Background Breathlessness is a common symptom in Long COVID (LC). Using hyperpolarised xenon MRI ( 129 Xe-MRI), we assessed whether this symptom could be attributed to abnormalities in the alveolar-capillary membrane not detected by standard investigations. We focused on never-hospitalised individuals without an identified cause for breathlessness. Methods In this prospective, multicentre study, we compared 129 Xe-MRI, lung function, exercise capacity, and symptom questionnaires in LC patients with breathlessness (BLC) to those without breathlessness (NBLC) and healthy controls. Primary outcome was whether BLC demonstrated measurable impairments in gas exchange focusing on dissolved-phase 129 Xe-MRI metrics: red-blood cell to membrane ratio (RBC:M) and red-blood cell to gas ratio (RBC:Gas). We also explored associations between symptoms and physiological measures. Results Of 269 participants recruited, 196 were included in the analysis (109 BLC, 43 NBLC, 44 controls), with age and sex well matched across groups. BLC had a significantly longer interval from infection to imaging (median 632 days; p<0·001). No significant differences in global or regional RBC:M or RBC:Gas were observed across groups. BLC showed lower FEV 1 , FVC, TLCO, and KCO z-scores compared to controls, though >90% of values remained within normal range. A subset of BLC participants with low TLCO (14/109) showed reduced 129 Xe-MRI metrics and higher breathlessness scores. Interpretation Most non-hospitalised LC participants exhibited no detectable pulmonary abnormalities, including those with breathlessness. However, approximately 13% of breathless individuals demonstrated minor reductions in TLCO and 129 Xe-MRI gas exchange suggesting a potential pulmonary contribution for symptoms in this subgroup.

Background:Breathlessness is a common symptom in long COVID (LC). Using hyperpolarised xenon magnetic resonance imaging (129Xe-MRI), we assessed whether this symptom could be attributed to abnormalities in the alveolar-capillary membrane not detected by standard investigations. We focused on never-hospitalised individuals without an identified cause for breathlessness. Methods:In this prospective, multicentre study, we compared 129Xe-MRI, lung function, exercise capacity and symptom questionnaires in LC patients with breathlessness (BLC) to those without breathlessness (NBLC) and healthy controls. Primary outcome was whether BLC demonstrated measurable impairments in gas exchange focusing on dissolved-phase 129Xe-MRI metrics: red blood cell to membrane ratio (RBC:M) and red blood cell to gas ratio (RBC:Gas). We also explored associations between symptoms and physiological measures. Results:Of 269 participants recruited, 196 were included in the analysis (109 BLC, 43 NBLC, 44 controls), with age and sex well matched across groups. BLC had a significantly longer interval from infection to MRI (median 632 days; p<0.001). No significant differences in global or regional RBC:M or RBC:Gas were observed across groups. BLC showed lower forced expiratory volume in 1 s, forced vital capacity, transfer factor of the lung for carbon monoxide (T L CO), and carbon monoxide transfer coefficient (K CO) z-scores compared to controls, though >90% of values remained within normal range. A subset of BLC participants with low T L CO (14 out of 109) showed reduced 129Xe-MRI metrics and higher breathlessness scores. Interpretation:Most nonhospitalised LC participants exhibited no detectable pulmonary abnormalities, including those with breathlessness. However, ∼13% of breathless individuals demonstrated minor reductions in T L CO and 129Xe-MRI gas exchange suggesting a potential pulmonary contribution for symptoms in this subgroup.

BACKGROUND:We report IMPROVE-DiCE (Improve Diabetic Cardiac Energetics), a 2-part open-label, phase 2a trial evaluating the safety and effectiveness of ninerafaxstat, a novel therapeutic designed to enhance cardiac energetics. Between May and September 2021, part 1 enrolled patients with type 2 diabetes and obesity without heart failure with preserved ejection fraction (HFpEF). Between January 2023 and June 2024, part 2 enrolled patients with type 2 diabetes, obesity, and HFpEF. METHODS:Forty-two participants received 200 mg ninerafaxstat twice daily (part 1, n=21, 43% women, 72±0.5 years of age, 4-8 weeks; part 2, n=21, 29% women, 71±6 years of age, 12 weeks). Myocardial energetics (phosphocreatine-to-ATP ratio [PCr/ATP], primary outcome) and function (rest and dobutamine stress) were assessed before and after treatment using magnetic resonance imaging, 31P- and 1H magnetic resonance spectroscopy. In part 1, hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopy to assess in vivo pyruvate dehydrogenase flux (n=9) and plasma metabolomics and proteomics were also performed. RESULTS:In part 1, in patients with diabetes and obesity but without HFpEF, the heart was characterized by impaired pyruvate dehydrogenase flux, reduced PCr/ATP, triglyceride deposition, and diastolic impairment. Treatment with ninerafaxstat was associated with improved PCr/ATP (+0.39±0.49 [95% CI, 0.16-0.62]; Cohen's d, 0.79; P=0.002) and lower myocardial triglyceride (by 34%, P=0.03). In part 2, in patients with diabetes, obesity, and symptomatic HFpEF, the heart was characterized by reduced PCr/ATP, diastolic impairment, and failure of systolic augmentation to exercise. Consistently, treatment with ninerafaxstat was associated with improvement in PCr/ATP (+0.15±0.25 [95% CI, 0.03-0.26]; Cohen's d, 0.60; P=0.02), improved systolic augmentation to exercise (+1.4 L/min, P=0.04), improved exercise capacity (6-minute walk distance +16 m, P=0.02), and improved New York Heart Association class symptom burden. CONCLUSIONS:These mechanistic phase 2a study results show that ninerafaxstat is safely tolerated and improves myocardial energetics in participants with obesity and diabetes without or with clinically manifest HFpEF. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04826159.

Background: NHLC patients typically have no structural cause on chest CT to explain their symptoms. Aims: EXPLAIN is a multi-centre, prospective, observational, cohort study comparing Lung Function Tests (LFT), dyspnoea scores and hyperpolarised 129Xe MRI in dyspnoeic and non-dyspnoeic NHLC patients and asymptomatic post-COVID controls. Here, we present the LFT interim analysis of 116 participants. Methods: NHLC patients were recruited from post-COVID clinics. Participants with significant smoking history and cardiorespiratory diseases were excluded from the study. The median time from infection was 463, 235, and 202 days in dyspnoeic NHLC patients, non-dyspnoeic NHLC patients and controls respectively. Results: All participants had normal or near-normal chest CT. At least 89% of participants were Caucasians in each group (p=0.5). Although within normal limits, FVC (101 vs 109%predicted, p=0.007) and DLCO (94 vs 102%predicted, p=0.013) were significantly lower in the breathless group compared with the control group. Conclusion: Preliminary data suggests unexplained lower FVC %predicted and DLCO %predicted seen in NHLC breathless patients with no associated CT abnormalities beyond a year of mild COVID-19 infection compared with fully recovered controls. We aim to use 129Xe MRI to elucidate the underlying mechanisms contributing to these observed differences.

Background Long-COVID is an umbrella term used to describe ongoing symptoms following COVID-19 infection after four weeks. Symptoms are wide-ranging but breathlessness is one of the most common and can persist for months after the initial infection. Investigations including Computed Tomography (CT), and physiological measurements (lung function tests) are usually unremarkable. The mechanisms driving breathlessness remain unclear, and this may be hindering the development of effective treatments. Methods Eleven non-hospitalised Long-COVID (NHLC, 4 male), 12 post-hospitalised COVID-19 (PHC, 10 male) patients were recruited from a Post-COVID Assessment clinic, and thirteen healthy controls (6 female) were recruited to undergo Hyperpolarized Xenon Magnetic Resonance Imaging (Hp-XeMRI). NHLC and PHC participants underwent contemporaneous CT, Hp-XeMRI, lung function tests, 1-minute sit-to-stand test and breathlessness questionnaires. Statistical analysis included group and pair-wise comparisons between patients and controls, and correlations between patient clinical and imaging data. Results NHLC and PHC patients were 287 {+/-} 79 [range 190-437] and 149 {+/-} 68 [range 68-269] days from infection, respectively. All NHLC patients had normal CT scans, and the PHC had normal or near normal CT scans (0.3/25 {+/-} 0.6 [range 0-2] and 7/25 {+/-} 5 [range 4-8], respectively). There was a significant difference in TLco (%) between NHLC and PHC patients (76 {+/-} 8 % vs 86 {+/-} 8%, respectively, p = 0.04) but no differences in other measurements of lung function. There were significant differences in RBC:TP mean between volunteers (0.45 {+/-} 0.07, range [0.33-0.55]) and PHC (0.31 {+/-} 0.11, [range 0.16-0.37]) and NHLC (0.35 {+/-} 0.09, [range 0.26-0.58]) patients, but not between NHLC and PHC (p = 0.26). Conclusion There are RBC:TP abnormalities in NHLC and PHC patients, with NHLC patients also demonstrating lower TLco than PHC patients despite their having normal CT scans. These abnormalities are present many months after the initial infection. Summary statement Hyperpolarized Xenon MRI and TLco demonstrate significantly impaired gas transfer in non-hospitalised long-COVID patients when all other investigations are normal.

Background Post-COVID-19 condition encompasses symptoms following COVID-19 infection that linger at least 4 weeks after the end of active infection. Symptoms are wide ranging, but breathlessness is common. Purpose To determine if the previously described lung abnormalities seen on hyperpolarized (HP) pulmonary xenon 129 (129Xe) MRI scans in participants with post-COVID-19 condition who were hospitalized are also present in participants with post-COVID-19 condition who were not hospitalized. Materials and Methods In this prospective study, nonhospitalized participants with post-COVID-19 condition (NHLC) and posthospitalized participants with post-COVID-19 condition (PHC) were enrolled from June 2020 to August 2021. Participants underwent chest CT, HP 129Xe MRI, pulmonary function testing, and the 1-minute sit-to-stand test and completed breathlessness questionnaires. Control subjects underwent HP 129Xe MRI only. CT scans were analyzed for post-COVID-19 interstitial lung disease severity using a previously published scoring system and full-scale airway network (FAN) modeling. Analysis used group and pairwise comparisons between participants and control subjects and correlations between participant clinical and imaging data. Results A total of 11 NHLC participants (four men, seven women; mean age, 44 years ± 11 [SD]; 95% CI: 37, 50) and 12 PHC participants (10 men, two women; mean age, 58 years ±10; 95% CI: 52, 64) were included, with a significant difference in age between groups (P = .05). Mean time from infection was 287 days ± 79 (95% CI: 240, 334) and 143 days ± 72 (95% CI: 105, 190) in NHLC and PHC participants, respectively. NHLC and PHC participants had normal or near normal CT scans (mean, 0.3/25 ± 0.6 [95% CI: 0, 0.63] and 7/25 ± 5 [95% CI: 4, 10], respectively). Gas transfer (Dlco) was different between NHLC and PHC participants (mean Dlco, 76% ± 8 [95% CI: 73, 83] vs 86% ± 8 [95% CI: 80, 91], respectively; P = .04), but there was no evidence of other differences in lung function. Mean red blood cell-to-tissue plasma ratio was different between volunteers (mean, 0.45 ± 0.07; 95% CI: 0.43, 0.47]) and PHC participants (mean, 0.31 ± 0.10; 95% CI: 0.24, 0.37; P = .02) and between volunteers and NHLC participants (mean, 0.37 ± 0.10; 95% CI: 0.31, 0.44; P = .03) but not between NHLC and PHC participants (P = .26). FAN results did not correlate with Dlco) or HP 129Xe MRI results. Conclusion Nonhospitalized participants with post-COVID-19 condition (NHLC) and posthospitalized participants with post-COVID-19 condition (PHC) showed hyperpolarized pulmonary xenon 129 MRI and red blood cell-to-tissue plasma abnormalities, with NHLC participants demonstrating lower gas transfer than PHC participants despite having normal CT findings. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Parraga and Matheson in this issue.

Background SARS-CoV-2 targets angiotensin-converting enzyme 2-expressing cells in the respiratory tract. There are reports of breathlessness in patients many months after infection. Purpose To determine whether hyperpolarized xenon 129 MRI (XeMRI) imaging could be used to identify the possible cause of breathlessness in patients at 3 months after hospital discharge following COVID-19 infection. Materials and Methods This prospective study was undertaken between August and December of 2020, with patients and healthy control volunteers being enrolled. All patients underwent lung function tests; ventilation and dissolved-phase XeMRI, with the mean red blood cell (RBC) to tissue or plasma (TP) ratio being calculated; and a low-dose chest CT, with scans being scored for the degree of abnormalities after COVID-19. Healthy control volunteers underwent XeMRI. The intraclass correlation coefficient was calculated for volunteer and patient scans to assess repeatability. A Wilcoxon rank sum test and Cohen effect size calculation were performed to assess differences in the RBC/TP ratio between patients and control volunteers. Results Nine patients (mean age, 57 years ± 7 [standard deviation]; six male patients) and five volunteers (mean age, 29 years ± 3; five female volunteers) were enrolled. The mean time from hospital discharge for patients was 169 days (range, 116-254 days). There was a difference in the RBC/TP ratio between patients and control volunteers (0.3 ± 0.1 vs 0.5 ± 0.1, respectively; P = .001; effect size, 1.36). There was significant difference between the RBC and gas phase spectral full width at half maximum between volunteers and patients (median ± range, 567 ± 1 vs 507 ± 81 [P = .002] and 104 ± 2 vs 122 ± 17 [P = .004], respectively). Results were reproducible, with intraclass correlation coefficients of 0.82 and 0.88 being demonstrated for patients and volunteers, respectively. Participants had normal or nearly normal CT scans (mean, seven of 25; range, zero of 25 to 10 of 25). Conclusion Hyperpolarized xenon 129 MRI results showed alveolar capillary diffusion limitation in all nine patients after COVID-19 pneumonia, despite normal or nearly normal results at CT. © RSNA, 2021 See also the editorial by Dietrich in this issue.

Patients with Type 2 Diabetes (T2D) are at a significantly increased risk of heart failure (HF) with the development of HF driven by energetic, metabolic, structural, and functional cardiac changes. In this study we have used a multi-nuclear MRI/MRS approach to demonstrate that the novel metabolic modulator, ninerafaxstat, can significantly improve myocardial energetics, cardiac steatosis and diastolic function in patients with T2D and obesity. In addition, using cardiac hyperpolarized [1-13C]pyruvate MRS, we have identified a potential signal for increased pyruvate dehydrogenase flux upon treatment with ninerafaxstat.