-CM , no significant bias was found with VDP values of fourth-eighth breaths (bias range = -2.0:12.5%, P range = 0.12:0.75). The overall spatial overlap of all VD maps increased with each breath, ranging from 61% to 81%, stabilizing at the fourth breath. DATA CONCLUSION: 3D PREFUL MRI parameters showed moderate to strong correlation with 19 F MRI. Depending on the 3D PREFUL VD map, the best regional agreement was found to 19 F VD maps of third-fifth breath. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Feasibility, Repeatability, and Correlation to Lung Function of Phase-Resolved Functional Lung (PREFUL) MRI-derived Pulmonary Artery Pulse Wave Velocity Measurements.

BACKGROUND: Pulse wave velocity (PWV) in the pulmonary arteries (PA) is a marker of vascular stiffening. Currently, only phase-contrast (PC) MRI-based options exist to measure PA-PWV. PURPOSE: To test feasibility, repeatability, and correlation to clinical data of Phase-Resolved Functional Lung (PREFUL) MRI-based calculation of PA-PWV. STUDY TYPE: Retrospective. SUBJECTS: 79 (26 female) healthy subjects (age range 19-78), 58 (24 female) patients with chronic obstructive pulmonary disease (COPD, age range 40-77), 60 (33 female) patients with suspected pulmonary hypertension (PH, age range 28-85). SEQUENCE: 2D spoiled gradient echo, 1.5T. ASSESSMENT: PA-PWV was measured from PREFUL-derived cardiac cycles based on the determination of temporal and spatial distance between lung vasculature voxels using a simplified (sPWV) method and a more comprehensive (cPWV) method including more elaborate distance calculation. For 135 individuals, PC MRI-based PWV (PWV-QA) was measured. STATISTICAL TESTS: Intraclass-correlation-coefficient (ICC) and coefficient of variation (CoV) were used to test repeatability. Nonparametric tests were used to compare cohorts. Correlation of sPWV/cPWV, PWV-QA, forced expiratory volume in 1 sec (FEV1 ) %predicted, residual volume (RV) %predicted, age, and right heart catheterization (RHC) data were tested. Significance level α = 0.05 was used. RESULTS: sPWV and cPWV showed no significant differences between repeated measurements (P-range 0.10-0.92). CoV was generally lower than 15%. COPD and PH patients had significantly higher sPWV and cPWV than healthy subjects. Significant correlation was found between sPWV or cPWV and FEV1 %pred. (R = -0.36 and R = -0.44), but not with RHC (P-range -0.11 - 0.91) or age (P-range 0.23-0.89). Correlation to RV%pred. was significant for cPWV (R = 0.42) but not for sPWV (R = 0.34, P = 0.055). For all cohorts, sPWV and cPWV were significantly correlated with PWV-QA (R = -0.41 and R = 0.48). DATA CONCLUSION: PREFUL-derived PWV is feasible and repeatable. PWV is increased in COPD and PH patients and correlates to airway obstruction and hyperinflation. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Effect of CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor on pulmonary ventilation derived by 3D phase-resolved functional lung MRI in cystic fibrosis patients.

OBJECTIVES: To investigate whether 3D phase-resolved functional lung (PREFUL)-MRI parameters are suitable to measure response to elexacaftor/tezacaftor/ivacaftor (ETI) therapy and their association with clinical outcomes in cystic fibrosis (CF) patients. METHODS: Twenty-three patients with CF (mean age: 21; age range: 14-46) underwent MRI examination at baseline and 8-16 weeks after initiation of ETI. Morphological and 3D PREFUL scans assessed pulmonary ventilation. Morphological images were evaluated using a semi-quantitative scoring system, and 3D PREFUL scans were evaluated by ventilation defect percentage (VDP) values derived from regional ventilation (RVent) and cross-correlation maps. Improved ventilation volume (IVV) normalized to body surface area (BSA) between baseline and post-treatment visit was computed. Forced expiratory volume in 1 second (FEV1) and mid-expiratory flow at 25% of forced vital capacity (MEF25), as well as lung clearance index (LCI), were assessed. Treatment effects were analyzed using paired Wilcoxon signed-rank tests. Treatment changes and post-treatment agreement between 3D PREFUL and clinical parameters were evaluated by Spearman's correlation. RESULTS: After ETI therapy, all 3D PREFUL ventilation markers (all p < 0.0056) improved significantly, except for the mean RVent parameter. The BSA normalized IVVRVent was significantly correlated to relative treatment changes of MEF25 and mucus plugging score (all |r| > 0.48, all p < 0.0219). In post-treatment analyses, 3D PREFUL VDP values significantly correlated with spirometry, LCI, MRI global, morphology, and perfusion scores (all |r| > 0.44, all p < 0.0348). CONCLUSIONS: 3D PREFUL MRI is a very promising tool to monitor CFTR modulator-induced regional dynamic ventilation changes in CF patients. CLINICAL RELEVANCE STATEMENT: 3D PREFUL MRI is sensitive to monitor CFTR modulator-induced regional ventilation changes in CF patients. Improved ventilation volume correlates with the relative change of mucus plugging, suggesting that reduced endobronchial mucus is predominantly responsible for regional ventilation improvement. KEY POINTS: • 3D PREFUL MRI-derived ventilation maps show significantly reduced ventilation defects in CF patients after ETI therapy. • Significant post-treatment correlations of 3D PREFUL ventilation measures especially with LCI, FEV1 %pred, and global MRI score suggest that 3D PREFUL MRI is sensitive to measure improved regional ventilation of the lung parenchyma due to reduced inflammation induced by ETI therapy in CF patients. • 3D PREFUL MRI-derived improved ventilation volume (IVV) correlated with MRI mucus plugging score changes suggesting that reduced endobronchial mucus is predominantly responsible for regional ventilation improvement 8-16 weeks after ETI therapy.

Alveolar membrane and capillary function in COVID-19 convalescents: insights from chest MRI.

OBJECTIVES: To investigate potential presence and resolution of longer-term pulmonary diffusion limitation and microvascular perfusion impairment in COVID-19 convalescents. MATERIALS AND METHODS: This prospective, longitudinal study was carried out between May 2020 and April 2023. COVID-19 convalescents repeatedly and age/sex-matched healthy controls once underwent MRI including hyperpolarized 129Xe MRI. Blood samples were obtained in COVID-19 convalescents for immunophenotyping. Ratios of 129Xe in red blood cells (RBC), tissue/plasma (TP), and gas phase (GP) as well as lung surface-volume ratio were quantified and correlations with CD4+/CD8+ T cell frequencies were assessed using Pearson's correlation coefficient. Signed-rank tests were used for longitudinal and U tests for group comparisons. RESULTS: Thirty-five participants were recruited. Twenty-three COVID-19 convalescents (age 52.1 ± 19.4 years, 13 men) underwent baseline MRI 12.6 ± 4.2 weeks after symptom onset. Fourteen COVID-19 convalescents underwent follow-up MRI and 12 were included for longitudinal comparison (baseline MRI at 11.5 ± 2.7 weeks and follow-up 38.0 ± 5.5 weeks). Twelve matched controls were included for comparison. In COVID-19 convalescents, RBC-TP was increased at follow-up (p = 0.04). Baseline RBC-TP was lower in patients treated on intensive care unit (p = 0.03) and in patients with severe/critical disease (p = 0.006). RBC-TP correlated with CD4+/CD8+ T cell frequencies (R = 0.61/ - 0.60) at baseline. RBC-TP was not significantly different compared to matched controls at follow-up (p = 0.25). CONCLUSION: Impaired microvascular pulmonary perfusion and alveolar membrane function persisted 12 weeks after symptom onset and resolved within 38 weeks after COVID-19 symptom onset. CLINICAL RELEVANCE STATEMENT: 129Xe MRI shows improvement of microvascular pulmonary perfusion and alveolar membrane function between 11.5 ± 2.7 weeks and 38.0 ± 5.5 weeks after symptom onset in patients after COVID-19, returning to normal in subjects without significant prior disease. KEY POINTS: • The study aims to investigate long-term effects of COVID-19 on lung function, in particular gas uptake efficiency, and on the cardiovascular system. • In COVID-19 convalescents, the ratio of 129Xe in red blood cells/tissue plasma increased longitudinally (p = 0.04), but was not different from matched controls at follow-up (p = 0.25). • Microvascular pulmonary perfusion and alveolar membrane function are impaired 11.5 weeks after symptom onset in patients after COVID-19, returning to normal in subjects without significant prior disease at 38.0 weeks.

Doppler-derived pulmonary pulse transit time measurements in chronic obstructive pulmonary disease: Reproducibility and cardiopulmonary function.

INTRODUCTION: Doppler-derived pulmonary pulse transit time (pPTT) is an auspicious hemodynamic marker in chronic pulmonary diseases. The aim is to compare four distinct pPTT measurements and its relation to right cardiac and pulmonary function. METHODS: Prospectively, 25 chronic obstructive pulmonary disease (COPD) patients (four patients excluded) and 32 healthy subjects underwent repeated distinct pPTT measurements, standard echocardiography, and pulmonary function testing on the same day. pPTT was defined as the interval from the R or Q-wave in the electrocardiogram to the corresponding pulse wave Doppler peak late systolic (S) 2 or diastolic (D) pulmonary vein flow velocity (pPTT R-S, Q-S, R-D, Q-D). Reproducibility was assessed using Bland-Altman analysis, coefficient of variation (COV), intraclass correlation coefficient (ICC), and power calculations. Associations with right ventricular RV tissue and pulse wave Doppler velocities (RV E', RV S', RV A', RV E, RV A, RV E/E', RV E/A), TAPSE, right ventricular fractional area change, left ventricular systolic and diastolic function (LV ejection fraction, E, A, E/A, E/E', septal E', lateral E'), LA diameters, as well as forced expiratory volume in 1 s, forced vital capacity (FVC) predicted (%), and in liters were analyzed. RESULTS: There was no significant difference and no bias between pPTT measures (p range: .1-.9). COV was in COPD 1.2%-2.3%, in healthy subjects 1.0%-3.1%. ICC ranged from .92 (COPD) to .96 (healthy subjects). In COPD significant correlations were found for pPTT R-S, Q-S and R-D with RV E`, (all > ρ: .49, < p = .0364), pPTT R-S, Q-S with RV E/E` (both > ρ: .49, < p = .0291), pPTT Q-S with RV S´ (ρ: .58, p = .0134), RV A (ρ: .59, p = .0339) and heart rate > ρ: -.39, < p = .0297). pPTT R-S, R-D showed significant correlations with FVC predicted (%) (ρ: .48 p = .0224) and FVC (l) (ρ:.47 p = .0347). CONCLUSIONS: All pPTT measures exhibited high reproducibility. In COPD patients pPTT measures correlate with diastolic right ventricular function. Defining Q as starting point seems clinically advantageous considering electromechanical desynchrony in patients with conduction disorders.

Phase-resolved Functional Lung (PREFUL) MRI-derived Ventilation and Perfusion Parameters Predict Future Lung Transplant Loss.

Background Chronic lung allograft dysfunction (CLAD), the physiologic correlate of chronic rejection, remains a major barrier to long-term survival following lung transplant. Biomarkers for early prediction of future transplant loss or death due to CLAD might open a window of opportunity for early diagnosis and treatment of CLAD. Purpose To evaluate the prognostic use of phase-resolved functional lung (PREFUL) MRI in predicting CLAD-related transplant loss or death. Materials and Methods In this prospective, longitudinal, single-center study, PREFUL MRI-derived ventilation and parenchymal lung perfusion parameters of bilateral lung transplant recipients without clinically suspected CLAD were assessed 6-12 months (baseline) and 2.5 years (follow-up) after transplant. MRI scans were acquired between August 2013 and December 2018. Regional flow volume loop (RFVL)-based ventilated volume (VV) and perfused volume were calculated using thresholds and spatially combined as ventilation-perfusion (V/Q) matching. Spirometry data were obtained on the same day. Exploratory models were calculated using receiver operating characteristic analysis, and subsequent survival analyses (Kaplan-Meier, hazard ratios [HRs]) of CLAD-related graft loss were performed to compare clinical and MRI parameters as clinical end points. Results At baseline MRI examination, 132 clinically stable patients of 141 patients (median age, 53 years [IQR, 43-59 years]; 78 men) were included (nine were excluded for deaths not associated with CLAD), 24 of which had CLAD-related graft loss (death or retransplant) within the observational period of 5.6 years. PREFUL MRI-derived RFVL VV was a predictor of poorer survival (cutoff, 92.3%; log-rank P = .02; HR for graft loss, 2.5 [95% CI: 1.1, 5.7]; P = .02), while perfused volume (P = .12) and spirometry (P = .33) were not predictive of differences in survival. In the evaluation of percentage change at follow-up MRI (92 stable patients vs 11 with CLAD-related graft loss), mean RFVL (cutoff, 97.1%; log-rank P < .001; HR, 7.7 [95% CI: 2.3, 25.3]), V/Q defect (cutoff, 498%; log-rank P = .003; HR, 6.6 [95% CI: 1.7, 25.0]), and forced expiratory volume in the first second of expiration (cutoff, 60.8%; log-rank P < .001; HR, 7.9 [95% CI: 2.3, 27.4]; P = .001) were predictive of poorer survival within 2.7 years (IQR, 2.2-3.5 years) after follow-up MRI. Conclusion Phase-resolved functional lung MRI ventilation-perfusion matching parameters were predictive of future chronic lung allograft dysfunction-related death or transplant loss in a large prospective cohort who had undergone lung transplant. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Fain and Schiebler in this issue.

Evaluation of image registration algorithms for 3D phase-resolved functional lung ventilation magnetic resonance imaging in healthy volunteers and chronic obstructive pulmonary disease patients.

The purpose of the current study was to assess the influence of the registration algorithms on the repeatability of three-dimensional (3D) phase-resolved functional lung (PREFUL) ventilation magnetic resonance imaging (MRI). Twenty-three healthy volunteers and 10 patients with chronic obstructive pulmonary disease (COPD) underwent 3D PREFUL MRI during tidal breathing. The registration of dynamically acquired data to a fixed image was executed using single-step, stepwise, and group-oriented registration (GOREG) approaches. Advanced Normalization Tools (ANTs) and the Forsberg image-registration package were used for the registration. Image registration algorithms were tested for differences and evaluated by the repeatability analysis of ventilation parameters using coefficient of variation (CoV), intraclass-correlation coefficient, Bland-Altman plots, and correlation to spirometry. Also, the registration time and image quality were computed for all registration approaches. Very strong to strong correlations (r range: 0.917-0.999) were observed between ventilation parameters derived using various registration approaches. Median CoV values of the cross-correlation (CC) parameter were significantly lower (all p ≤ 0.0054) for ANTs GOREG compared with single-step and stepwise ANTs registration. The majority of comparisons between COPD patients and age-matched healthy volunteers showed agreement among the registration approaches. The repeatability of regional ventilation (RVent)-based ventilation defect percentage (VDPRVent ) and VDPCC was significantly higher (both p ≤ 0.0054) for Forsberg GOREG compared with ANTs GOREG. All 3D PREFUL-derived ventilation parameters correlated with forced expiratory volume in 1 s (FEV1 ) and the FEV1 / forced vital capacity (FVC) ratio (all |r| > 0.40, all p < 0.03). The image sharpness of RVent maps was statistically elevated (all p < 0.001) using GOREG compared with single-step and stepwise registration approaches using ANTs. The best computational performance was achieved with Forsberg GOREG. The GOREG scheme improves the repeatability and image quality of dynamic 3D PREFUL ventilation parameters. Registration time can be ~10-fold reduced to 9 min using the Forsberg method with equal or even improved repeatability and comparable PREFUL ventilation results compared with the ANTs method.

Validation of Phase-Resolved Functional Lung (PREFUL) Magnetic Resonance Imaging Pulse Wave Transit Time Compared to Echocardiography in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Phase-resolved functional lung (PREFUL) magnetic resonance imaging (MRI) pulmonary pulse wave transit time (pPTT) is a contrast agent free, vascular imaging biomarker, but has not been validated in chronic obstructive pulmonary disease (COPD). PURPOSE: To validate PREFUL with echocardiographic pPTT as a reference standard and to compare arterial/venous pPTT mapping with spirometry and clinical parameters. STUDY TYPE: Prospective. POPULATION: Twenty-one patients (62% female) with COPD and 44 healthy participants (50% female). FIELD STRENGTH/SEQUENCE: 1.5 T; 2D-spoiled gradient-echo sequence. ASSESSMENT: Three coronal PREFUL MRI slices, echocardiography, and spirometry including forced expiratory volume in 1 second (FEV1, liter) and predicted defined as FEV1 in% divided by the population average FEV1%, were performed. Pulmonary pulse transit time from the main artery to the microvasculature (PREFUL pPTT), to the right upper lobe vein (PREFUL pPTTav , echo pPTTav ), from microvasculature to right upper lobe vein (PREFULvein ) and the ratio of PREFUL pPTT to PREFUL pPTTvein were calculated. Body mass index (BMI), Global Initiative for COPD (GOLD) stage 1-4, disease duration, and cigarette packs smoked per day multiplied by the smoked years (pack years) were computed. STATISTICAL TESTS: Shapiro-Wilk-test, paired-two-sided-t-tests, Bland-Altman-analysis, coefficient of variation, Pearson ρ were applied, pPTT data were compared between 21 subjects from the 44 healthy subjects who were age- and sex-matched to the COPD cohort, P < 0.05 was considered statistically significant. RESULTS: PREFUL pPTTav significantly correlated with echo pPTTav (ρ = 0.95) with 1.85 msec bias, 95% limits of agreement: 55.94 msec, -52.23 msec in all participants (P = 0.59). In the healthy participants, PREFUL and echo pPTTav significantly correlated with age (ρ = 0.81, ρ = 0.78), FEV1 (ρ = -0.47, ρ = -0.34) and BMI (ρ = 0.56, ρ = 0.51). In COPD patients, PREFUL pPTT significantly correlated with FEV1 predicted (ρ = -0.59), GOLD (ρ = 0.53), disease duration (ρ = 0.54), and pack years (ρ = 0.49). DATA CONCLUSION: Arteriovenous PTT measured by PREFUL MRI corresponds precisely to echocardiography and appears to be feasible even in severe COPD. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Evaluation of tissue shrinkage after CT-guided microwave ablation in patients with liver malignancies using Jacobian determinant.

PURPOSE: To assess short-term tissue shrinkage in patients with liver malignancies undergoing computed tomography (CT)-guided microwave ablation (MWA) using Jacobian determinant (JD). MATERIALS AND METHODS: Twenty-nine patients with 29 hepatic malignancies (primary n = 24; metastases n = 5; median tumor diameter 18 mm) referred to CT-guided MWA (single position; 10 min, 100 W) were included in this retrospective IRB-approved study, after exclusion of five patients. Following segmentation of livers and tumors on pre-interventional images, segmentations were registered on post-interventional images. JD mapping was applied to quantify voxelwise tissue volume changes after MWA. Percentual volume changes were evaluated in the ablated tumor, a 5-cm tumor perimeter and in the whole liver and compared in different clinical conditions (tumor entity: primary vs. secondary; tumor location: subcapsular vs. non-subcapsular; tumor volume: >/<6 ml: cirrhosis: yes vs. no; prior chemotherapy: yes vs. no using Shapiro-Wilk, χ2 and Wilcoxon rank sum tests, respectively (with p < 0.05 deemed significant). RESULTS: Tissue volume change was 0.6% in the ablated tumor, 1.6% in the 5-cm perimeter and 0.3% in the whole liver. Shrinkage in the ablated tumor was pronounced in non-subcapsular located tumors, whereas tissue expansion was noted in subcapsular tumors (median -3.5 vs. 1.1%; p = 0.0195). Shrinkage in the whole liver was higher in tumor volumes >6ml, compared with smaller tumors, in which tissue expansion was noted (median -1.0 vs. 2.5%; p = 0.002). Other clinical conditions had no significant influence on the extent of tissue shrinkage (p > 0.05). CONCLUSION: 3D Jacobian analysis shows that hepatic tissue deformation following MWA is most pronounced in a 5-cm area surrounding the treated tumor. Tumor location and tumor volume may have an impact on the extent of tissue shrinkage which may affect estimation of the safety margin.

Perfusion quantification using voxel-wise proton density and median signal decay in PREFUL MRI.

PURPOSE: Contrast-free lung MRI based on Fourier decomposition is an attractive method to monitor various lung diseases. However, the accuracy of the current perfusion quantification is limited. In this study, a new approach for perfusion quantification based on voxel-wise proton density and median signal decay toward the steady state for Fourier decomposition-based techniques is proposed called QQuantified (QQuant ). METHODS: Twenty patients with chronic obstructive pulmonary disease and 18 patients with chronic thromboembolic pulmonary hypertension received phase-resolved functional lung-MRI (PREFUL) and dynamic contrast-enhanced (DCE)-MRI. Nine healthy participants received phase-resolved functional lung-MRI only. Median values of QQuant were compared to a Fourier decomposition perfusion quantification presented by Kjørstad et al (QKjørstad ) and validated toward pulmonary blood flow derived by DCE-MRI (PBFDCE ). Blood fraction maps determined by the new approach were calculated. Regional and global correlation coefficients were calculated, and Bland-Altman plots were created. Histogram analyses of all cohorts were created. RESULTS: The introduced parameter QQuant showed only 2 mL/min/100 mL mean deviation to PBFDCE in the patient cohort and showed less bias than QKjørstad . Significant increases of regional correlation with PBFDCE were achieved (r = 0.3 vs. r = 0.2, P < .01*). The trend of global correlation toward PBFDCE is not uniform, showing higher values for QKjørstad in the chronic obstructive pulmonary disease cohort than for QQuant and vice versa in the chronic thromboembolic pulmonary hypertension cohort. In contrast to QKjørstad , QQuant perfusion maps indicate a physiologic dorsoventral gradient in supine position similar to PBFDCE with similar value distribution in the histograms. CONCLUSION: We proposed a new approach for perfusion quantification of phase-resolved functional lung measurements. The developed parameter QQuant reveals a higher accuracy compared to QKjørstad .

3D phase-resolved functional lung ventilation MR imaging in healthy volunteers and patients with chronic pulmonary disease.

PURPOSE: To test the feasibility of 3D phase-resolved functional lung (PREFUL) MRI in healthy volunteers and patients with chronic pulmonary disease, to compare 3D to 2D PREFUL, and to investigate the required temporal resolution to obtain stable 3D PREFUL measurement. METHODS: Sixteen participants underwent MRI using 2D and 3D PREFUL. Retrospectively, the spatial resolution of 3D PREFUL (4 × 4 × 4 mm3 ) was decreased to match the spatial resolution of 2D PREFUL (4 × 4 × 15 mm3 ), abbreviated as 3Dlowres . In addition to regional ventilation (RVent), flow-volume loops were computed and rated by a cross-correlation (CC). Ventilation defect percentage (VDP) maps were obtained. RVent, CC, VDPRVent , and VDPCC were compared for systematic differences between 2D, 3Dlowres , and 3D PREFUL. Dividing the 3D PREFUL data into 4- (≈ 20 phases), 8- (≈ 40 phases), and 12-min (≈ 60 phases) acquisition pieces, the ventilation parameter maps, including the heterogeneity of ventilation time to peak, were tested regarding the required temporal resolution. RESULTS: RVent, CC, VDPRVent , and VDPCC  presented significant correlations between 2D and 3D PREFUL (r = 0.64-0.94). CC and VDPCC  of 2D and 3Dlowres  PREFUL were significantly different (P < .0113). Comparing 3Dlowres  and 3D PREFUL, all parameters were found to be statistically different (P < .0045). CONCLUSION: 3D PREFUL MRI depicts the whole lung volume and breathing cycle with superior image resolution and with likely more precision compared to 2D PREFUL. Furthermore, 3D PREFUL is more sensitive to detect regions of hypoventilation and ventilation heterogeneity compared to 3Dlowres  PREFUL, which is important for early detection and improved monitoring of patients with chronic lung disease.

Repeatability of Phase-Resolved Functional Lung (PREFUL)-MRI Ventilation and Perfusion Parameters in Healthy Subjects and COPD Patients.

BACKGROUND: Free-breathing phase-resolved functional lung (PREFUL)-MRI may be useful for treatment monitoring in chronic obstructive pulmonary disease (COPD) patients with dyspnea. PREFUL test-retest reliability is essential for clinical application. PURPOSE: To measure the repeatability of PREFUL-MRI ventilation (V) and perfusion (Q) parameters. STUDY TYPE: Retrospective and prospective. POPULATION: A total of 28 COPD patients and 57 healthy subjects. FIELD STRENGTH/SEQUENCE: 1.5T MRI/2D spoiled gradient echo imaging. ASSESSMENT: V and Q lung parameter maps based on three coronal slices were obtained at baseline and after 14 days (COPD patients) or after a short pause outside the scanner (healthy subjects). Regional ventilation (RVent) and imaging flow volume loops by cross-correlation (ccVent) were quantified. Q was normalized to the signal of the main pulmonary artery (QN ) and quantified (QQuant ). Pulmonary pulse wave transit time (pPTT), voxel-by-voxel (regional), and whole lung (global) ventilation defect percentage based on RVent (VDPRVent ) and ccVent (VDPccVent ), perfusion defect percentage (QDP), and ventilation/perfusion match based on RVent (VQMRVent ) and ccVent (VQMccVent ) were calculated. STATISTICAL TESTS: Regional V and Q were analyzed globally for each subject. Each parameter's median of scans 1 and 2 were assessed by Wilcoxon sign rank test. A parameter's repeatability was analyzed by Bland-Altman analyses, coefficients of variation, intraclass correlation coefficients (ICC), and power calculations. The regional voxel repeatability was examined by calculating the Sørensen-Dice coefficient. RESULTS: There was no bias and no significant differences between the first and second MRI for any parameters (P > 0.05). Coefficient of variation ranged from 2.26% (ccVent) to 19.31% (QDP), ICC from 0.93 (QDP) to 0.60 (pPTT), the smallest detectable difference was 0.002 ccVent. Regional comparison showed the highest overlap (84%) in VDPRVent in healthy voxels and the lowest (53%) in VDPccVent defect voxels. DATA CONCLUSION: V and Q PREFUL-MRI parameters were repeatable over two scan sessions in both healthy controls and COPD patients. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

Repeatability of dynamic 3D phase-resolved functional lung (PREFUL) ventilation MR Imaging in patients with chronic obstructive pulmonary disease and healthy volunteers.

BACKGROUND: A previous study has demonstrated the feasibility of 3D phase-resolved functional lung (PREFUL) MRI in healthy volunteers and patients with chronic pulmonary disease. Before clinical use, the repeatability of the ventilation parameters derived from 3D PREFUL MRI must be determined. PURPOSE: To evaluate repeatability of 3D PREFUL and to compare with pulmonary functional lung testing (PFT). STUDY TYPE: Prospective. POPULATION: Fifty-three healthy subjects and 13 patients with chronic obstructive pulmonary disease (COPD). FIELD STRENGTH/SEQUENCE: A prototype 3D stack-of-stars spoiled-gradient-echo sequence at 1.5 T. ASSESSMENT: Study participants underwent repeated MRI examination (median time interval between scans COPD/healthy subjects [interquartile range]: 7/0 days [6-8/0-0 days]) and one PFT carried out at the time of the baseline MRI. For 3D PREFUL, regional ventilation (RVent) and flow-volume loops were computed and rated by cross-correlation (CC). Also, ventilation time-to-peak (VTTP) was computed. Ventilation defect percentage (VDP) maps were obtained for RVent and CC. STATISTICAL TESTS: Repeatability of 3D PREFUL parameters was evaluated using Bland-Altman analysis, coefficient of variation (COV) and intraclass correlation coefficient (ICC). The relation between 3D PREFUL and PFT measures (forced expiratory volume in 1 second (FEV1 ) and forced vital capacity (FVC) was assessed using the Pearson correlation coefficient (r). RESULTS: In healthy subjects and COPD patients, no significant bias (all P range: 0.09-0.77) and a moderate to good repeatability of RVent, VTTP, and VDPRVent were found (COV range: 0.1%-18.2%, ICC range: 0.51-0.88). For CC and VDPCC moderate repeatability was found (COV range: 0.6%-43.6%, ICC: 0.38-0.60). CC, VDPRVent , and VDPCC showed a good correlation with FEV1 (all |r| > 0.58, all P < 0.05) and FEV1 /FVC ratio (all |r| > 0.62, all P < 0.05). DATA CONCLUSION: 3D PREFUL provided a good repeatability of RVent, VTTP, and VDPRVent and moderate repeatability of CC and VDPCC in healthy volunteers and COPD patients, and correlated well with FEV1 and FEV1 /FVC. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

Flow Volume Loop and Regional Ventilation Assessment Using Phase-Resolved Functional Lung (PREFUL) MRI: Comparison With 129 Xenon Ventilation MRI and Lung Function Testing.

BACKGROUND: Regional flow volume loop ventilation-weighted noncontrast-enhanced proton lung MRI in free breathing has emerged as a novel technique for assessment of regional lung ventilation, but has yet not been validated with 129 Xenon MRI (129 Xe-MRI), a direct visualization of ventilation in healthy volunteers, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD) patients. PURPOSE: To compare regional ventilation and regional flow volume loops measured by noncontrast-enhanced ventilation-weighted phase-resolved functional lung MRI (PREFUL-MRI) with 129 Xe-MRI ventilation imaging and with lung function test parameters. STUDY TYPE: Retrospective study. POPULATION: Twenty patients with COPD, eight patients with CF, and six healthy volunteers. FIELD STRENGTH/SEQUENCE: PREFUL and 129 Xe-MRI gradient echo sequences were acquired at 1.5T. ASSESSMENT: Coronal slices of PREFUL-MRI (free breathing) and 129 Xe-MRI (single breath-hold) were acquired on the same day, matched by their ventrodorsal position and coregistered for evaluation. Ventilation defect percentage (VDP) was calculated based on regional ventilation (RV), regional flow volume loops (RFVL), or 129 Xe-MRI with two different threshold methods. A combined VDP was calculated for RV and RFVL. Additionally, lung function testing was performed (such as the forced expiratory volume in 1 second [FEV1 ]) was used. STATISTICAL TESTS: The obtained parameters were compared using Wilcoxon tests, correlated using Spearman's correlation coefficient (r), and agreement between PREFUL and 129 Xe-MRI parameters was assessed using Bland-Altman analysis and Dice coefficients. RESULTS: VDP measured by PREFUL and 129 Xe were significantly correlated with both thresholding techniques (r = 0.62-0.69, P < 0.05 for all) and with lung function test parameters. Combined RV and RFVL PREFUL defect maps correlated with lung function testing (eg, with FEV1 r = -0.87 P < 0.05), and showed better regional agreement to 129 Xe-MRI ventilation defects (Dice coefficient defect 0.413) with significantly higher VDP values (10.2 ± 27.3, P = 0.04) than either PREFUL defect map alone. DATA CONCLUSION: Combined RV and RFVL PREFUL defect maps likely increase sensitivity to mild airway obstruction with increased VDP values compared to 129 Xe-MRI, and correlate strongly with lung function test parameters. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

Effect of intravenously injected gadolinium-based contrast agents on functional lung parameters derived by PREFUL MRI.

PURPOSE: To evaluate the influence of intravenously administered gadolinium-based contrast agents on functional ventilation and perfusion parameters derived by phase-resolved functional lung (PREFUL) MRI. METHODS: Fourteen participants underwent functional MRI at 1.5T using a 2D spoiled gradient echo sequence during free breathing. Three data sets of PREFUL images were obtained-the 1st data set was acquired in mean 33:46 min (SD = 6:20 min) prior, the 2nd and 3rd data sets 43 and 91 s (both SD = 1.9 s), respectively, after i.v. application of gadobutrol. Full respiratory and cardiac cycles were reconstructed and functional parameters of regional ventilation (RV), perfusion (Q), and quantified perfusion (QQuant ) together with perfusion-defected percentages (QDP), ventilation-defected percentages (VDP), and ventilation-perfusion match (VQM) were calculated and compared for systematic differences between the acquired data sets. RESULTS: RV- and Q-values presented no significant alteration after gadobutrol administration. Consequently, QDP, VDP, and VQ maps were not significantly different. Sørensen-Dice coefficients of QDP and VDP maps between the different series varied up to ±9%. QQuant was significantly increased after the application of gadobutrol (1st vs. 2nd series, P = 0.0021; 1st vs. 3rd, P = 0.0188), which can be explained by the velocity-dependent signal in the completely blood-filled voxel (ROI of the aorta) after shortening of T1 relaxation time (1st vs. 2nd series, P = 0.0003; 1st vs. 3rd series, P = 0.0008). CONCLUSION: Except for quantified perfusion, all evaluated functional parameters including ventilation- and perfusion-weighted maps derived by PREFUL MRI were independent of gadolinium-based contrast agents, which is important for the design of MRI protocols in future studies.

Validation of Automated Perfusion-Weighted Phase-Resolved Functional Lung (PREFUL)-MRI in Patients With Pulmonary Diseases.

BACKGROUND: Perfusion-weighted (Qw) noncontrast-enhanced proton lung MRI is a promising technique for assessment of pulmonary perfusion, but still requires validation. PURPOSE: To improve perfusion-weighted phase-resolved functional lung (PREFUL)-MRI, to validate PREFUL with perfusion single photon emission computed tomography (SPECT) as a gold standard, and to compare PREFUL with dynamic contrast-enhanced (DCE)-MRI as a reference. STUDY TYPE: Retrospective. POPULATION: Twenty patients with chronic obstructive pulmonary disease (COPD), 14 patients with cystic fibrosis (CF), and 21 patients with chronic thromboembolic pulmonary hypertension (CTEPH) were included. FIELD STRENGTH/SEQUENCE: For PREFUL-MRI, a spoiled gradient echo sequence and for DCE-MRI a 3D time-resolved angiography with stochastic trajectories sequence were used at 1.5T. ASSESSMENT: PREFUL-MRI coronal slices were acquired in free-breathing. DCE-MRI was performed in breath-hold with injection of 0.03 mmol/kg bodyweight of gadoteric acid at a rate of 4 cc/s. Perfusion SPECT images were obtained for six CTEPH patients. Images were coregistered. An algorithm to define the appropriate PREFUL perfusion phase was developed using perfusion SPECT data. Perfusion defect percentages (QDP) and Qw-values were calculated for all methods. For PREFUL quantitative perfusion values (PREFULQ ) and for DCE pulmonary blood flow (PBF) was calculated. STATISTICAL TESTS: Obtained parameters were assessed using Pearson correlation and Bland-Altman analysis. RESULTS: Qw-SPECT correlated with Qw-DCE (r = 0.50, P < 0.01) and Qw-PREFUL (r = 0.47, P < 0.01). Spatial overlap of QDP maps showed an agreement ≥67.7% comparing SPECT and DCE, ≥64.1% for SPECT and PREFUL, and ≥60.2% comparing DCE and PREFUL. Significant correlations of Qw-PREFUL and Qw-DCE were found (COPD: r = 0.79, P < 0.01; CF: r = 0.77, P < 0.01; CTEPH: r = 0.73, P < 0.01). PREFULQ /PBF correlations were similar/lower (CF, CTEPH: P > 0.12; COPD: P < 0.01) compared to Qw-PREFUL/DCE correlations. PREFULQ -values were higher/similar compared to PBF-values (COPD, CF: P < 0.01; CTEPH: P = 0.026). DATA CONCLUSION: The automated PREFUL algorithm may allow for noncontrast-enhanced pulmonary perfusion assessment in COPD, CF, and CTEPH patients comparable to DCE-MRI. Level of Evidence 3 Technical Efficacy Stage 2 J. Magn. Reson. Imaging 2020;52:103-114.

Noninvasive Monitoring of the Response of Human Lungs to Low-Dose Lipopolysaccharide Inhalation Challenge Using MRI: A Feasibility Study.

BACKGROUND: Development of antiinflammatory drugs for lung diseases demands novel methods for noninvasive assessment of inflammatory processes in the lung. PURPOSE: To investigate the feasibility of hyperpolarized 129 Xe MRI, 1 H T1 time mapping, and dynamic contrast-enhanced (DCE) perfusion MRI for monitoring the response of human lungs to low-dose inhaled lipopolysaccharide (LPS) challenge compared to inflammatory cell counts from induced-sputum analysis. STUDY TYPE: Prospective feasibility study. POPULATION: Ten healthy volunteers underwent MRI before and 6 hours after inhaled LPS challenge with subsequent induced-sputum collection. FIELD STRENGTH/SEQUENCES: 1.5T/hyperpolarized 129 Xe MRI: Interleaved multiecho imaging of dissolved and gas phase, ventilation imaging, dissolved-phase spectroscopy, and chemical shift saturation recovery spectroscopy. 1 H MRI: Inversion recovery fast low-angle shot imaging for T1 mapping, time-resolved angiography with stochastic trajectories for DCE MRI. ASSESSMENT: Dissolved-phase ratios of 129 Xe in red blood cells (RBC), tissue/plasma (TP) and gas phase (GP), ventilation defect percentage, septal wall thickness, surface-to-volume ratio, capillary transit time, lineshape parameters in dissolved-phase spectroscopy, 1 H T1 time, blood volume, flow, and mean transit time were determined and compared to cell counts. STATISTICAL TESTS: Wilcoxon signed-rank test, Pearson correlation. RESULTS: The percentage of neutrophils in sputum was markedly increased after LPS inhalation compared to baseline, P = 0.002. The group median RBC-TP ratio was significantly reduced from 0.40 to 0.31, P = 0.004, and 1 H T1 was significantly elevated from 1157.6 msec to 1187.8 msec after LPS challenge, P = 0.027. DCE MRI exhibited no significant changes in blood volume, P = 0.64, flow, P = 0.17, and mean transit time, P = 0.11. DATA CONCLUSION: Hyperpolarized 129 Xe dissolved-phase MRI and 1 H T1 mapping may provide biomarkers for noninvasive assessment of the response of human lungs to LPS inhalation. By its specificity to the alveolar region, hyperpolarized 129 Xe MRI together with 1 H T1 mapping adds value to sputum analysis. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1669-1676.

Chronic Thromboembolic Pulmonary Hypertension Perioperative Monitoring Using Phase-Resolved Functional Lung (PREFUL)-MRI.

BACKGROUND: The translation of phase-resolved functional lung (PREFUL)-MRI to routine practice in monitoring chronic thromboembolic pulmonary hypertension (CTEPH) still requires clinical corresponding imaging biomarkers of pulmonary vascular disease. PURPOSE: To evaluate successful pulmonary endarterectomy (PEA) via PREFUL-MRI with pulmonary pulse wave transit time (pPTT). STUDY TYPE: Retrospective. POPULATION: Thirty CTEPH patients and 12 healthy controls were included. FIELD STRENGTH/SEQUENCE: For PREFUL-MRI a 2D spoiled gradient echo sequence and for DCE-MRI a 3D time-resolved angiography with stochastic trajectories (TWIST) sequence were performed on 1.5T. ASSESSMENT: Eight coronal slices of PREFUL-MRI were obtained on consecutive 13 days before and 14 days after PEA. PREFUL quantitative lung perfusion (PREFULQ ) phases over the whole cardiac cycle were calculated to quantify pPTT, the time the pulmonary pulse wave travels from the central pulmonary arteries to the pulmonary capillaries. Also, perfusion defect percentage based on pPTT (QDPpPTT ), PREFULQ (QDPPREFUL ), and V/Q match were calculated. For DCE-MRI, pulmonary blood flow (PBF) and QDPPBF were computed as reference. For clinical correlation, mean pulmonary arterial pressure (mPAP) and 6-minute walking distance were evaluated preoperatively and after PEA. STATISTICAL TESTS: The Shapiro-Wilk test, paired two-sided Wilcoxon rank sum test, Dice coefficient, and Spearman's correlation coefficient (ρ) were applied. RESULTS: Median pPTT was significantly lower post PEA (139 msec) compared to pre PEA (193 msec), P = 0.0002. Median pPTT correlated significantly with the mPAP post PEA (r = 0.52, P < 0.008). Median pPTT was distributed more homogeneously after PEA: IQR pPTT decreased from 336 to 281 msec (P < 0.004). Median PREFULQ (P < 0.0002), QDPpPTT (P < 0.0478), QDPPREFUL (P < 0.0001) and V/Q match (P < 0.0001) improved significantly after PEA. Percentage change of PREFULQ correlated significantly with percentage change of 6-minute walking distance (ρ = 0.61; P = 0.0031) 5 months post PEA. DATA CONCLUSION: Perioperative perfusion changes in CTEPH can be detected and quantified by PREFUL-MRI. Normalization of pPTT reflects surgical success and improvement of PREFULQ predicts 6-minute walking distance changes. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2 J. Magn. Reson. Imaging 2020;52:610-619.