Faculty Bibliography

RATIONALE AND OBJECTIVES/OBJECTIVE:Pulmonary Hypertension (PH) is associated with significant morbidity and mortality. Ground glass opacities (GGOs) are common in Group 1 PH, but their clinical significance is unclear. We sought to characterise the clinical features and outcomes of Group 1 PH patients with and without GGOs in the PVDOMICS study, a prospective multicentre cohort study aimed at deep phenotyping PH. STUDY DESIGN AND METHODS/METHODS:Incident and prevalent PH patients were enrolled across 7 US centres. We included Group 1 PH patients and excluded those with parenchymal lung disease or without chest imaging, resulting in a cohort of 242 patients. RESULTS:GGOs were common among Group 1 PH patients (43% prevalence), associated with female sex, younger age, prostanoid use, longer disease duration and were more common among patients with familial PAH (FPAH) and pulmonary veno-occlusive disease. GGOs were associated with established markers of disease severity, including echocardiographic (right ventricular systolic pressure and tricuspid annular plane systolic excursion), biomarkers (N-terminal pro B- type natriuretic peptide) and worse hemodynamics (higher mean pulmonary artery pressure, pulmonary vascular resistance, and pulmonary artery wedge pressure). GGOs were associated with worse transplant-free survival [HR 2.49 (95% CI 1.43-4.32, p = 0.001)] and had independent prognostic value for predicting transplant-free survival after adjusting for European Society of Cardiology (ESC)/European Respiratory Society (ERS) risk stratification (HR 2.19, 95% CI 1.20-3.99, p=0.01). CONCLUSIONS:Overall, GGOs were associated with specific clinical characteristics and disease phenotypes as well as worse hemodynamics, longer disease duration, prostanoid use and worse survival. Future studies evaluating the pathophysiology and "omic" correlates of GGOs are warranted. CLINICAL TRIAL REGISTRATION/BACKGROUND:Brief Title: Pulmonary Vascular Disease Phenomics Program (PVDOMICS) Official Title: Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics (PVDOMICS) ID: NCT02980887. https://clinicaltrials.gov/study/NCT02980887?term=NCT02980887&rank=1.

Environmental exposure-associated diseases, particularly in the context of rising air pollution and inhalant use, are an active area of research. Our group is dedicated to the study of exposure-related inflammation and its downstream adverse health effects. While many studies have focused on the impact of environmental exposures on respiratory sequelae, there is growing evidence of the involvement of other systems including gastrointestinal. This systematic review provides updates on the associations between inhalation exposures and the risk of upper gastrointestinal disease. Primary search identified N = 764 PubMed and N = 1,036 Web of Science studies, of which N = 111 met eligibility criteria. Our systematic review and meta-analysis showed significant associations between inhalational exposures (cigarette smoking, waterpipe smoking, and particulate matter) and upper gastrointestinal diseases. The pooled estimate of esophagitis was 1.32 (95% confidence interval [CI], 1.06-1.65; I²:86%), gastroesophageal reflux disease was 1.71 (1.14-2.55; I²:94%), peptic ulcer disease was 1.21 (1.03-1.43; I²:93%), esophageal cancer was 1.83 (1.54-2.18; I²:73%), and gastric cancer was 1.71 (1.39-2.10; I²:73%). However, the pooled estimate for Barrett's esophagus was 0.93 (0.65-1.34; I²:76%), indicating no significant association. Sensitivity analyses confirmed these findings. Risk of bias assessment showed most studies were of good quality. Our findings emphasize the impact of inhalational exposures on gastrointestinal disease risk, highlighting the need for further research to better understand this interaction and targeted public health interventions.

RATIONALE/BACKGROUND:A subset of group 1 pulmonary hypertension(PH) have superimposed left heart abnormalities with unclear metabolic implications Objectives: To compare serum/transpulmonary metabolome between group 1 PH stratified by heart failure with preserved ejection fraction(HFpEF) probability. METHODS:Patients with group 1 PH were stratified into low(<25%) and high(≥75%) HFpEF-ABA probability, with healthy controls and clinical HFpEF for comparison of venous and transpulmonary metabolomics Measurements and Main results: Group 1 PH+high HFpEF probability(n=131) was associated with significant increase in 207 metabolites(false discovery rate(FDR) p<0.05 and Fold change>1)(n=193,T-test) and decrease in 231 metabolites (FDR p<0.05 and Fold change<1)(n=193,T-test) compared to group 1 PH+low HFpEF probability(n=62). Group 1 PH+high HFpEF probability was associated with enhanced tryptophan metabolism with higher downstream kynurenine metabolite levels and lower serotonin levels(FDR p<0.002 for all,n=193,T-test). Linoleate(precursor to arachidonic acid and prostaglandins), arginine and homoarginine(precursors to nitric oxide) were all lower in group 1 PH+high HFpEF probability(FDR p<0.03 for all,n=193,T-test). Metabolome changes in group 1 PH+high HFpEF probability overlapped with clinical HFpEF(n=240), but were abnormal relative to controls(n=85)(p<0.0001 for all,n=456,T-test). There was no evidence of differential transpulmonary uptake/release of most metabolites, suggesting probable non-pulmonary origin(except for serotonin, interaction p=0.04 and kynurenine, interaction p=0.03,n=433,mixed model). CONCLUSIONS:Patients with group 1 PH+high HFpEF probability have a unique metabolome characterized by enhanced tryptophan-kynurenine pathway breakdown, deficiency of amino acids(such as glycine and serine), lower serotonin, and decreased prostaglandin and nitric oxide precursors. Despite fulfilling clinical criteria for group 1 PH, these metabolome changes were comparable to clinical HFpEF, supporting biological overlap between these two forms of pulmonary hypertension.

BACKGROUND:Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood. METHODS:We performed global untargeted metabolomics on plasma from 55 patients who underwent gold-standard RV-PA coupling measurements using multibeat pressure volume loop assessment in a single-center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex-adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares-discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. RESULTS:RV-PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α-ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level. CONCLUSIONS:We identify an association between circulating TCA cycle intermediate levels and RV-PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV-targeted therapies.

BACKGROUND:Particulate matter exposure (PM) is a cause of aerodigestive disease globally. The destruction of the World Trade Center (WTC) exposed first responders and inhabitants of New York City to WTC-PM and caused obstructive airways disease (OAD), gastroesophageal reflux disease (GERD) and Barrett's Esophagus (BE). GERD not only diminishes health-related quality of life but also gives rise to complications that extend beyond the scope of BE. GERD can incite or exacerbate allergies, sinusitis, bronchitis, and asthma. Disease features of the aerodigestive axis can overlap, often necessitating more invasive diagnostic testing and treatment modalities. This presents a need to develop novel non-invasive biomarkers of GERD, BE, airway hyperreactivity (AHR), treatment efficacy, and severity of symptoms. METHODS:Our observational case-cohort study will leverage the longitudinally phenotyped Fire Department of New York (FDNY)-WTC exposed cohort to identify Biomarkers of Airway Disease, Barrett's and Underdiagnosed Reflux Noninvasively (BAD-BURN). Our study population consists of n = 4,192 individuals from which we have randomly selected a sub-cohort control group (n = 837). We will then recruit subgroups of i. AHR only ii. GERD only iii. BE iv. GERD/BE and AHR overlap or v. No GERD or AHR, from the sub-cohort control group. We will then phenotype and examine non-invasive biomarkers of these subgroups to identify under-diagnosis and/or treatment efficacy. The findings may further contribute to the development of future biologically plausible therapies, ultimately enhance patient care and quality of life. DISCUSSION/CONCLUSIONS:Although many studies have suggested interdependence between airway and digestive diseases, the causative factors and specific mechanisms remain unclear. The detection of the disease is further complicated by the invasiveness of conventional GERD diagnosis procedures and the limited availability of disease-specific biomarkers. The management of reflux is important, as it directly increases risk of cancer and negatively impacts quality of life. Therefore, it is vital to develop novel noninvasive disease markers that can effectively phenotype, facilitate early diagnosis of premalignant disease and identify potential therapeutic targets to improve patient care. TRIAL REGISTRATION/BACKGROUND:Name of Primary Registry: "Biomarkers of Airway Disease, Barrett's and Underdiagnosed Reflux Noninvasively (BADBURN)". Trial Identifying Number: NCT05216133 . Date of Registration: January 31, 2022.

Environmental exposure-associated disease is an active area of study, especially in the context of increasing global air pollution and use of inhalants. Our group is dedicated to the study of exposure-related inflammation and downstream health effects. While many studies have focused on the impact of inhalants on respiratory sequelae, there is growing evidence of the involvement of other systems including autoimmune, endocrine, and gastrointestinal. This systematic review aims to provide a recent update that will underscore the associations between inhalation exposures and upper gastrointestinal disease in the contexts of our evolving environmental exposures. Keywords focused on inhalational exposures and gastrointestinal disease. Primary search identified n = 764 studies, of which n = 64 met eligibility criteria. In particular, there was support for existing evidence that PM increases the risk of upper gastrointestinal diseases. Smoking was also confirmed to be major risk factor. Interestingly, studies in this review have also identified waterpipe use as a significant risk factor for gastroesophageal reflux and gastric cancer. Our systematic review identified inhalational exposures as risk factors for aerodigestive disease, further supporting the association between environmental exposure and digestive disease. However, due to limitations on our review’s scope, further studies must be done to better understand this interaction.

BACKGROUND:Particulate matter exposure (PM) is a cause of aerodigestive disease globally. The destruction of the World Trade Center (WTC) exposed first responders and inhabitants of New York City to WTC-PM and caused obstructive airways disease (OAD), gastroesophageal reflux disease (GERD) and Barrett's Esophagus (BE). GERD not only diminishes health-related quality of life but also gives rise to complications that extend beyond the scope of BE. GERD can incite or exacerbate allergies, sinusitis, bronchitis, and asthma. Disease features of the aerodigestive axis can overlap, often necessitating more invasive diagnostic testing and treatment modalities. This presents a need to develop novel non-invasive biomarkers of GERD, BE, airway hyperreactivity (AHR), treatment efficacy, and severity of symptoms. METHODS:No GERD or AHR, from the sub-cohort control group. We will then phenotype and examine non-invasive biomarkers of these subgroups to identify under-diagnosis and/or treatment efficacy. The findings may further contribute to the development of future biologically plausible therapies, ultimately enhance patient care and quality of life. DISCUSSION/CONCLUSIONS:Although many studies have suggested interdependence between airway and digestive diseases, the causative factors and specific mechanisms remain unclear. The detection of the disease is further complicated by the invasiveness of conventional GERD diagnosis procedures and the limited availability of disease-specific biomarkers. The management of reflux is important, as it directly increases risk of cancer and negatively impacts quality of life. Therefore, it is vital to develop novel noninvasive disease markers that can effectively phenotype, facilitate early diagnosis of premalignant disease and identify potential therapeutic targets to improve patient care. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov Identifier: NCT05216133; January 18, 2022.