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Abstract Background We recently reported a strong association between CT markers of pulmonary artery (PA) dilation and mean PA pressure (mPAP) in subjects with World Symposium on Pulmonary Hypertension (WSPH) group 1 and 2 pulmonary hypertension (PH). The relationship between PA size and mPAP in subjects with WSPH group 3 PH, in which parenchymal changes may influence PA dilation, remains uncertain. We sought to investigate this relationship in subjects with and without PH who have significant parenchymal pulmonary disease or hypoxia. Methods We measured PA diameter and PA:aorta (PA:A) ratio on CT for all subjects with WSPH group 3 PH, matched disease comparators, and healthy controls in the Pulmonary Vascular Disease Phenomics (PVDOMICS) cohort. PH and comparator subjects were categorized by group 3 etiology into obstructive (including chronic obstructive pulmonary disease [COPD] and cystic fibrosis), interstitial (including idiopathic pulmonary fibrosis, unspecified interstitial lung disease, combined pulmonary fibrosis and emphysema, and chronic hypersensitivity pneumonitis), and non-parenchymal (including obesity hypoventilation syndrome, obstructive sleep apnea, and extrinsic restrictive disease) subgroups. Primary outcome was mPAP on right heart catheterization (RHC). Association with mPAP was evaluated using multivariable linear regression adjusted for age, sex, and BMI. Results 339 subjects met inclusion criteria (101 WSPH group 3 PH, 153 disease comparators, 85 healthy controls). 83 subjects had obstructive disease, 125 had interstitial disease, and 46 had non-parenchymal disease. PA diameter and PA:A were associated with mPAP in all subjects and in each subgroup (p < 0.001; see figure 1). The association was notably stronger in the non-parenchymal group (ρ = 0.707 for diameter, 0.750 for PA:A) compared to obstructive (ρ = 0.566 for diameter, 0.529 for PA:A) and interstitial (ρ = 0.432 for diameter, 0.373 for PA:A) groups. Change in PA size between 25th and 75th percentile mPAP was lower in the interstitial group (3.88 mm, ratio 0.12) than in the obstructive (4.88 mm, ratio 0.17) and non-parenchymal (4.80 mm, ratio 0.19) groups (see figure 1). Conclusions PA size on CT is associated with mPAP in subjects with chronic lung disease with and without PH. This association is strongest in subjects without parenchymal lung disease but with features of hypercarbia or hypoxia alone. These data suggest that features of parenchymal lung disease in certain patients may limit expected PA dilation in response to elevated PA pressures. Further study is needed regarding the implications of these findings for early identification of PH in patients with chronic lung disease. This abstract is funded by: The NHLBI and Pulmonary Hypertension Association

Abstract Rationale Pulmonary hypertension (PH) is a heterogeneous condition classified into 5 WSPH groups but lacking detailed molecular distinction. The PVDOMICS cohort includes all PH groups alongside healthy and disease comparators, is deeply clinically phenotyped and has RNA sequencing data. Pseudogenes are conserved genome elements that due to sequence-defects cannot be translated into functional proteins. Some pseudogenes never-the-less produce RNA-transcripts which can regulate the expression of other, protein coding genes. Therefore, our study was focused on identifying differentially expressed pseudogene-transcripts within the dataset from the PVDOMICS study and gaining insights into their potential function. Methods Peripheral venous whole blood was collected from PVDOMICS participants [n = 525 PH patients; n = 312 controls without PH who were comparators (n = 256) or healthy (n = 56)]. RNA was isolated, RNA sequencing was performed. After quality control, differential transcript expression between PH and control groups was analyzed using the limma-voom pipeline, rSEA with adjustment for age, sex, race, smoking, WSPH group, latent factors and false discovery rate. We focused on a) transcripts expressed at increased levels (n = 218): the first 200 DEG (differentially-expressed-genes)-transcripts based on log2 difference plus increased DEG within the first 200 most significant p-values; and b) transcripts expressed at decreased levels (n = 292): last 200 DEG based on log2 difference plus decreased DEG within the first 200 most significant p-values. Results Six pseudogene transcripts were among the increased and 35 pseudogene transcripts were among the decreased DEG in the PH group compared to controls. Some of the differentially expressed pseudogenes (DEP) belonged to gene families, like the ribosomal protein family (7 DEP), mitochondria expressed transcripts (3 DEP), zinc finger proteins (2 DEP). Associations of pseudogenes with biological function or disease were extracted via GeneCards(R) and information from GWAS analysis. The DUSP8P5 pseudogene was among the DEP and is known for its association with left heart disease and hypertension; 2 additional DEP have known association with hypertension. Further known associations were with inhibitory or inflammatory immune processes (8 DEP), bone density (6 DEP), metabolism and diabetes (6 DEP), respiratory function or disease (4 DEP), erythrocyte biology (3 DEP), cancer (5 DEP), kidney disease (1 DEP), and demographic parameters like eye or hair color (2 DEP). Ten DEP had no known association with function or disease. Conclusions We identified pseudogene RNA-transcripts associated with PH across WSPH groups. The local vs. systemic effects of these pseudogene transcripts on PH remain to be determined and regulators of pseudogene-transcript expression (e.g. environmental exposures) identified. This abstract is funded by: 1 X01 HL148611 (TopMed), PVDOMICS NHLBI, PVDOMICS Pulmonary Hypertension Association, HT9425-25-1-0533 (GG), 1R21OH012955-01 (GG)

Abstract Rationale Postoperative pulmonary complications (PPCs) importantly contribute to postoperative morbidity and mortality, particularly for American Society of Anesthesiologists (ASA) physical status III patients. It remains unclear whether risk factors for PPCs depend on sex. We hypothesised that sex modifies the relationship between perioperative risk factors and PPCs in ASA III patients undergoing noncardiothoracic surgery with general anesthesia. Methods We performed a secondary analysis of prospective data from 1,202 ASA III patients undergoing non-cardiothoracic surgery. Data consisted of preoperative demographics, comorbidities, intraoperative physiology, medications, and procedure information. The primary outcome was a composite of PPCs by postoperative day 7. Mixed-effects linear models incorporated sex as main effect and interaction with covariates. Results Age, chronic obstructive pulmonary disease, upper abdominal surgery, surgical duration, and emergency surgery significantly increased the odds of ≥ 1 PPC by postoperative day 7. Male patients presented a higher rate of ≥ 3 PPCs, and mechanical ventilation was less protective in female patients. Yet, sex did not significantly modify the relationship between perioperative factors and the primary outcome (no p<0.05 for the interaction effect with sex). In the secondary analysis, gastroesophageal reflux disease affected atelectasis more strongly in male than female patients (relative odds-ratios for female versus male =0.27; 95% CI 0.13 to 0.57). Conclusions In ASA III patients undergoing non-cardiothoracic surgery with general anesthesia, perioperative factors are predominantly not significantly modified by sex in their relationship to PPCs. GERD’s association with atelectasis in male patients could be explored in future prospective studies as a target for reducing pulmonary complications. This abstract is funded by: NHLBI - UH3 HL140177

Abstract Rationale Lymphangioleiomyomatosis (LAM) is a rare, progressive, cystic lung disease affecting women. Sirolimus has been shown to stabilize lung function in women with LAM, but real-world data on long-term safety and efficacy are limited. Methods The NIH Multicenter Safety and Durability of Sirolimus for LAM (MIDAS, NCT02432560) observational registry was launched in 2015. All adult (≥18 years) women with LAM (treated or untreated) were eligible to enroll at any of the 20 U.S. sites and followed longitudinally with serial assessments of lung function, health-related quality of life, and treatment related adverse event (TRAEs). Baseline cohort characteristics and TRAEs are summarized using descriptive analyses. Marginal structural models (MSMs) with inverse probability of treatment weighting estimated the causal effect of sirolimus on annualized forced expiratory volume in one-second (FEV1) decline, adjusting for age at LAM diagnosis, prior treatment with sirolimus, menopausal status, race, presence of angiomyolipomas, supplemental oxygen use; time-varying covariates included diffusing capacity for carbon monoxide (DLCO) and serum vascular endothelial growth factor-D (VEGF-D) levels. Results Longitudinal data was available in 350 LAM patients, most of whom (246, 70.3%) had sporadic LAM. The median age at the baseline pulmonary function test (PFT) measurement was 46 years (range: 19 - 74) and the median (IQR) number of serial PFTs obtained per patient was 3 (1 - 5). The average follow-up duration per patient was 2.8 years. Over half of the patients (196, 56%) were treated with sirolimus during the MIDAS observation period for a median (IQR) treatment duration of 4.9 (2.4 - 7.5) years. MSM analysis demonstrated that sirolimus treatment was durably effective and reduced FEV₁ decline by 74.36 mL/year (95% CI: 15.87 - 132.85) compared with no treatment (-85.31 mL/year for the untreated group vs. -10.95 mL/year for the treated group, p = 0.01). Sirolimus was generally well tolerated; treatment interruption ≥3 months was observed in 38 (19.4%) of the 196 sirolimus treated patients. Logistic regression analysis showed that higher levels of FEV1 (odds ratio: OR = 3.12 [1.45 - 7.11], p = 0.005), VEGF-D (OR = 1.0007 [1.0004 - 1.001], p < 0.001), and DLCO (OR = 1.023 [1.0053 - 1.0413, p = 0.01]), were associated with treatment interruption. Conclusions In the MIDAS cohort, sirolimus treatment resulted in durable stabilization of lung function with a favorable safety profile over a 5-year period. These real-world data support sirolimus as a chronic suppressive therapy for LAM, demonstrating durable efficacy in slowing lung disease progression and tolerability with long-term use. This abstract is funded by: National Institutes of Health

Abstract Rationale Interstitial lung abnormalities (ILA) are abnormal findings on chest CT scans that may represent early-stages of interstitial lung disease. The presence of fibrosis (traction bronchiectasis and/or honeycombing) identifies those with ILA at an increased risk for mortality, however, determining who will progress remains a challenge, and the role of blood-based biomarkers in ILA risk-stratification is unknown. Methods Data from four prospective cohort studies were used to identify associations between plasma proteins measured with DNA aptamers (SomaScan) and ILA, fibrosis, and mortality. The Genetic Epidemiology of COPD Study (COPDGene) was used to identify protein associations, and findings were replicated by meta-analysis of the Age, Gene/Environment Susceptibility-Reykjavik study (AGES-Reykjavik), SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS), and Framingham Heart Study (FHS). Protein associations with ILA and with fibrotic ILA compared to non-fibrotic ILA were performed using multivariable logistic regression; among those with ILA, Cox proportional hazards models were used to identify protein associations with mortality. Models were adjusted for age, gender, race, BMI, smoking status, pack-year smoking history, and for mortality, COPD. Benjamini-Hochberg false discovery rate p-values <0.05 were considered significant. Results 524 (10.7%) of 4,899 COPDGene participants had ILA, of whom 57 (10.9%) had fibrosis; of 8,146 AGES-Reykjavik, SPIROMICS and FHS participants included in the meta-analysis, 666 (8.2%) had ILA, of whom 198 (29.7%) had fibrosis. In COPDGene, 230 proteins were associated with ILA; the most significant of which were SFTPD (adjusted odds ratio per standard deviation [SD] of protein [OR]=2.21, p = 3.7E-41) and SFTPB (OR = 1.82, p = 7.9E-37). In the meta-analysis, 159 of the ILA-associated proteins were replicated. Of the 230 ILA-associated proteins in COPDGene, 9 were associated with fibrosis, and 5 of these 9 proteins were associated with mortality among those with ILA. The 5 proteins associated with all three outcomes were WFDC2 (ORILA=1.90, p = 2.6E-34; ORFibrosis=2.00, p = 0.0001; adjusted hazards of mortality per SD of protein [HR]=1.59, p = 3.4E-05), GDF15 (ORILA=1.67, p = 3.6E-23; ORFibrosis=1.78, p = 0.0006; HR = 1.63, p = 1.4E-06), SCGB3A1 (ORILA=1.52, p = 4.5e-14; ORFibrosis=1.80, p = 0.0002; HR = 1.25, p = 0.02), TREM1 (ORILA=1.44, p = 1.4e-14; ORFibrosis=1.62, p = 0.001; HR = 1.25, p = 0.02) ICAM5 (ORILA=1.42, p = 1.2e-11; ORFibrosis=1.79, p = 0.0001; HR = 1.31, p = 0.002). In the meta-analysis, 6 of the 9 fibrosis-associated proteins and all 5 ILA mortality-associated proteins replicated. Conclusion This represents the first plasma proteomic screen demonstrating reproducible biomarker associations not only with ILA presence, but also with measures of severity and adverse outcomes. These results provide compelling targets for further study, including their prospective evaluation as clinical biomarkers for early disease identification and prognostication. This abstract is funded by: Multiple Sources

Abstract Rationale Deficiency of alpha-1 antitrypsin (AAT), the protein encoded by SERPINA1, remains the strongest genetic risk factor for COPD. Individuals heterozygote for the type Z variant, termed the PI*MZ genotype (estimated global prevalence n = 35,000,000), experience varying respiratory morbidity beyond expected from tobacco smoking alone. AAT is a pleiotropic protein which inhibits not only neutrophil elastase but also neutrophil chemotaxis mediated by leukotriene B4 (LTB4) [by antagonizing the LTB4 receptor (LTB4R)] and interleukin-8 (IL-8). Although LTB-4 and IL-8 gene variants and protein levels have independently been implicated in COPD, their potential role in PI*MZ is unknown. Methods COPDGene and SPIROMICS are observational tobacco-smoke and COPD-enriched cohort studies. Participants were phenotyped by spirometry and CT imaging, with whole genome sequencing data available via TOPMed. We analyzed participants with PI*MM (COPDGene n = 9,732; SPIROMICS n = 2,105) and PI*MZ (COPDGene n = 300; SPIROMICS n = 83). LTB-4 (ALOX5AP, LTA4H, LTB4R) and IL-8 (CXCL8, CXCR1, CXCR2) associated gene variants (exonic and intronic) with a minor allele frequency of ≥ 0.05 were extracted. We assessed statistical interactions between MZ status and chest CT outcomes or FEV1% predicted using the SPAGxECCT package with adjustment for relatedness (genetic related matrix) and ancestry (top ten PCs). Baseline protein LTB4R (SPIROMICS only) and IL-8 (both cohorts) protein levels were measured via SomaScan, and statistical interactions between MZ status and AAT concentration were explored. Models were adjusted for age, sex, BMI, smoking status, and pack-years. Given the candidate gene discovery approach, significance was defined as nominal p-value<0.05 Results We identified the following number of variants in genes of the LTB-4 or IL-8 pathways: 87 shared between cohorts; 133 unique to COPDGene; 1 unique to SPIROMICS. LTB-4-related polymorphisms were associated (p < 0.05) with any radiographic outcomes in 22 variants (COPDGene) vs. 23 variants (SPIROMICS), with a single overlap (rs17074984 in ALOX5AP). Two LTB-4-pathway variants were associated with FEV1% predicted in SPIROMICS (both in ALOX5AP), but none in COPDGene. AAT plasma concentrations displayed a statistically significant interaction with FEV1% predicted (p = 0.046) and PRMemphysema (p = 0.013) for LTBR4, but not for IL-8. There was not an interaction by MM/MZ status and protein levels. Conclusions Predominantly LTB-4, and not IL-8, pathway-related genetic variants and protein levels may contribute to disease heterogeneity among PI*MZ individuals. The association of circulating LTB4R protein with reduced lung function, particularly among those with low AAT levels, further suggest interactions between AAT and the leukotriene pathway in PI*MZ individuals. Thus, PI*MZ individuals may uniquely derive benefit from leukotriene-targeting pharmacotherapy. This abstract is funded by: NIH NHLBI K23HL173570

Abstract Rationale To construct multi-trait polygenic scores (PRS) predicting chronic obstructive pulmonary disease (COPD) and exacerbations, validate their performance in diverse cohorts, and identify PRS-related proteins for potential therapeutic targeting. Methods PRSmix+, a multi-trait PRS framework, is used to train a composite PRS (PRSmulti) in COPDGene non-Hispanic white participants (n = 6,647). Associations of PRSmulti with COPD status (GOLD 2-4 vs. GOLD 0 or ICD) and exacerbation frequency were tested in COPDGene African American (n = 2,466), ECLIPSE (n = 1,858), MassGeneral Brigham Biobank (n = 15,152), and All of Us (n = 118,566). Protein prediction models were applied to GWAS summary statistics from traits contributing to PRSmulti and were validated with proteomic data in COPDGene (n = 5,173) and UK Biobank (n = 5,012). Results PRSmix+ selected 7 traits for PRSmulti. In multivariable models, PRSmulti was associated with COPD status (meta-analysis random effects (RE) OR 1.58 [95% CI: 1.28-1.94]) and exacerbation frequency (meta-analysis RE beta 0.21 [95% CI: 0.11-0.31]), with higher effect sizes observed in smoking-enriched cohorts. PRSmulti outperformed traditional single-trait PRS in all tested cohorts. Using protein prediction models, we identified 73 proteins associated with the PRS that were also validated with measured protein levels in COPDGene and UK biobank. Of these proteins, 25 were linked to approved or investigational drugs. Notable targets include AGER (RAGE), IL1RL1, and SCARF2, all implicated in COPD pathogenesis and exacerbations. Conclusions Multi-trait PRS improves prediction of COPD and exacerbation risk. Integration with proteomic data identifies druggable protein targets, offering a promising avenue for precision medicine in COPD management. Trial registration. COPDGene: NCT00608764; ECLIPSE: NCT00292552. This abstract is funded by: NIH and the COPD Foundation

Abstract Rationale Alpha-1 antitrypsin deficiency (AATD) continues to be underdiagnosed. The estimated prevalence of the most common severe deficient genotype, PI*ZZ, is ∼1:3500 or 100,000 Americans but only ∼10,000 such individuals have been recognized. Diagnostic delays persist and these delays are associated with worse disease. High-resolution CT (HRCT) imaging may contain latent phenotypic AATD signatures that are not visibly apparent to clinicians. We hypothesized a deep learning model could identify imaging patterns predictive of AATD from inspiratory HRCT scans. Methods Confirmed genotypes and HRCT scans were pooled from COPDGene, SPIROMICS, and GRADS, yielding 350 MM, 102 MZ, and 69 ZZ participants. Only scans reconstructed with smooth kernels (GE STANDARD, Philips B, Siemens B31f/B35f) and slice thickness < =1.25mm were used. The cohort was selected to have similar distributions of quantitative emphysema, sex, and age by matching five MZ and two MM subjects to each ZZ subject (<10-year age difference, same sex, and <3% difference in %LAA). Tobacco smoke-exposure was more prevalent among the MM/MZ groups given these were predominantly from the tobacco smoke-enriched COPDGene and SPIROMICS cohorts. A DenseNet121 convolutional neural network (CNN) was trained using the MONAI platform to predict genotype by outputting probabilities for MM, MZ, and ZZ. Input to the CNN was a three-channel LAA-910, LAA-950, and LAA-970 map downsampled to 2.0mm3 resolution to remove bias due to differences in scanner and image reconstruction parameters. Five-fold cross-validation was performed. Area under the curve (AUC) was calculated for classification of ZZ vs other genotypes (MM/MZ) and MZ vs MM, with statistical significance assessed at p < 0.05. Results The three groups were similar across age (mean±SD years: MM 57.9±8.8, MZ: 57.5±8.9, ZZ: 55.0±10.7), sex (% female: MM: 48.2%, MZ: 46.7%, ZZ: 47.6), and emphysema (LAA-950%: MM: 13.0±12.2, MZ: 12.4±11.8, ZZ: 13.1±11.9). There was a higher prevalence of ever smokers among MM (100%) and MZ (91.7%), compared to ZZ (47.6%). The model achieved an AUC of 0.806 (p < 0.001) for classification of ZZ vs other genotypes, demonstrating robust discriminatory ability for homozygous AATD. Classification of MZ vs other genotypes did not achieve an AUC significantly greater than 0.5. Conclusions This proof-of-concept study demonstrates that deep learning applied to routine inspiratory HRCT can accurately identify homozygous AATD. These findings support the potential role of imaging-based machine learning as a non-invasive screening tool for undiagnosed ZZ individuals. Future work will focus on cohort enrichment, integration with clinical parameters, and explainability of model-derived imaging features. This abstract is funded by: NIH NHLBI K23HL173570

Abstract Rationale Alpha-1 antitrypsin (AAT) deficiency, primarily caused by homozygous SERPINA1 Z mutation, increases the risk of COPD. Individuals carrying one Z and one normal M allele (MZ) have higher COPD risk than MM individuals, although many never develop disease. COPD is a polygenic condition influenced by numerous genetic factors across the genome and by environmental exposures such as smoking. We aimed to examine how polygenic factors and smoking modify risk of airflow obstruction in MZ compared with MM. Methods We included participants with the MZ and MM genotypes from the Framingham Heart Study. We first tested the association between AAT genotype (MZ coded as 1 and MM as 0) and FEV1/FVC, stratified by ever-smoking status, and further evaluated interactions between AAT genotype and smoking pack-years. Next, for each participant we calculated a polygenic risk score (PRS) for FEV1/FVC, which was derived from external genome-wide association studies in the UK Biobank and SpiroMeta Consortium. To reflect risk for airflow limitation, higher PRSs correspond to lower FEV1/FVC. We then tested the interaction between the PRS and AAT genotype, stratified by ever-smoking. Models were adjusted for age, sex, height, current smoking, pack-years (among ever-smokers), familial relatedness, and in PRS models, principal components of genetic ancestry. Results Among 4,220 participants (mean age 53.7 years, 54.2% female, 50.2% ever-smokers, mean FEV1/FVC 74.6%), 133 (3.2%) had MZ genotype. In never-smokers, MZ individuals had 1.72% higher FEV1/FVC compared with MM (P = 0.032), whereas no difference was observed among ever-smokers (β= -0.39%; P = 0.65). Cumulative smoking modified the effect of MZ genotype on FEV1/FVC (interaction β= -0.13% per pack-year; P = 0.003); this interaction persisted among ever-smokers (β= -0.11% per pack-year; P = 0.044). A one-standard-deviation increase in the FEV1/FVC PRS was associated with lower FEV1/FVC in both never- (β= -2.37%; P < 0.0001) and ever-smokers (β= -2.46%; P < 0.0001). A higher PRS was disproportionately associated with reduced FEV1/FVC in MZ compared to MM (interaction β= -1.87% per standard-deviation PRS increase, P = 0.027) among ever-smokers, but not in never-smokers (P = 0.15). Conclusions In this community-based cohort, the AAT MZ genotype was associated with higher FEV1/FVC among non-smokers compared to MM. The interaction between MZ genotype and pack-years suggested a dose-dependent modifying effect of smoking on the MZ-related COPD risk. Among ever-smokers, higher polygenic risk further amplified susceptibility to airflow obstruction in MZ compared with MM. These findings highlight the roles of both polygenic and environmental risk factors in COPD susceptibility in MZ. Replication of the results is needed. This abstract is funded by: This work is supported by an Alpha-1 Foundation Grant and a Boston University Department of Medicine Career Investment Award

Abstract Background Muscle loss in COPD results from both disuse atrophy and systemic inflammation. We sought to identify inflammatory biomarkers associated with loss of pectoralis muscle area in COPD using serial CT scans and peripheral blood proteomics. Design We analyzed five-year longitudinal data from COPDGene, an ongoing observational cohort of current and former tobacco smokers with or without airflow obstruction. We quantified pectoralis major muscle (PMM) area on chest CT scans using a 3D convolutional neural network (CNN) trained on CT volumes and annotations provided by the TotalSegmentator project. We compared participants with CT PMM data and plasma proteins by SOMAScan (1K platform) from Phase 2 and 3 (paired n = 1,191). The correlation coefficient (r) between longitudinal changes in protein and in PMM area was plotted against the false discovery rate (FDR)-adjusted p-values. Proteins significantly associated with muscle loss (blue) or gain (red) were visualized using volcano plots. We then analyzed a subset (paired n = 500) of individuals with BMI>25 in Phase 2 whose BMI declined in Phase 3. Proteomic models were adjusted for age and clinical center. Pathway analysis utilized G:Profiler. Results Of the participants with paired proteomic and PMM data, mean PMM area was 21.7 ± 17.3 cm² at Phase 2 and 21.3 ± 17.9 cm² at Phase 3, with an annual change in PMM area of -0.31 + 0.99 cm². Multiple proteins were associated with muscle loss from Phase 2 to 3 (including leptin, FABP, and growth hormone receptor) and muscle gain (including F172A, GMEB2, and RNF41) (Fig 1a). Significant pathways were related to cancer, growth factor receptor dysregulation, and PI3K/AKT signaling. When restricting to those with BMI>25 who experienced BMI decline at Phase 3, muscle loss was associated with increased leptin and PACAP, versus association of gain with increased GDF118, EF1β, and FJF6 (Fig 1b). In the entire group, leptin declined between Phase 2 to Phase 3 in n = 571 participants and increased or was unchanged in n = 620. Compared with leptin decline, unchanged or increased leptin was associated with significantly greater interval PMM loss (−2.25 ± 9.75 cm² vs + 0.98 ± 9.43 cm²; p < 0.001) (Fig 1c). Conclusion Loss of PMM over five years was associated with several plasma proteins, including FABP and growth hormone receptor. The top biomarker, leptin, is a pleiotropic adipokine that regulates energy balance and inflammation. Integrating imaging and proteomics may identify future therapeutic targets to mitigate skeletal muscle loss in COPD. This abstract is funded by: This work was supported by NHLBI grants U01 HL089897 and U01 HL089856 and by NIH contract 75N92023D00011