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Metabolomic differences in connective tissue disease-associated versus idiopathic pulmonary arterial hypertension in the PVDOMICS cohort

Simpson, Catherine E; Hemnes, Anna R; Griffiths, Megan; Grunig, Gabriele; Tang, W H Wilson; Garcia, Joe G N; Barnard, John; Comhair, Suzy A; Damico, Rachel L; Mathai, Stephen C; Hassoun, Paul M
OBJECTIVE:Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) experience worse survival and derive less benefit from pulmonary vasodilator therapies than patients with idiopathic PAH (IPAH). We sought to identify differential metabolism in CTD-PAH versus IPAH patients that might underlie these observed clinical differences. METHODS:Adult subjects with CTD-PAH (n=141) and IPAH (n=165) from the PVDOMICS (Pulmonary Vascular Disease Phenomics) Study were included. Detailed clinical phenotyping was performed at cohort enrollment, including broad-based global metabolomic profiling of plasma samples. Subjects were followed prospectively for ascertainment of outcomes. Supervised and unsupervised machine learning algorithms and regression models were used to compare CTD-PAH versus IPAH metabolomic profiles and to measure metabolite-phenotype associations and interactions. Gradients across the pulmonary circulation were assessed using paired mixed venous and wedged samples in a subset of 115 subjects. RESULTS:Metabolomic profiles distinguished CTD-PAH from IPAH, with CTD-PAH patients demonstrating aberrant lipid metabolism, with lower circulating levels of sex steroid hormones and higher free fatty acids (FA) and FA intermediates in CTD-PAH. Acylcholines were taken up by the right ventricular-pulmonary vascular circulation, particularly in CTD-PAH, while free FAs and acylcarnitines were released. In both PAH subtypes, dysregulated lipid metabolites, among others, were associated with hemodynamic and right ventricular measurements and with transplant-free survival. CONCLUSIONS:CTD-PAH is characterized by aberrant lipid metabolism that may signal shifted metabolic substrate utilization. Abnormalities in RV-pulmonary vascular FA metabolism may imply reduced capacity for mitochondrial beta oxidation within the diseased pulmonary circulation.
PMID: 37335853
ISSN: 2326-5205
CID: 5542552

SEVERITY OF COVID IS ASSOCIATED WITH AIR POLLUTION: A SINGLE-CENTER ASSESSMENT OF RISK

Kwon, Sophia; Crowley, George; Javed, Urooj; Podury, Sanjiti; Grunig, Gabriele; Nolan, Anna
ORIGINAL:0017074
ISSN: 0012-3692
CID: 5573422

DIET AND THE MICROBIOME IN WTC PARTICULATE MATTER-EXPOSED FIREFIGHTERS WITH LUNG DISEASE: THE FIREHOUSE RANDOMIZED CLINICAL TRIAL

Lam, Rachel; Kim, James; Ramprasad, Mihika; Javed, Urooj; Podury, Sanjiti; Kwon, Sophia; Crowley, George; Schwartz, Theresa; Zeig-Owens, Rachel; J.Prezant, David; Grunig, Gabriele; Nolan, Anna
ORIGINAL:0017077
ISSN: 0012-3692
CID: 5573452

Kynurenine pathway metabolism evolves with development of preclinical and scleroderma-associated pulmonary arterial hypertension

Simpson, Catherine E; Ambade, Anjira S; Harlan, Robert; Roux, Aurelie; Aja, Susan; Graham, David; Shah, Ami A; Hummers, Laura K; Hemnes, Anna R; Leopold, Jane A; Horn, Evelyn M; Berman-Rosenzweig, Erika S; Grunig, Gabriele; Aldred, Micheala A; Barnard, John; Comhair, Suzy A A; Tang, W H Wilson; Griffiths, Megan; Rischard, Franz; Frantz, Robert P; Erzurum, Serpil C; Beck, Gerald J; Hill, Nicholas S; Mathai, Stephen C; Hassoun, Paul M; Damico, Rachel L; ,
Understanding metabolic evolution underlying pulmonary arterial hypertension (PAH) development may clarify pathobiology and reveal disease-specific biomarkers. Patients with systemic sclerosis (SSc) are regularly surveilled for PAH, presenting an opportunity to examine metabolic change as disease develops in an at-risk cohort. We performed mass spectrometry-based metabolomics on longitudinal serum samples collected before and near SSc-PAH diagnosis, compared with time-matched SSc subjects without PAH, in a SSc surveillance cohort. We validated metabolic differences in a second cohort and determined metabolite-phenotype relationships. In parallel, we performed serial metabolomic and hemodynamic assessments as the disease developed in a preclinical model. For differentially expressed metabolites, we investigated corresponding gene expression in human and rodent PAH lungs. Kynurenine and its ratio to tryptophan (kyn/trp) increased over the surveillance period in patients with SSc who developed PAH. Higher kyn/trp measured two years before diagnostic right heart catheterization increased the odds of SSc-PAH diagnosis (OR 1.57, 95% CI 1.05-2.36, P = 0.028). The slope of kyn/trp rise during SSc surveillance predicted PAH development and mortality. In both clinical and experimental PAH, higher kynurenine pathway metabolites correlated with adverse pulmonary vascular and RV measurements. In human and rodent PAH lungs, expression of TDO2, which encodes tryptophan 2,3 dioxygenase (TDO), a protein that catalyzes tryptophan conversion to kynurenine, was significantly upregulated and tightly correlated with pulmonary hypertensive features. Upregulated kynurenine pathway metabolism occurs early in PAH, localizes to the lung, and may be modulated by TDO2. Kynurenine pathway metabolites may be candidate PAH biomarkers and TDO warrants exploration as a potential novel therapeutic target.NEW & NOTEWORTHY Our study shows an early increase in kynurenine pathway metabolism in at-risk subjects with systemic sclerosis who develop pulmonary arterial hypertension (PAH). We show that kynurenine pathway upregulation precedes clinical diagnosis and that this metabolic shift is associated with increased disease severity and shorter survival times. We also show that gene expression of TDO2, an enzyme that generates kynurenine from tryptophan, rises with PAH development.
PMID: 37786941
ISSN: 1522-1504
CID: 5610352

Resistin-like Molecule α and Pulmonary Vascular Remodeling: A Multi-Strain Murine Model of Antigen and Urban Ambient Particulate Matter Co-Exposure

Durmus, Nedim; Chen, Wen-Chi; Park, Sung-Hyun; Marsh, Leigh M; Kwon, Sophia; Nolan, Anna; Grunig, Gabriele
Pulmonary hypertension (PH) has a high mortality and few treatment options. Adaptive immune mediators of PH in mice challenged with antigen/particulate matter (antigen/PM) has been the focus of our prior work. We identified key roles of type-2- and type-17 responses in C57BL/6 mice. Here, we focused on type-2-response-related cytokines, specifically resistin-like molecule (RELM)α, a critical mediator of hypoxia-induced PH. Because of strain differences in the immune responses to type 2 stimuli, we compared C57BL/6J and BALB/c mice. A model of intraperitoneal antigen sensitization with subsequent, intranasal challenges with antigen/PM (ovalbumin and urban ambient PM2.5) or saline was used in C57BL/6 and BALB/c wild-type or RELMα-/- mice. Vascular remodeling was assessed with histology; right ventricular (RV) pressure, RV weights and cytokines were quantified. Upon challenge with antigen/PM, both C57BL/6 and BALB/c mice developed pulmonary vascular remodeling; these changes were much more prominent in the C57BL/6 strain. Compared to wild-type mice, RELMα-/- had significantly reduced pulmonary vascular remodeling in BALB/c, but not in C57BL/6 mice. RV weights, RV IL-33 and RV IL-33-receptor were significantly increased in BALB/c wild-type mice, but not in BALB/c-RELMα-/- or in C57BL/6-wild-type or C57BL/6-RELMα-/- mice in response to antigen/PM2.5. RV systolic pressures (RVSP) were higher in BALB/c compared to C57BL/6J mice, and RELMα-/- mice were not different from their respective wild-type controls. The RELMα-/- animals demonstrated significantly decreased expression of RELMβ and RELMγ, which makes these mice comparable to a situation where human RELMβ levels would be significantly modified, as only humans have this single RELM molecule. In BALB/c mice, RELMα was a key contributor to pulmonary vascular remodeling, increase in RV weight and RV cytokine responses induced by exposure to antigen/PM2.5, highlighting the significance of the genetic background for the biological role of RELMα.
PMCID:10418630
PMID: 37569308
ISSN: 1422-0067
CID: 5595412

Iron deficiency in pulmonary vascular disease: pathophysiological and clinical implications

Martens, Pieter; Yu, Shilin; Larive, Brett; Borlaug, Barry A; Erzurum, Serpil C; Farha, Samar; Finet, J Emanuel; Grunig, Gabriele; Hemnes, Anna R; Hill, Nicholas S; Horn, Evelyn M; Jacob, Miriam; Kwon, Deborah H; Park, Margaret M; Rischard, Franz P; Rosenzweig, Erika B; Wilcox, Jennifer D; Tang, Wai Hong Wilson
AIMS/OBJECTIVE:Iron deficiency is common in pulmonary hypertension, but its clinical significance and optimal definition remain unclear. METHODS AND RESULTS/RESULTS:Phenotypic data for 1028 patients enrolled in the Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics study were analyzed. Iron deficiency was defined using the conventional heart failure definition and also based upon optimal cut-points associated with impaired peak oxygen consumption (peakVO2), 6-min walk test distance, and 36-Item Short Form Survey (SF-36) scores. The relationships between iron deficiency and cardiac and pulmonary vascular function and structure and outcomes were assessed. The heart failure definition of iron deficiency endorsed by pulmonary hypertension guidelines did not identify patients with reduced peakVO2, 6-min walk test, and SF-36 (P > 0.208 for all), but defining iron deficiency as transferrin saturation (TSAT) <21% did. Compared to those with TSAT ≥21%, patients with TSAT <21% demonstrated lower peakVO2 [absolute difference: -1.89 (-2.73 to -1.04) mL/kg/min], 6-min walk test distance [absolute difference: -34 (-51 to -17) m], and SF-36 physical component score [absolute difference: -2.5 (-1.3 to -3.8)] after adjusting for age, sex, and hemoglobin (all P < 0.001). Patients with a TSAT <21% had more right ventricular remodeling on cardiac magnetic resonance but similar pulmonary vascular resistance on catheterization. Transferrin saturation <21% was also associated with increased mortality risk (hazard ratio 1.63, 95% confidence interval 1.13-2.34; P = 0.009) after adjusting for sex, age, hemoglobin, and N-terminal pro-B-type natriuretic peptide. CONCLUSION/CONCLUSIONS:The definition of iron deficiency in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines does not identify patients with lower exercise capacity or functional status, while a definition of TSAT <21% identifies patients with lower exercise capacity, worse functional status, right heart remodeling, and adverse clinical outcomes.
PMID: 36879444
ISSN: 1522-9645
CID: 5541112

RELMalpha and Pulmonary Vascular Remodeling: a Multi-Strain Murine Model of Antigen and Urban Ambient PM Co-Exposure

Durmus, Nedim; Chen, Wen Chi; Park, Sung-Hyun; Marsh, Leigh; Kwon, Sophia; Nolan, Anna; Grunig, Gabriele
ORIGINAL:0016943
ISSN: 2310-287x
CID: 5518862

Severe Acute Respiratory Syndrome and Particulate Matter Exposure: A Systematic Review

Podury, Sanjiti; Kwon, Sophia; Javed, Urooj; Farooqi, Muhammad S; Li, Yiwei; Liu, Mengling; Grunig, Gabriele; Nolan, Anna
BACKGROUND:Particulate matter (PM) exposure is responsible for seven million deaths annually and has been implicated in the pathogenesis of respiratory infections such as severe acute respiratory syndrome (SARS). Understanding modifiable risk factors of high mortality, resource burdensome C19 and exposure risks such as PM is key to mitigating their devastating effects. This systematic review focuses on the literature available, identifying the spatial and temporal variation in the role of quantified PM exposure in SARS disease outcome and planning our future experimental studies. METHODS:The systematic review utilized keywords adhered to the PRISMA guidelines. We included original human research studies in English. RESULTS:and SARS-related outcomes. A geographic and temporal variation in both PM and C19's role was observed. CONCLUSION/CONCLUSIONS:C19 is a high mortality and resource intensive disease which devastated the globe. PM exposure is also a global health crisis. Our systematic review focuses on the intersection of this impactful disease-exposure dyad and understanding the role of PM is important in the development of interventions to prevent future spread of viral infections.
PMCID:9962044
PMID: 36836898
ISSN: 2075-1729
CID: 5422392

LET'S MEET AT DUPONT CIRCLE: NEW MOLECULAR TRAFFIC PATTERNS IN PULMONARY HYPERTENSION [Meeting Abstract]

Kown, Sophia; Durmus, N; Park, SH; Chen W-C; Veerappan, A; Nolan, Anna; Grunig, G
ORIGINAL:0016946
ISSN: 1073-449x
CID: 5519182

Aerodigestive Disease Overlap: Defining the Cohort for an Observational Non-invasive Biomarker Study in World Trade Center Exposed First Responders [Meeting Abstract]

Javed, U; Kwon, Sophia; Podury, S; Li, Y; Grunig, G; Veerappan, A; Liu, M; Schwartz, T; Zeig-Owens, R; Presant, D; Nolan, Anna
ORIGINAL:0016945
ISSN: 1073-449x
CID: 5519172