Human iPSC-derived Committed Cardiac Progenitors Generate Cardiac Tissue Grafts in a Swine Ischemic Cardiomyopathy Model without Triggering Ventricular Arrhythmias.

BACKGROUND: The adult human heart following a large myocardial infarction is unable to regenerate heart muscle and instead forms scar with the risk of progressive heart failure. Large animal studies have shown that intramyocardial injection of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) following a myocardial infarction result in cell grafts but also ventricular arrhythmias. We hypothesized that intramyocardial injection of committed cardiac progenitor cells (CCPs) derived from iPSCs, combined with cardiac fibroblast-derived extracellular matrix (cECM) to enhance cell retention will: i) form cardiomyocyte containing functional grafts, ii) be free of ventricular arrhythmias and iii) restore left ventricular contractility in a post-myocardial infarction (MI) cardiomyopathy swine model. METHODS: hiPSCs were differentiated using bioreactors and small molecules to produce a population of committed cardiac progenitor cells (CCPs). MI was created using a coronary artery balloon occlusion and reperfusion model in Yucatan mini pigs. Four weeks later, epicardial needle injections of CCPs+cECM were performed in a small initial feasibility cohort, and then transendocardial injections (TEI) of CCPs+cECM, CCPs alone, cECM alone or vehicle control into the peri-infarct region in a larger randomized cohort. A 4-drug immunosuppression regimen was administered to prevent rejection of human CCPs. Arrhythmias were evaluated using implanted event recorders. Magnetic resonance imaging (MRI) and invasive pressure volume assessment were used to evaluate left ventricular anatomic and functional performance, including viability. Detailed histology was performed on the heart to detect human grafts. RESULTS: A scalable biomanufacturing protocol was developed generating CCPs which can efficiently differentiate to cardiomyocytes or endothelial cells in vitro. Intramyocardial delivery of CCPs to post-MI porcine hearts resulted in engraftment and differentiation of CCPs to form ventricular cardiomyocyte rich grafts. There was no significant difference in cardiac MRI-based measured cardiac volumes or function between control, CCP and CCP+cECM groups; however, dobutamine stimulated functional reserve was improved in CCP and CCP+cECM groups. TEI delivery of CCPs with or without cECM did not result in tumors or trigger ventricular arrhythmias. CONCLUSIONS: CCPs are a promising cell source for post-MI heart repair using clinically relevant TEI with a low risk of engraftment ventricular arrhythmias.

MR Angiography of Pulmonary Vasculature.

Pulmonary MR angiography (MRA) is a useful alternative to computed tomographic angiography (CTA) for the study of the pulmonary vasculature. For pulmonary hypertension and partial anomalous pulmonary venous return, a cardiac MR imaging and the pulmonary MRA are useful for flow quantification and planning treatment. For the diagnosis of pulmonary embolism (PE), MRA-PE has been shown to have non-inferior outcomes at 6 months when compared with CTA-PE. Over the last 15 years, pulmonary MRA has become a routine and reliable examination for the workup of pulmonary hypertension and the primary diagnosis of PE at the University of Wisconsin.

MRA as the Preferred Test for Pulmonary Embolism During the Iodinated Contrast Media Shortage of 2022: A Single-Center Experience.

BACKGROUND. Closure of a GE Healthcare facility in Shanghai, China, in 2022 disrupted the iodinated contrast media supply. Technologic advances have addressed limitations associated with the use of pulmonary MRA for diagnosis of pulmonary embolism (PE). OBJECTIVE. The purpose of this study was to describe a single institution's experience in the use of pulmonary MRA as an alternative to CTA for the diagnosis of PE in the general population during the iodinated contrast media shortage in 2022. METHODS. This retrospective single-center study included all CTA and MRA examinations performed to exclude PE from April 1 through July 31 (18 weekly periods) in 2019 (before the COVID-19 pandemic and contrast media shortage), 2021 (during the pandemic but before the shortage), and 2022 (during both the pandemic and the shortage). From early May through mid-July of 2022, MRA served as the preferred test for PE diagnosis, to preserve iodinated contrast media. CTA and MRA reports were reviewed. The total savings in iodinated contrast media volume resulting from preferred use of MRA was estimated. RESULTS. The study included 4491 examinations of 4006 patients (mean age, 57 ± 18 [SD] years; 1715 men, 2291 women): 1245 examinations (1111 CTA, 134 MRA) in 2019, 1547 examinations (1403 CTA, 144 MRA) in 2021, and 1699 examinations (1282 CTA, 417 MRA) in 2022. In 2022, the number of MRA examinations was four (nine when normalized to a 7-day period) in week 1, and this number increased to a maximum of 63 in week 10 and then decreased to 10 in week 18. During weeks 8-11, more MRA examinations (range, 45-63 examinations) than CTA examinations (range, 27-46 examinations) were performed. In 2022, seven patients with negative MRA underwent subsequent CTA within 2 weeks; CTA was negative in all cases. In 2022, 13.9% of CTA examinations (vs 10.3% of MRA examinations) were reported as having limited image quality. The estimated 4-month savings resulting from preferred use of MRA in 2022, under the assumption of uniform simple linear growth in CTA utilization annually and a CTA dose of 1 mL/kg, was 27 L of iohexol (350 mg I/mL). CONCLUSION. Preferred use of pulmonary MRA for PE diagnosis in the general population helped to conserve iodinated contrast media during the 2022 shortage. CLINICAL IMPACT. This single-center experience shows pulmonary MRA to be a practical substitute for pulmonary CTA in emergency settings.

Pulmonary MRA During Pregnancy: Early Experience With Ferumoxytol.

BACKGROUND: Ferumoxytol, an intravenous iron supplement, is commonly used to treat anemia in pregnancy. Ferumoxytol-enhanced magnetic resonance angiography (Fe-MRA) is a viable off-label alternative to gadolinium-enhanced MRA for assessment of pulmonary embolism (PE) in pregnancy. PURPOSE: To describe our clinical experience with Fe-MRA in pregnant women with suspected PE. STUDY TYPE: Retrospective, observational, cohort. POPULATION: A total of 98 Fe-MRA exams (consecutive sample) performed in 94 pregnant women. FIELD STRENGTH/SEQUENCE: A 1.5 T and 3.0 T, 3D T1-weighted MRA. ASSESSMENT: After IRB approval including a waiver of informed consent, electronic health records were reviewed retrospectively for all Fe-MRA exams performed at our institution in pregnant between January, 2017 and March, 2022. The Fe-MRA protocol included 3D-MRA for assessment of pulmonary arteries, and T1-weighted imaging for ancillary findings. Fe-MRA exam duration was measured from image time stamps. Fe-MRA exams were reviewed by three cardiovascular imagers using a 4-point Likert scale for image quality and confidence for PE diagnosis (score 4 = best, 1 = worst), and tabulation of ancillary findings. STATISTICAL TESTS: Continuous data are presented as mean ± standard deviation. The overall image quality and confidence score is given as the mean of three readers. RESULTS: The 98 Fe-MRA exams were performed in 94 pregnant women (age 30 ± 6, range 19-48 years, gestational week 23 ± 10, range 3-38 weeks), with four undergoing two Fe-MRA exams during their pregnancy. Median Fe-MRA exam durration was 8 minutes (interquantile range 6 minutes). Overall image quality score was 3.3 ± 0.9. Confidence score for diagnosing PE was 3.5 ± 0.8. One subject was positive for PE (1/94, 1%); 42 of the 94 (45%) subjects Fe-MRA had ancillary findings including hydronephrosis or pneumonia. CONCLUSION: Ferumoxytol enhanced MRA is a radiation- and gadolinium-free alternative for diagnosis of PE during pregancy. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 5.

Left upper lobe and lingula torsion after transplantation of single lung with complete major and minor fissures: A case report.

BACKGROUND: Native lung torsion is rare and torsion in a lung transplant is even rarer. CASE PRESENTATION: Here we report a case of left upper lobe (LUL) and lingula torsion in a patient with a unilateral left lung transplantation. The transplant was complicated by a graft with a short pulmonary artery cuff, which required significant vascular reconstruction and manipulation. Additionally, the graft had complete left major and minor fissures, which are documented risk factors for torsion. After 24 h postoperatively, the patient failed to wean off ventilation. The patient was worked up with bronchoscopy, a computed tomography (CT), and a CT angiogram (CTA). A CT without intravenous (IV) contrast showed the findings suggestive of torsion of the LUL and lingula and the CTA confirmed the diagnosis. Immediate re-exploration was performed for detorsion to preserve the vitality of the allograft. Following the failed detorsion, the patient had re-transplantation of the left lung with good results. CONCLUSION: Lung torsion should be watched for in patients with major risk factors like complete fissure. CT and/or CTA are effective tools to confirm the diagnosis.

Mucus Plugs in Asthma at CT Associated with Regional Ventilation Defects at 3He MRI.

Background Airway mucus plugs in asthma are associated with exacerbation frequency, increased eosinophilia, and reduced lung function. The relationship between mucus plugs and spatially overlapping ventilation abnormalities observed at hyperpolarized gas MRI has not been assessed quantitatively. Purpose To assess regional associations between CT mucus plugs scored by individual bronchopulmonary segment and corresponding measurements of segmental ventilation defect percentage (VDP) at hyperpolarized helium 3 (3He) MRI. Materials and Methods In this secondary analysis of a Health Insurance Portability and Accountability Act-compliant prospective observational cohort, participants in the Severe Asthma Research Program (SARP) III (NCT01760915) between December 2012 and August 2015 underwent hyperpolarized 3He MRI to determine segmental VDP. Segmental mucus plugs at CT were scored by two readers, with segments scored as plugged only if both readers agreed independently. A linear mixed-effects model controlling for interpatient variability was then used to assess differences in VDP in plugged versus plug-free segments. Results Forty-four participants with asthma were assessed (mean age ± standard deviation, 47 years ± 15; 29 women): 19 with mild-to-moderate asthma and 25 with severe asthma. Mucus plugs were observed in 49 total bronchopulmonary segments across eight of 44 patients. Segments containing mucus plugs had a median segmental VDP of 25.9% (25th-75th percentile, 7.3%-38.3%) versus 1.4% (25th-75th percentile, 0.1%-5.2%; P < .001) in plug-free segments. Similarly, the model estimated a segmental VDP of 18.9% (95% CI: 15.7, 22.2) for mucus-plugged segments versus 5.1% (95% CI: 3.3, 7.0) for plug-free segments (P < .001). Participants with one or more mucus plugs had a median whole-lung VDP of 11.1% (25th-75th percentile, 7.1%-18.9%) versus 3.1% (25th-75th percentile, 1.1%-4.4%) in those without plugs (P < .001). Conclusion Airway mucus plugging at CT was associated with reduced ventilation in the same bronchopulmonary segment at hyperpolarized helium 3 MRI, suggesting that mucus plugging may be an important cause of ventilation defects in asthma. © RSNA, 2021 Online supplemental material is available for this article.

Patient Preferences for Diagnostic Imaging: CTA vs MRA When Diagnosing Pulmonary Embolism.

OBJECTIVE: To identify preferences regarding choice of diagnostic imaging (computed tomographic angiography [CTA] vs magnetic resonance angiography [MRA]) for the evaluation of pulmonary embolism. METHODS: We conducted 4 focus group discussions with residents of 2 Wisconsin cities. Community members ≥18 years old were recruited via telephone using a commercially available telephone database. The discussions were audio recorded and professionally transcribed. Three investigators (a research specialist, emergency physician, and qualitative methodologist) independently analyzed these transcripts using inductive thematic coding to identify the overarching themes and underlying concepts. Intercoder discrepancies were resolved through consensus discussion by the reviewers. RESULTS: Focus groups were held over a 3-month period and included 29 participants (16 female). Ages were well represented: 18-30 (n = 7), 31-40 (n = 8), 41-55 (n = 6), and 56+ (n = 8) years old. Analysis revealed 3 central themes: time, risk, and experience. Participants who preferred CTA commonly cited the need for immediate results in the emergency department. When nonemergent scenarios were discussed, the option to undergo MRA was considered more strongly; participants weighed additional details like radiation and diagnostic accuracy. Regarding risks, discussants expressed concerns from multiple sources, including radiation and intravenous contrast. However, understanding of this risk varied across the groups. Prior experience with medical imaging-both personal and indirect experiences-carried considerable weight. CONCLUSIONS: Preferences regarding imaging choice in the diagnosis of pulmonary embolism were mixed, often reliant on vicarious experiences and an exaggerated notion of the difference in timing of imaging results. Participants frequently used incomplete or even incorrect information as the basis for decision-making.

Guidance for computed tomography (CT) imaging of the lungs for patients with cystic fibrosis (CF) in research studies.

Numerous issues must be addressed when developing standard operating procedures for clinical research studies involving chest computed tomography of lung disease in patients with cystic fibrosis (CF). Study success depends on the provision of adequate funding and the identification of personnel with the necessary expertise to conduct the study, along with clear guidelines that detail the CT operating procedure at each site, including breathing maneuvers, and image reconstruction. Close coordination of the quality assurance process between sites and the central review organization is required to maintain protocol adherence. The data transfer process must ensure the integrity and security of the data to comply with patient privacy regulations, and study outcome measures are best assessed with a scoring system or other structured method of imaging data analysis. The recommendations provided are designed to serve as a valuable reference guide for planning clinical research studies of patients with CF involving chest CT.

Comparison of gadolinium-enhanced and ferumoxytol-enhanced conventional and UTE-MRA for the depiction of the pulmonary vasculature.

PURPOSE: To evaluate the feasibility of ferumoxytol (FE)-enhanced UTE-MRA for depiction of the pulmonary vascular and nonvascular structures. METHODS: Twenty healthy volunteers underwent contrast-enhanced pulmonary MRA at 3 T during 2 visits, separated by at least 4 weeks. Visit 1: The MRA started with a conventional multiphase 3D T1 -weighted breath-held spoiled gradient-echo MRA before and after the injection of 0.1 mmol/kg gadobenate dimeglumine (GD). Subsequently, free-breathing GD-UTE-MRA was acquired as a series of 3 flip angles (FAs) (6°, 12°, 18°) to optimize T1 weighting. Visit 2: After the injection of 4 mg/kg FE, MRA was performed during the steady state, starting with a conventional 3D T1 -weighted breath-held spoiled gradient-echo MRA and followed by free-breathing FE-UTE-MRA, both at 4 different FAs (6°, 12°, 18°, 24°). The optimal FA for best T1 contrast was evaluated. Image quality at the optimal FA was compared between methods on a 4-point ordinal scale, using multiphase GD conventional pulmonary MRA (cMRA) as standard of reference. RESULTS: Flip angle in the range of 18°-24° resulted in best T1 contrast for FE cMRA and both UTE-MRA techniques (p > .05). At optimized FA, image quality of the vasculature was good/excellent with both FE-UTE-MRA and GD cMRA (98% versus 97%; p = .51). Both UTE techniques provided superior depiction of nonvascular structures compared with either GD-enhanced or FE-enhanced cMRA (p < .001). However, GD-UTE-MRA showed the lowest image quality of the angiogram due to low image contrast. CONCLUSION: Free-breathing UTE-MRA using FE is feasible for simultaneous assessment of the pulmonary vasculature and nonvascular structures. Patient studies should investigate the clinical utility of free-breathing UTE-MRA for assessment of pulmonary emboli.

Deep convolutional neural networks with multiplane consensus labeling for lung function quantification using UTE proton MRI.

BACKGROUND: Ultrashort echo time (UTE) proton MRI has gained popularity for assessing lung structure and function in pulmonary imaging; however, the development of rapid biomarker extraction and regional quantification has lagged behind due to labor-intensive lung segmentation. PURPOSE: To evaluate a deep learning (DL) approach for automated lung segmentation to extract image-based biomarkers from functional lung imaging using 3D radial UTE oxygen-enhanced (OE) MRI. STUDY TYPE: Retrospective study aimed to evaluate a technical development. POPULATION: Forty-five human subjects, including 16 healthy volunteers, 5 asthma, and 24 patients with cystic fibrosis. FIELD STRENGTH/SEQUENCE: 1.5T MRI, 3D radial UTE (TE = 0.08 msec) sequence. ASSESSMENT: Two 3D radial UTE volumes were acquired sequentially under normoxic (21% O2 ) and hyperoxic (100% O2 ) conditions. Automated segmentation of the lungs using 2D convolutional encoder-decoder based DL method, and the subsequent functional quantification via adaptive K-means were compared with the results obtained from the reference method, supervised region growing. STATISTICAL TESTS: Relative to the reference method, the performance of DL on volumetric quantification was assessed using Dice coefficient with 95% confidence interval (CI) for accuracy, two-sided Wilcoxon signed-rank test for computation time, and Bland-Altman analysis on the functional measure derived from the OE images. RESULTS: The DL method produced strong agreement with supervised region growing for the right (Dice: 0.97; 95% CI = [0.96, 0.97]; P < 0.001) and left lungs (Dice: 0.96; 95% CI = [0.96, 0.97]; P < 0.001). The DL method averaged 46 seconds to generate the automatic segmentations in contrast to 1.93 hours using the reference method (P < 0.001). Bland-Altman analysis showed nonsignificant intermethod differences of volumetric (P ≥ 0.12) and functional measurements (P ≥ 0.34) in the left and right lungs. DATA CONCLUSION: DL provides rapid, automated, and robust lung segmentation for quantification of regional lung function using UTE proton MRI. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:1169-1181.

"Structure-Function Imaging of Lung Disease Using Ultrashort Echo Time MRI".

RATIONALE AND OBJECTIVES: The purpose of this review is to acquaint the reader with recent advances in ultrashort echo time (UTE) magnetic resonance imaging (MRI) of the lung and its implications for pulmonary MRI when used in conjunction with functional MRI technique. MATERIALS AND METHODS: We provide an overview of recent technical advances of UTE and explore the advantages of combined structure-function pulmonary imaging in the context of restrictive and obstructive pulmonary diseases such as idiopathic pulmonary fibrosis (IPF) and cystic fibrosis (CF). RESULTS: UTE MRI clearly shows the lung parenchymal changes due to IPF and CF. The use of UTE MRI, in conjunction with established functional lung MRI in chronic lung diseases, will serve to mitigate the need for computed tomography in children. CONCLUSION: Current limitations of UTE MRI include long scan times, poor delineation of thin-walled structures (e.g. cysts and reticulation) due to limited spatial resolution, low signal to noise ratio, and imperfect motion compensation. Despite these limitations, UTE MRI can now be considered as an alternative to multidetector computed tomography for the longitudinal follow-up of the morphological changes from lung diseases in neonates, children, and young adults, particularly as a complement to the unique functional capabilities of MRI.

Three-dimensional Isotropic Functional Imaging of Cystic Fibrosis Using Oxygen-enhanced MRI: Comparison with Hyperpolarized 3He MRI.

Purpose To compare the performance of three-dimensional radial ultrashort echo time (UTE) oxygen-enhanced (OE) MRI with that of hyperpolarized helium 3 (3He) MRI with respect to quantitative ventilation measurements in patients with cystic fibrosis (CF). Materials and Methods In this prospective study conducted from June 2013 to May 2015, 25 participants with CF aged 10-55 years (14 male; age range, 13-55 years; 11 female; age range, 10-37 years) successfully underwent pulmonary function tests, hyperpolarized 3He MRI, and OE MRI. OE MRI used two sequential 3.5-minute normoxic and hyperoxic steady-state free-breathing UTE acquisitions. Seven participants underwent imaging at two separate examinations 1-2 weeks apart to assess repeatability. Regional ventilation was quantified as ventilation defect percentage (VDP) individually from OE MRI and hyperpolarized 3He MRI by using the same automated quantification tool. Bland-Altman analysis, intraclass correlation coefficient (ICC), Spearman correlation coefficient, and Wilcoxon signed-rank test were used to evaluate repeatability. Results In all 24 participants, the global VDP measurements from either OE MRI (ρ = -0.66, P < .001) or hyperpolarized 3He MRI (ρ = -0.75, P < .001) were significantly correlated with the percentage predicted forced expiratory volume in 1 second. VDP reported at OE MRI was 5.0% smaller than (P = .014) but highly correlated with (ρ = 0.78, P < .001) VDP reported at hyperpolarized 3He MRI. Both OE MRI-based VDP and hyperpolarized 3He MRI-based VDP demonstrated good repeatability (ICC = 0.91 and 0.95, respectively; P ≤ .001). Conclusion In lungs with cystic fibrosis, ultrashort echo time oxygen-enhanced MRI showed similar performance compared with hyperpolarized 3He MRI for quantitative measures of ventilation defects and their repeatability. © RSNA, 2018 Online supplemental material is available for this article.

Clinical outcomes after magnetic resonance angiography (MRA) versus computed tomographic angiography (CTA) for pulmonary embolism evaluation.

PURPOSE: To compare patient outcomes following magnetic resonance angiography (MRA) versus computed tomographic angiography (CTA) ordered for suspected pulmonary embolism (PE). METHODS: In this IRB-approved, single-center, retrospective, case-control study, we reviewed the medical records of all patients evaluated for PE with MRA during a 5-year period along with age- and sex-matched controls evaluated with CTA. Only the first instance of PE evaluation during the study period was included. After application of our exclusion criteria to both study arms, the analysis included 1173 subjects. The primary endpoint was major adverse PE-related event (MAPE), which we defined as major bleeding, venous thromboembolism, or death during the 6 months following the index imaging test (MRA or CTA), obtained through medical record review. Logistic regression, chi-square test for independence, and Fisher's exact test were used with a p < 0.05 threshold. RESULTS: The overall 6-month MAPE rate following MRA (5.4%) was lower than following CTA (13.6%, p < 0.01). Amongst outpatients, the MAPE rate was lower for MRA (3.7%) than for CTA (8.0%, p = 0.01). Accounting for age, sex, referral source, BMI, and Wells' score, patients were less likely to suffer MAPE than those who underwent CTA, with an odds ratio of 0.44 [0.24, 0.80]. Technical success rate did not differ significantly between MRA (92.6%) and CTA (90.5%) groups (p = 0.41). CONCLUSION: Within the inherent limitations of a retrospective case-controlled analysis, we observed that the rate of MAPE was lower (more favorable) for patients following pulmonary MRA for the primary evaluation of suspected PE than following CTA.

Downstream Imaging Utilization After MR Angiography Versus CT Angiography for the Initial Evaluation of Pulmonary Embolism.

OBJECTIVE: To compare the proportion of emergency department (ED) patients who undergo subsequent chest CT or MR within 1 year of an initially negative scan for pulmonary embolism (PE). METHODS: This single-center, retrospective, observational study examined the use of chest CT or MR for ED patients with MR angiography (MRA) negative for PE during April 2008 to March 2013. We compared the 1-year scan utilization for these cases to an age- and sex-matched cohort of patients who underwent CT angiography (CTA). We also calculated time to first follow-up scan and mean radiation dose in each arm. Trained data abstractors used a standardized protocol and electronic case report form to gather all outcomes of interest. Results are reported as means or proportions with their associated confidence intervals (CIs). RESULTS: In all, 717 ED patients (430 MRAs and 287 CTAs) were included. At 1 year, the proportion undergoing subsequent imaging (MRA 16.7%, CTA 15.3%; difference = 1.4%, 95% CI 4.05%-6.86%) and time to first follow-up scan (difference = 13 days, 95% CI -22.69-48.7) did not differ between arms. Mean radiation dose per patient at 1 year was significantly higher in the CTA arm (9.82 mSv; 95% CI 9.12-10.53) compared with 2.92 mSv (95% CI 1.86-3.98) with MRA. Those with an index MRA were more likely to undergo subsequent MRAs (odds ratio 3.68; 95% CI 1.22-11.12) than those with an index CTA. However, in both arms, the majority (85%) of subsequent scans were CTAs. CONCLUSIONS: When comparing patients initially undergoing MRA versus CTA for the evaluation of PE, there was no difference in downstream chest CT or MR use at 1 year.

Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction.

BACKGROUND: The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown. METHODS: In clinical studies, we developed and applied a bronchopulmonary segment-based scoring system to quantify mucus plugs on multidetector computed tomography (MDCT) lung scans from 146 subjects with asthma and 22 controls, and analyzed relationships among mucus plug scores, forced expiratory volume in 1 second (FEV1), and airway eosinophils. Additionally, we used airway mucus gel models to explore whether oxidants generated by eosinophil peroxidase (EPO) oxidize cysteine thiol groups to promote mucus plug formation. RESULTS: Mucus plugs occurred in at least 1 of 20 lung segments in 58% of subjects with asthma and in only 4.5% of controls, and the plugs in subjects with asthma persisted in the same segment for years. A high mucus score (plugs in ≥ 4 segments) occurred in 67% of subjects with asthma with FEV1 of less than 60% of predicted volume, 19% with FEV1 of 60%-80%, and 6% with FEV1 greater than 80% (P < 0.001) and was associated with marked increases in sputum eosinophils and EPO. EPO catalyzed oxidation of thiocyanate and bromide by H2O2 to generate oxidants that crosslink cysteine thiol groups and stiffen thiolated hydrogels. CONCLUSION: Mucus plugs are a plausible mechanism of chronic airflow obstruction in severe asthma, and EPO-generated oxidants may mediate mucus plug formation. We propose an approach for quantifying airway mucus plugging using MDCT lung scans and suggest that treating mucus plugs may improve airflow in chronic severe asthma. TRIAL REGISTRATION: Clinicaltrials.gov NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01759186, NCT01716494, and NCT01760915. FUNDING: NIH grants P01 HL107201, R01 HL080414, U10 HL109146, U10 HL109164, U10 HL109172, U10 HL109086, U10 HL109250, U10 HL109168, U10 HL109257, U10 HL109152, and P01 HL107202 and National Center for Advancing Translational Sciences grants UL1TR0000427, UL1TR000448, and KL2TR000428.

Regional Heterogeneity of Lobar Ventilation in Asthma Using Hyperpolarized Helium-3 MRI.

RATIONALE AND OBJECTIVES: To determine lobar ventilation patterns in asthmatic lungs with hyperpolarized 3He magnetic resonance imaging (HP 3He MRI). MATERIALS AND METHODS: Eighty-two subjects (14 normal, 48 mild-to-moderate asthma, and 20 severe asthma) underwent HP 3He MRI, computed tomography (CT), and pulmonary function testing. After registering proton to 3He images, we segmented the lungs from proton MRI and further segmented the five lung lobes (right upper lobe [RUL], right middle lobe [RML], and right lower lobe [RLL]; left upper lobe and left lower lobe [LLL]) by referring to the lobar segmentation from CT. We classified the gas volume into four signal intensity levels as follows: ventilation defect percent (VDP), low ventilation percent, medium ventilation percent, and high ventilation percent. The local signal intensity variations in the ventilated volume were estimated using heterogeneity score (Hs). We compared each ventilation level and Hs measured in the whole lung and lobar regions across the three subject groups. RESULTS: In mild-to-moderate asthma, the RML and RUL showed significantly greater VDP than the two lower lobes (RLL and LLL) (P ≤ .047). In severe asthma, the pattern was more variable with the VDP in the RUL significantly greater than in the RLL (P = .026). In both asthma groups, the lower lobes (RLL and LLL) showed significantly higher high ventilation percent and Hs compared to the three upper lobes (all P ≤ .015). CONCLUSIONS: In asthma, the RML and RUL showed greater ventilation abnormalities, and the RLL and LLL were more highly ventilated with greater local heterogeneity. These findings may facilitate guided bronchoscopic sampling and localized airway treatment in future studies.

Motion robust high resolution 3D free-breathing pulmonary MRI using dynamic 3D image self-navigator.

PURPOSE: To achieve motion robust high resolution 3D free-breathing pulmonary MRI utilizing a novel dynamic 3D image navigator derived directly from imaging data. METHODS: Five-minute free-breathing scans were acquired with a 3D ultrashort echo time (UTE) sequence with 1.25 mm isotropic resolution. From this data, dynamic 3D self-navigating images were reconstructed under locally low rank (LLR) constraints and used for motion compensation with one of two methods: a soft-gating technique to penalize the respiratory motion induced data inconsistency, and a respiratory motion-resolved technique to provide images of all respiratory motion states. RESULTS: Respiratory motion estimation derived from the proposed dynamic 3D self-navigator of 7.5 mm isotropic reconstruction resolution and a temporal resolution of 300 ms was successful for estimating complex respiratory motion patterns. This estimation improved image quality compared to respiratory belt and DC-based navigators. Respiratory motion compensation with soft-gating and respiratory motion-resolved techniques provided good image quality from highly undersampled data in volunteers and clinical patients. CONCLUSION: An optimized 3D UTE sequence combined with the proposed reconstruction methods can provide high-resolution motion robust pulmonary MRI. Feasibility was shown in patients who had irregular breathing patterns in which our approach could depict clinically relevant pulmonary pathologies. Magn Reson Med 79:2954-2967, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Pulmonary ventilation imaging in asthma and cystic fibrosis using oxygen-enhanced 3D radial ultrashort echo time MRI.

BACKGROUND: A previous study demonstrated the feasibility of using 3D radial ultrashort echo time (UTE) oxygen-enhanced MRI (UTE OE-MRI) for functional imaging of healthy human lungs. The repeatability of quantitative measures from UTE OE-MRI needs to be established prior to its application in clinical research. PURPOSE: To evaluate repeatability of obstructive patterns in asthma and cystic fibrosis (CF) with UTE OE-MRI with isotropic spatial resolution and full chest coverage. STUDY TYPE: Volunteer and patient repeatability. POPULATION: Eighteen human subjects (five asthma, six CF, and seven normal subjects). FIELD STRENGTH/SEQUENCE: Respiratory-gated free-breathing 3D radial UTE (80 µs) sequence at 1.5T. ASSESSMENT: Two 3D radial UTE volumes were acquired sequentially under normoxic and hyperoxic conditions. A subset of subjects underwent repeat acquisitions on either the same day or ≤15 days apart. Asthma and CF subjects also underwent spirometry. A workflow including deformable registration and retrospective lung density correction was used to compute 3D isotropic percent signal enhancement (PSE) maps. Median PSE (MPSE) and ventilation defect percent (VDP) of the lung were measured from the PSE map. STATISTICAL TESTS: The relations between MPSE, VDP, and spirometric measures were assessed using Spearman correlations. The test-retest repeatability was evaluated using Bland-Altman analysis and intraclass correlation coefficients (ICC). RESULTS: Ventilation measures in normal subjects (MPSE = 8.0%, VDP = 3.3%) were significantly different from those in asthma (MPSE = 6.0%, P = 0.042; VDP = 21.7%, P = 0.018) and CF group (MPSE = 4.5%, P = 0.0006; VDP = 27.2%, P = 0.002). MPSE correlated significantly with forced expiratory lung volume in 1 second percent predicted (ρ = 0.72, P = 0.017). The ICC of the test-retest VDP and MPSE were both ≥0.90. In all subject groups, an anterior/posterior gradient was observed with higher MPSE and lower VDP in the posterior compared to anterior regions (P ≤ 0.0021 for all comparisons). DATA CONCLUSION: 3D radial UTE OE-MRI supports quantitative differentiation of diseased vs. healthy lungs using either whole lung VDP or MPSE with excellent test-retest repeatability. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1287-1297.

Magnetic Resonance Imaging for the Evaluation of Pulmonary Embolism.

Pulmonary embolism (PE) is a leading cause of acute cardiovascular death throughout the world. Although computed tomography angiography (CTA) is the primary imaging study used to diagnose acute PE, pulmonary magnetic resonance angiography (MRA) is increasingly being used in patients with contraindications for CTA. This manuscript reviews the MRA techniques used for the diagnosis of PE and discuss how these techniques can be implemented in routine clinical practice. In addition, the efficacy and effectiveness of these techniques will be compared to other modalities.