Publications by authors named "Raed A Dweik"

161 Publications

Disease Specific Platelet Signaling Defects in Idiopathic Pulmonary Arterial Hypertension.

Am J Physiol Lung Cell Mol Physiol 2021 Feb 17. Epub 2021 Feb 17.

Pulmonary, Allergy and Critical Care Medicine, Cleveland Clinic, United States.

Background Idiopathic pulmonary arterial hypertension (IPAH) is a rapidly progressive disease with several treatment options. Long-term mortality remains high with great heterogeneity in treatment response. Even though most of the pathology of IPAH is observed in the lung, there is systemic involvement. Platelets from IPAH patients have characteristic metabolic shifts and defects in activation, therefore we investigated whether they could be used to identify other disease specific abnormalities. Methods We used proteomics to investigate protein expression changes in platelets from IPAH patients compared to healthy controls. Key abnormalities of nitric oxide pathway were tested in platelets from a larger cohort of unique IPAH patients. Results Platelets showed abnormalities in the prostacyclin and nitric oxide pathways, which are dysregulated in IPAH and hence targets of therapy. We detected reduced expression of G-protein as and increased expression of the regulatory subunits of the cAMP-dependent protein kinase (PKA) type II isoforms, supporting an overall decrease in the activation of the prostacyclin pathway. We noted reduced levels of the soluble guanylate cyclase (sGC) subunits and increased expression of the phosphodiesterase type 5A (PDE5A); conditions that affect the response to nitric oxide. Ensuing analysis of 38 unique patients with IPAH demonstrated considerable variation in the levels and specific activity of sGC, a finding with novel implications for personalized therapy. Interpretation Platelets have some of the characteristic vasoactive signal abnormalities seen in IPAH and may provide comprehensive ex-vivo mechanistic information to direct therapeutic decisions.
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http://dx.doi.org/10.1152/ajplung.00500.2020DOI Listing
February 2021

Informing Healthcare Decisions with Observational Research Assessing Causal Effect. An Official American Thoracic Society Research Statement.

Am J Respir Crit Care Med 2021 01;203(1):14-23

Decisions in medicine are made on the basis of knowledge and reasoning, often in shared conversations with patients and families in consideration of clinical practice guideline recommendations, individual preferences, and individual goals. Observational studies can provide valuable knowledge to inform guidelines, decisions, and policy. The American Thoracic Society (ATS) created a multidisciplinary committee to develop a research statement to clarify the role of observational studies-alongside randomized controlled trials (RCTs)-in informing clinical decisions in pulmonary, critical care, and sleep medicine. The committee examined the strengths of observational studies assessing causal effects, how they complement RCTs, factors that impact observational study quality, perceptions of observational research, and, finally, the practicalities of incorporating observational research into ATS clinical practice guidelines. There are strengths and weakness of observational studies as well as RCTs. Observational studies can provide evidence in representative and diverse patient populations. Quality observational studies should be sought in the development of ATS clinical practice guidelines, and medical decision-making in general, when ) no RCTs are identified or RCTs are appraised as being of low- or very low-quality (); ) RCTs are of moderate quality because of indirectness, imprecision, or inconsistency, and observational studies mitigate the reason that RCT evidence was downgraded (); or ) RCTs do not provide evidence for outcomes that a guideline committee considers essential for decision-making (e.g., rare or long-term outcomes; "). Observational studies should be considered in developing clinical practice guidelines and in making clinical decisions.
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http://dx.doi.org/10.1164/rccm.202010-3943STDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781125PMC
January 2021

A special issue: Flow, pressure, volume and time as dependent variables in breath analysis.

J Breath Res 2020 Oct 21;15(1):010201. Epub 2020 Oct 21.

Editor-in-Chief, Journal of Breath Research.

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http://dx.doi.org/10.1088/1752-7163/abbe39DOI Listing
October 2020

Breath research in times of a global pandemic and beyond: the game changer.

J Breath Res 2020 10 6;14(4):040202. Epub 2020 Oct 6.

Editor-in-Chief, Journal of Breath Research.

In contrast to blood and urine samples, breath is invisible and ubiquitous in the environment. Different precautions are now necessary beyond the usual 'Universal Precautions'. In the era of COVID-19, breath (especially the aerosol fraction) can no longer be considered as harmless in the clinic or laboratory. As Journal of Breath Research is a primary resource for breath-related research, we (the editors) are presently developing safety guidance applicable to all breath research , not just for those projects that involve known COVID-19 infected subjects. We are starting this process by implementing requirements on reporting safety precautions in research papers and notes. This editorial announces that authors of all new submissions to JBR henceforth must state clearly the procedures undertaken for assuring laboratory and clinical safety, much like the existing requirements for disclosing Ethics Committee or Institutional Review Board protocols for studies on human subjects. In the following, we additionally make some recommendations based on best practices drawn from our experience and input from the JBR Editorial Board.
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http://dx.doi.org/10.1088/1752-7163/abb99aDOI Listing
October 2020

Volatile organic compounds in bile can distinguish pancreatic cancer from chronic pancreatitis: a prospective observational study.

Endoscopy 2020 Sep 7. Epub 2020 Sep 7.

Pathobiology, Lerners Research Institute, Cleveland Clinic, Cleveland, Ohio, United States.

Background:  Early and accurate diagnosis of pancreatic cancer is important. Our aim was to identify potential volatile organic compounds (VOCs) in the bile that can help distinguish pancreatic cancer from chronic pancreatitis.

Methods:  In this prospective observational study, bile was aspirated from patients undergoing endoscopic retrograde cholangiopancreatography for chronic pancreatitis and pancreatic cancer, and the gaseous headspace was analyzed using mass spectrometry.

Results:  The study included a discovery cohort of 57 patients (46 pancreatic cancer, 11 chronic pancreatitis) and a validation cohort of 31 patients (19 and 12, respectively). Using logistic regression analysis, the model [0.158 × age + 9.747 × log (ammonia) - 3.994 × log (acetonitrile) + 5.044 × log (trimethylamine) - 30.23] successfully identified patients with pancreatic cancer with a sensitivity of 93.5 % and specificity of 100 % (likelihood ratio 40.9, area under the curve 0.98, 95 % confidence interval 0.95 - 1.00). The diagnostic accuracy of this model was confirmed in the second independent validation cohort.

Conclusion:  The measurement of VOCs in bile helped to accurately distinguish pancreatic cancer from chronic pancreatitis.
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http://dx.doi.org/10.1055/a-1255-9169DOI Listing
September 2020

Specific O-GlcNAc modification at Ser-615 modulates eNOS function.

Redox Biol 2020 09 27;36:101625. Epub 2020 Jun 27.

Inflammation and Immunity, Lerner Research Institute. Cleveland Clinic, OH, USA; Department of Pulmonary, Allergy and Critical Care Medicine. Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address:

Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and devastating disease characterized by vascular smooth muscle and endothelial cell proliferation leading to a narrowing of the vessels in the lung. The increased resistance in the lung and the higher pressures generated result in right heart failure. Nitric Oxide (NO) deficiency is considered a hallmark of IPAH and altered function of endothelial nitric oxide synthase (eNOS), decreases NO production. We recently demonstrated that glucose dysregulation results in augmented protein serine/threonine hydroxyl-linked N-Acetyl-glucosamine (O-GlcNAc) modification in IPAH. In diabetes, dysregulated glucose metabolism has been shown to regulate eNOS function through inhibition of Ser-1177 phosphorylation. However, the link between O-GlcNAc and eNOS function remains unknown. Here we show that increased protein O-GlcNAc occurs on eNOS in PAH and Ser-615 appears to be a novel site of O-GlcNAc modification resulting in reduced eNOS dimerization. Functional characterization of Ser-615 demonstrated the importance of this residue on the regulation of eNOS activity through control of Ser-1177 phosphorylation. Here we demonstrate a previously unidentified regulatory mechanism of eNOS whereby the O-GlcNAc modification of Ser-615 results in reduced eNOS activity and endothelial dysfunction under conditions of glucose dysregulation.
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http://dx.doi.org/10.1016/j.redox.2020.101625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334407PMC
September 2020

Chronic Beryllium Disease: Update on a Moving Target.

Chest 2020 Dec 6;158(6):2458-2466. Epub 2020 Aug 6.

Division of Environmental and Occupational Health Sciences, National Jewish Health, Denver, CO.

Beryllium exposure remains an ongoing occupational health concern for workers worldwide. Since the initial Occupational Safety and Health Administration (OSHA) ruling on a permissible exposure limit (PEL) for beryllium in 1971, our understanding of the risks of beryllium sensitization and chronic beryllium disease (CBD) has evolved substantially. A new OSHA ruling released in early 2017 and implemented in late 2018 reduced the PEL for beryllium, increased requirements for medical screening and monitoring, and may ultimately enhance worker protection. This review highlights advances in our understanding of the pathway from beryllium exposure to sensitization and progression to CBD that guided the development of this OSHA ruling. Screening workers exposed to beryllium and management of CBD will also be discussed. Finally, we will discuss the role of beryllium as a cause of morbidity and mortality among exposed workers in this potentially preventable occupational lung disease.
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http://dx.doi.org/10.1016/j.chest.2020.07.074DOI Listing
December 2020

Mixed Venous Oxygen Saturation Is a Better Prognosticator Than Cardiac Index in Pulmonary Arterial Hypertension.

Chest 2020 Dec 3;158(6):2546-2555. Epub 2020 Jul 3.

Department of Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH. Electronic address:

Background: European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines include thermodilution cardiac index (TDCI) and mixed venous oxygen saturation (SvO) as two of the three hemodynamic determinations used in risk assessment of patients with pulmonary arterial hypertension (PAH). SvO may be a better measurement than TDCI to assess prognosis in patients with either idiopathic or heritable PAH.

Research Question: What is the concordance between TDCI and SvO ESC/ERS risk group allocation and their prognostic value in patients with PAH?

Study Design And Methods: In this retrospective study, we assessed the correlation between SvO and TDCI in patients with idiopathic and heritable PAH. We determined concordance in the ESC/ERS risk group allocation and association with survival, both at baseline and follow-up.

Results: A total of 158 patients (mean age, 58 ± 17 years; 72% women) with idiopathic (91%) and heritable (9%) PAH were included. There was moderate association between TDCI and SvO (r = 0.50; 95% CI, 0.37-0.62). Weighted kappa revealed a fair agreement between TDCI and SvO (κ = 0.30; 95% CI, 0.18-0.42), with concordance in risk group allocation in 49% of patients. During a median follow-up of 45 months (interquartile range, 23-105), 62 patients (39%) died. Using Kaplan-Meier analysis, survival was impacted by the SvO (log rank = 0.002) but not by the TDCI risk group allocation (log-rank = 0.51). Using the Cox proportional hazard model, adjusted for age and sex, SvO (but not TDCI) was associated with mortality (hazard ratio per 1% change, 0.94; 95% CI, 0.91-0.97; P < .001).

Interpretation: When using the cutoffs proposed by the ESC/ERS guidelines, we noted poor concordance in risk score allocation between TDCI and SvO. In patients with idiopathic or heritable PAH, SvO measurements are superior to TDCI in predicting long-term mortality.
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http://dx.doi.org/10.1016/j.chest.2020.06.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768941PMC
December 2020

Breath Metabolomics Provides an Accurate and Noninvasive Approach for Screening Cirrhosis, Primary, and Secondary Liver Tumors.

Hepatol Commun 2020 Jul 26;4(7):1041-1055. Epub 2020 Apr 26.

Department of Quantitative Health Sciences Lerner Research Institute Cleveland Clinic Cleveland OH.

Hepatocellular carcinoma (HCC) and secondary liver tumors, such as colorectal cancer liver metastases are significant contributors to the overall burden of cancer-related morality. Current biomarkers, such as alpha-fetoprotein (AFP) for HCC, result in too many false negatives, necessitating noninvasive approaches with improved sensitivity. Volatile organic compounds (VOCs) detected in the breath of patients can provide valuable insight into disease processes and can differentiate patients by disease status. Here, we investigate whether 22 VOCs from the breath of 296 patients can distinguish those with no liver disease (n = 54), cirrhosis (n = 30), HCC (n = 112), pulmonary hypertension (n = 49), or colorectal cancer liver metastases (n = 51). This work extends previous studies by evaluating the ability for VOC signatures to differentiate multiple diseases in a large cohort of patients. Pairwise disease comparisons demonstrated that most of the VOCs tested are present in significantly different relative abundances (false discovery rate  < 0.1), indicating broad impacts on the breath metabolome across diseases. A predictive model developed using random forest machine learning and cross validation classified patients with 85% classification accuracy and 75% balanced accuracy. Importantly, the model detected HCC with 73% sensitivity compared with 53% for AFP in the same cohort. An added value of this approach is that influential VOCs in the predictive model may provide insight into disease etiology. Acetaldehyde and acetone, both of which have roles in tumor promotion, were considered important VOCs for differentiating disease groups in the predictive model and were increased in patients with cirrhosis and HCC compared to patients with no liver disease (false discovery rate  < 0.1). The use of machine learning and breath VOCs shows promise as an approach to develop improved, noninvasive screening tools for chronic liver disease and primary and secondary liver tumors.
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http://dx.doi.org/10.1002/hep4.1499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327218PMC
July 2020

Estrogen Signaling and Portopulmonary Hypertension: The Pulmonary Vascular Complications of Liver Disease Study (PVCLD2).

Hepatology 2021 Feb 29;73(2):726-737. Epub 2020 Sep 29.

Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Background And Aims: Portopulmonary hypertension (POPH) was previously associated with a single-nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH.

Approach And Results: We performed a multicenter case-control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn-sec/cm , and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome-wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.12-4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2-hydroxyestrogen/16-α-hydroxyestrone (OR per 1-ln decrease = 2.04; 95% CI, 1.16-3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone-sulfate (OR per 1-ln decrease = 2.38; 95% CI, 1.56-3.85; P < 0.001), and higher plasma levels of 16-α-hydroxyestradiol (OR per 1-ln increase = 2.16; 95% CI, 1.61-2.98; P < 0.001) were associated with POPH.

Conclusions: Genetic variation in aromatase and changes in estrogen metabolites were associated with POPH.
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http://dx.doi.org/10.1002/hep.31314DOI Listing
February 2021

Comparison of volatile organic compound profiles in exhaled breath versus plasma headspace in different diseases.

J Breath Res 2020 05 27;14(3):036003. Epub 2020 May 27.

Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America.

Breath analysis is the study of volatile organic compounds (VOC's) in exhaled breath. This analysis provides information on the body's condition. In this study we investigated the relationship between 22 VOC's detected in exhaled breath and plasma headspace using a selected ion flow tube mass spectrometer (SYFT-MS). We compared pairs of exhaled breath and plasma samples from patients with pulmonary hypertension inflammatory bowel disease (IBD), and IBD patients after J-pouch surgery (pouch group). Half of the measured VOC's from exhaled breath were significantly associated with the VOC's from plasma headspace. Interestingly, six breath VOC's (trimethyl amine (FDR p = 0.02), hydrogen sulfide (FDR p = 7.64 × 10), ethanol (FDR p = 1.56 × 10), dimethyl sulfide (FDR p = 5.70 × 10), benzene (FDR p = 8.40 × 10), and acetaldehyde (FDR p = 4.27 × 10)) and two plasma headspace VOC's (1-Octene (FDR p = 0.02) and 2-propanol (FDR p = 2.47 × 10)) were able to differentiate between the three groups. Breath and plasma headspace share a similar signature with significant association in half of the measured VOCs. The disease discriminatory capacity of breath and plasma headspace appear to be different. Therefore, using the VOC's print from both breath and plasma headspace may better help diagnose patients.
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http://dx.doi.org/10.1088/1752-7163/ab8866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583492PMC
May 2020

Plasma metabolomic profile in chronic thromboembolic pulmonary hypertension.

Pulm Circ 2020 Jan-Mar;10(1):2045894019890553. Epub 2020 Feb 4.

Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, OH, USA.

We aimed to characterize the plasma metabolome of chronic thromboembolic pulmonary hypertension patients using a high-throughput unbiased omics approach. We collected fasting plasma from a peripheral vein in 33 operable chronic thromboembolic pulmonary hypertension patients, 31 healthy controls, and 21 idiopathic pulmonary arterial hypertension patients matched for age, gender, and body mass index. Metabolomic analysis was performed using an untargeted approach (Metabolon Inc. Durham, NC). Of the total of 862 metabolites identified, 362 were different in chronic thromboembolic pulmonary hypertension compared to controls: 178 were higher and 184 were lower. Compared to idiopathic pulmonary arterial hypertension, 147 metabolites were different in chronic thromboembolic pulmonary hypertension: 45 were higher and 102 were lower. The plasma metabolome allowed us to distinguish subjects with chronic thromboembolic pulmonary hypertension and healthy controls with a predictive accuracy of 89%, and chronic thromboembolic pulmonary hypertension versus idiopathic pulmonary arterial hypertension with 80% accuracy. Compared to idiopathic pulmonary arterial hypertension and healthy controls, chronic thromboembolic pulmonary hypertension patients had higher fatty acids and glycerol; while acyl cholines and lysophospholipids were lower. Compared to healthy controls, both idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension patients had increased acyl carnitines, beta-hydroxybutyrate, amino sugars and modified amino acids and nucleosides. The plasma global metabolomic profile of chronic thromboembolic pulmonary hypertension suggests aberrant lipid metabolism characterized by increased lipolysis, fatty acid oxidation, and ketogenesis, concomitant with reduced acyl choline and phospholipid moieties. Future research should investigate the pathogenetic and therapeutic potential of modulating lipid metabolism in chronic thromboembolic pulmonary hypertension.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000865PMC
February 2020

Lipids and ketones dominate metabolism at the expense of glucose control in pulmonary arterial hypertension: a hyperglycaemic clamp and metabolomics study.

Eur Respir J 2020 04 9;55(4). Epub 2020 Apr 9.

Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

Individuals with idiopathic pulmonary arterial hypertension (PAH) display reduced oral glucose tolerance. This may involve defects in pancreatic function or insulin sensitivity but this hypothesis has not been tested; moreover, fasting nutrient metabolism remains poorly described in PAH. Thus, we aimed to characterise fasting nutrient metabolism and investigated the metabolic response to hyperglycaemia in PAH.12 participants (six PAH, six controls) were administered a hyperglycaemic clamp, while 52 (21 PAH, 31 controls) underwent plasma metabolomic analysis. Glucose, insulin, C-peptide, free fatty acids and acylcarnitines were assessed from the clamp. Plasma metabolomics was conducted on fasting plasma samples.The clamp verified a reduced insulin response to hyperglycaemia in PAH (-53% control), but with similar pancreatic insulin secretion. Skeletal muscle insulin sensitivity was unexpectedly greater in PAH. Hepatic insulin extraction was elevated in PAH (+11% control). Plasma metabolomics identified 862 metabolites: 213 elevated, 145 reduced in PAH (p<0.05). In both clamp and metabolomic cohorts, lipid oxidation and ketones were elevated in PAH. Insulin sensitivity, fatty acids, acylcarnitines and ketones correlated with PAH severity, while hepatic extraction and fatty acid:ketone ratio correlated with longer six-min walk distance.Poor glucose control in PAH could not be explained by pancreatic β-cell function or skeletal muscle insulin sensitivity. Instead, elevated hepatic insulin extraction emerged as an underlying factor. In agreement, nutrient metabolism in PAH favours lipid and ketone metabolism at the expense of glucose control. Future research should investigate the therapeutic potential of reinforcing lipid and ketone metabolism on clinical outcomes in PAH.
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http://dx.doi.org/10.1183/13993003.01700-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263739PMC
April 2020

Platelet glycolytic metabolism correlates with hemodynamic severity in pulmonary arterial hypertension.

Am J Physiol Lung Cell Mol Physiol 2020 03 5;318(3):L562-L569. Epub 2020 Feb 5.

Department of Pulmonary, Allergy, and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio.

Group 1 pulmonary hypertension (PH), i.e., pulmonary arterial hypertension (PAH), is associated with a metabolic shift favoring glycolysis in cells comprising the lung vasculature as well as skeletal muscle and right heart. We sought to determine whether this metabolic switch is also detectable in circulating platelets from PAH patients. We used Seahorse Extracellular Flux to measure bioenergetics in platelets isolated from group 1 PH (PAH), group 2 PH, patients with dyspnea and normal pulmonary artery pressures, and healthy controls. We show that platelets from group 1 PH patients exhibit enhanced basal glycolysis and lower glycolytic reserve compared with platelets from healthy controls but do not differ from platelets of group 2 PH or dyspnea patients without PH. Although we were unable to identify a glycolytic phenotype unique to platelets from PAH patients, we found that platelet glycolytic metabolism correlated with hemodynamic severity only in group 1 PH patients, supporting the known link between PAH pathology and altered glycolytic metabolism and extending this association to ex vivo platelets. Pulmonary artery pressure and pulmonary vascular resistance in patients with group 1 PH were directly associated with basal platelet glycolysis and inversely associated with maximal and reserve glycolysis, suggesting that PAH progression reduces the capacity for glycolysis even while demanding an increase in glycolytic metabolism. Therefore, platelets may provide an easy-to-harvest, real-time window into the metabolic shift occurring in the lung vasculature and represent a useful surrogate for interrogating the glycolytic shift central to PAH pathology.
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http://dx.doi.org/10.1152/ajplung.00389.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099433PMC
March 2020

O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension.

Int J Mol Sci 2019 Dec 13;20(24). Epub 2019 Dec 13.

Department of Inflammation & Immunity, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA.

Idiopathic pulmonary arterial hypertension (IPAH) is considered a vasculopathy characterized by elevated pulmonary vascular resistance due to vasoconstriction and/or lung remodeling such as plexiform lesions, the hallmark of the PAH, as well as cell proliferation and vascular and angiogenic dysfunction. The serine/threonine hydroxyl-linked N-Acetylglucosamine (O-GlcNAc) transferase (OGT) has been shown to drive pulmonary arterial smooth muscle cell (PASMC) proliferation in IPAH. OGT is a cellular nutrient sensor that is essential in maintaining proper cell function through the regulation of cell signaling, proliferation, and metabolism. The aim of this study was to determine the role of OGT and O-GlcNAc in vascular and angiogenic dysfunction in IPAH. Primary isolated human control and IPAH patient PASMCs and pulmonary arterial endothelial cells (PAECs) were grown in the presence or absence of OGT inhibitors and subjected to biochemical assessments in monolayer cultures and tube formation assays, in vitro vascular sprouting 3D spheroid co-culture models, and de novo vascularization models in NODSCID mice. We showed that knockdown of OGT resulted in reduced vascular endothelial growth factor (VEGF) expression in IPAH primary isolated vascular cells. In addition, specificity protein 1 (SP1), a known stimulator of VEGF expression, was shown to have higher O-GlcNAc levels in IPAH compared to control at physiological (5 mM) and high (25 mM) glucose concentrations, and knockdown resulted in decreased VEGF protein levels. Furthermore, human IPAH PAECs demonstrated a significantly higher degree of capillary tube-like structures and increased length compared to control PAECs. Addition of an OGT inhibitor, OSMI-1, significantly reduced the number of tube-like structures and tube length similar to control levels. Assessment of vascular sprouting from an in vitro 3D spheroid co-culture model using IPAH and control PAEC/PASMCs and an in vivo vascularization model using control and PAEC-embedded collagen implants demonstrated higher vascularization in IPAH compared to control. Blocking OGT activity in these experiments, however, altered the vascular sprouting and de novo vascularization in IPAH similar to control levels when compared to controls. Our findings in this report are the first to describe a role for the OGT/O-GlcNAc axis in modulating VEGF expression and vascularization in IPAH. These findings provide greater insight into the potential role that altered glucose uptake and metabolism may have on the angiogenic process and the development of plexiform lesions. Therefore, we believe that the OGT/O-GlcNAc axis may be a potential therapeutic target for treating the angiogenic dysregulation that is present in IPAH.
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http://dx.doi.org/10.3390/ijms20246299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941156PMC
December 2019

Performance Measure Development, Use, and Measurement of Effectiveness Using the Guideline on Mechanical Ventilation in Acute Respiratory Distress Syndrome. An Official American Thoracic Society Workshop Report.

Ann Am Thorac Soc 2019 12;16(12):1463-1472

Guideline implementation tools are designed to improve uptake of guideline recommendations in clinical settings but do not uniformly accompany the clinical practice guideline documents. Performance measures are a type of guideline implementation tool with the potential to catalyze behavior change and greater adherence to clinical practice guidelines. However, many performance measures suffer from serious flaws in their design and application, prompting the American Thoracic Society (ATS) to define its own performance measure development standards in a previous workshop in 2012. This report summarizes the proceedings of a follow-up workshop convened to advance the ATS's work in performance measure development and guideline implementation. To illustrate the application of the ATS's performance measure development framework, we used the example of a low-tidal volume ventilation performance measure created from the 2017 ATS/European Society of Intensive Care Medicine/Society of Critical Care Medicine mechanical ventilation in acute respiratory distress syndrome clinical practice guideline. We include a detailed explanation of the rationale for the specifications chosen, identification of areas in need of further validity testing, and a preliminary strategy for pilot testing of the performance measure. Pending additional resources and broader performance measure expertise, issuing "preliminary performance measures" and their specifications alongside an ATS clinical practice guideline offers a first step to further the ATS's guideline implementation agenda. We recommend selectively proceeding with full performance measure development for those measures with positive early user feedback and the greatest potential impact in accordance with ATS leadership guidance.
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http://dx.doi.org/10.1513/AnnalsATS.201909-665STDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956829PMC
December 2019

Breath analysis in gastrointestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Blood Adv 2019 09;3(18):2732-2737

Department of Pulmonary and Critical Care Medicine, Respiratory Institute, and.

Volatile organic compounds (VOCs) are generated during pathologic processes, and their assessment can be used to diagnose and monitor a variety of diseases. Given the role of the microbiome in graft-versus-host disease (GVHD), we hypothesized that microorganisms producing volatile metabolites may alter VOCs expelled in breath in patients with gastrointestinal (GI) GVHD. In this pilot study, exhaled breath samples were obtained from 19 patients with grade 2 to 4 acute GI GVHD, 10 patients with no GVHD at day 100, and 10 healthy control subjects; the samples were analyzed by using mass spectrometry. Overall, nine (47%) patients had grade 2 GVHD, eight (42%) patients had grade 3 GVHD, and two (11%) patients had grade 4 GVHD; 26% had upper GI, 21% had lower GI, and 53% had both upper and lower GI manifestations. Stepwise canonical discriminant analysis identified 5 VOCs distinguishing patients with and without GI GVHD: 2-propanol, acetaldehyde, dimethyl sulfide, isoprene, and 1-decene (Wilks' Λ, 0.43; F statistic, 6.08; = .001). The model correctly classified 89% (17 of 19) and 90% (9 of 10) of patients with and without GI GVHD, respectively. Breath analysis is a feasible and promising noninvasive method to detect acute GI GVHD. Further study of serial breath analysis and the gut microbiome in a larger cohort are ongoing to validate these findings.
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http://dx.doi.org/10.1182/bloodadvances.2019000345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759739PMC
September 2019

A pilot study on the kinetics of metabolites and microvascular cutaneous effects of nitric oxide inhalation in healthy volunteers.

PLoS One 2019 30;14(8):e0221777. Epub 2019 Aug 30.

Department of Pulmonary, Allergy and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH, United States of America.

Rationale: Inhaled nitric oxide (NO) exerts a variety of effects through metabolites and these play an important role in regulation of hemodynamics in the body. A detailed investigation into the generation of these metabolites has been overlooked.

Objectives: We investigated the kinetics of nitrite and S-nitrosothiol-hemoglobin (SNO-Hb) in plasma derived from inhaled NO subjects and how this modifies the cutaneous microvascular response.

Findings: We enrolled 15 healthy volunteers. Plasma nitrite levels at baseline and during NO inhalation (15 minutes at 40 ppm) were 102 (86-118) and 114 (87-129) nM, respectively. The nitrite peak occurred at 5 minutes of discontinuing NO (131 (104-170) nM). Plasma nitrate levels were not significantly different during the study. SNO-Hb molar ratio levels at baseline and during NO inhalation were 4.7E-3 (2.5E-3-5.8E-3) and 7.8E-3 (4.1E-3-13.0E-3), respectively. Levels of SNO-Hb continued to climb up to the last study time point (30 min: 10.6E-3 (5.3E-3-15.5E-3)). The response to acetylcholine iontophoresis both before and during NO inhalation was inversely associated with the SNO-Hb level (r: -0.57, p = 0.03, and r: -0.54, p = 0.04, respectively).

Conclusions: Both nitrite and SNO-Hb increase during NO inhalation. Nitrite increases first, followed by a more sustained increase in Hb-SNO. Nitrite and Hb-SNO could be a mobile reservoir of NO with potential implications on the systemic microvasculature.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221777PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716644PMC
March 2020

Comparison of Different Methods to Estimate Cardiac Index in Pulmonary Arterial Hypertension.

Circulation 2019 08 19;140(8):705-707. Epub 2019 Aug 19.

Department of Pulmonary, Allergy, and Critical Care Medicine (G.K., R.A.D., A.R.T.), Respiratory Institute.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.041614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182442PMC
August 2019

Evaluation and Management of Obesity Hypoventilation Syndrome. An Official American Thoracic Society Clinical Practice Guideline.

Am J Respir Crit Care Med 2019 08;200(3):e6-e24

The purpose of this guideline is to optimize evaluation and management of patients with obesity hypoventilation syndrome (OHS). A multidisciplinary panel identified and prioritized five clinical questions. The panel performed systematic reviews of available studies (up to July 2018) and followed the Grading of Recommendations, Assessment, Development, and Evaluation evidence-to-decision framework to develop recommendations. All panel members discussed and approved the recommendations. After considering the overall very low quality of the evidence, the panel made five conditional recommendations. We suggest that: ) clinicians use a serum bicarbonate level <27 mmol/L to exclude the diagnosis of OHS in obese patients with sleep-disordered breathing when suspicion for OHS is not very high (<20%) but to measure arterial blood gases in patients strongly suspected of having OHS, ) stable ambulatory patients with OHS receive positive airway pressure (PAP), ) continuous positive airway pressure (CPAP) rather than noninvasive ventilation be offered as the first-line treatment to stable ambulatory patients with OHS and coexistent severe obstructive sleep apnea, ) patients hospitalized with respiratory failure and suspected of having OHS be discharged with noninvasive ventilation until they undergo outpatient diagnostic procedures and PAP titration in the sleep laboratory (ideally within 2-3 mo), and ) patients with OHS use weight-loss interventions that produce sustained weight loss of 25% to 30% of body weight to achieve resolution of OHS (which is more likely to be obtained with bariatric surgery). Clinicians may use these recommendations, on the basis of the best available evidence, to guide management and improve outcomes among patients with OHS.
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http://dx.doi.org/10.1164/rccm.201905-1071STDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680300PMC
August 2019

Evidence-Based Medicine and the American Thoracic Society Guidelines.

JAMA Intern Med 2019 07;179(7):1003-1004

Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jamainternmed.2019.1867DOI Listing
July 2019

Pulmonary Edema Following Initiation of Parenteral Prostacyclin Therapy for Pulmonary Arterial Hypertension: A Retrospective Study.

Chest 2019 07 15;156(1):45-52. Epub 2019 Feb 15.

Department of Pulmonary Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH. Electronic address:

Background: Pulmonary edema may complicate the use of pulmonary arterial hypertension (PAH)-targeted therapies. We aimed to determine the proportion of patients who develop pulmonary edema after initiation of parenteral prostacyclin therapy, to identify its risk factors, and to assess its implications for hospital length of stay and mortality.

Methods: A retrospective cohort study of patients with PAH at the initiation of parenteral prostacyclin between 1997 and 2015 enrolled in the Cleveland Clinic PAH registry. Pulmonary edema was defined as at least one symptom or clinical sign and radiographic evidence of pulmonary edema. We determined patient characteristics predictive of pulmonary edema as well as the association between pulmonary edema and hospital length of stay (LOS) and 6-month mortality.

Results: One hundred and fifty-five patients were included (median age, 51 years; female, 72%; white, 85%; idiopathic, 64%; and connective tissue disease [CTD], 23%). Pulmonary edema developed in 33 of 155 patients (21%). Independent predictors of pulmonary edema were high right atrial pressure (RAP), CTD etiology, and the presence of three or more risk factors for left heart disease (LHD). Pulmonary edema was associated with a 4.5-day increase in hospital LOS (95% CI, 1.4-7.5 days; P < .001) and a 4-fold increase in 6-month mortality (OR, 4.3; 95% CI, 1.28-14.36; P = .031).

Conclusions: Pulmonary edema occurred in 21% of patients with PAH initiated on parenteral prostacyclin. Three or more risk factors for LHD, CTD-PAH, and a high baseline RAP were independent predictors of pulmonary edema. Pulmonary edema was associated with a prolonged hospital LOS and increased 6-month mortality.
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http://dx.doi.org/10.1016/j.chest.2019.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607426PMC
July 2019

Gasometric gradients between blood obtained from the pulmonary artery wedge and pulmonary artery positions in pulmonary arterial hypertension.

Respir Res 2019 Jan 8;20(1). Epub 2019 Jan 8.

Department of Pulmonary, Allergy and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue A-90, Cleveland, OH, 44195, USA.

Introduction: Little is known on the pulmonary gradients of oxyhemoglobin, carboxyhemoglobin and methemoglobin in pulmonary arterial hypertension (PAH). We sought to determine these gradients in group 1 PAH and assess their association with disease severity and survival.

Methods: During right heart catheterization (RHC) we obtained blood from pulmonary artery (PA) and pulmonary artery wedge (PAW) positions and used co-oximetry to test their gasometric differences.

Results: We included a total of 130 patients, 65 had group 1 PAH, 40 had pulmonary hypertension (PH) from groups 2-5 and 25 had no PH during RHC. In all groups, PAW blood had higher pH, carboxyhemoglobin and lactate as well as lower pCO than PA blood. In group 1 PAH (age 58 ± 15 years, 72% females), methemoglobin in the PAW was lower than in the PA blood (0.83% ± 0.43 vs 0.95% ± 0.50, p = 0.03) and was directly associated with the degree of change in pulmonary vascular resistance (R = 0.35, p = 0.02) during inhaled nitric oxide test. Oxyhemoglobin in PA (HR (95%CI): 0.90 (0.82-0.99), p = 0.04) and PAW (HR (95%CI): 0.91 (0.84-0.98), p = 0.003) blood was associated with adjusted survival in PAH.

Conclusions: Marked differences were observed in the gasometric determinations between PAW and PA blood. The pulmonary gradient of methemoglobin was lower in PAH patients compared to controls and a higher PAW blood methemoglobin was associated with a more pronounced pulmonary vascular response to inhaled nitric oxide. Pulmonary artery and PAW oxyhemoglobin tracked with disease severity and survival in PAH.
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http://dx.doi.org/10.1186/s12931-018-0969-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325872PMC
January 2019

Survival After an ICU Hospitalization for Pulmonary Hypertension.

Chest 2018 07;154(1):229-231

Pulmonary and Critical Care Faculty, Cleveland Clinic, Cleveland, OH. Electronic address:

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http://dx.doi.org/10.1016/j.chest.2018.03.028DOI Listing
July 2018

Myeloperoxidase aggravates pulmonary arterial hypertension by activation of vascular Rho-kinase.

JCI Insight 2018 06 7;3(11). Epub 2018 Jun 7.

Heart Center, Department of Cardiology.

Pulmonary arterial hypertension (PAH) remains a disease with limited therapeutic options and dismal prognosis. Despite its etiologic heterogeneity, the underlying unifying pathophysiology is characterized by increased vascular tone and adverse remodeling of the pulmonary circulation. Myeloperoxidase (MPO), an enzyme abundantly expressed in neutrophils, has potent vasoconstrictive and profibrotic properties, thus qualifying as a potential contributor to this disease. Here, we sought to investigate whether MPO is causally linked to the pathophysiology of PAH. Investigation of 2 independent clinical cohorts revealed that MPO plasma levels were elevated in subjects with PAH and predicted adverse outcome. Experimental analyses showed that, upon hypoxia, right ventricular pressure was less increased in Mpo-/- than in WT mice. The hypoxia-induced activation of the Rho-kinase pathway, a critical subcellular signaling pathway yielding vasoconstriction and structural vascular remodeling, was blunted in Mpo-/- mice. Mice subjected to i.v. infusion of MPO revealed activation of Rho-kinase and increased right ventricular pressure, which was prevented by coinfusion of the Rho-kinase inhibitor Y-27632. In the Sugen5416/hypoxia rat model, PAH was attenuated by the MPO inhibitor AZM198. The current data demonstrate a tight mechanistic link between MPO, the activation of Rho-kinase, and adverse pulmonary vascular function, thus pointing toward a potentially novel avenue of treatment.
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http://dx.doi.org/10.1172/jci.insight.97530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124430PMC
June 2018

Plasma levels of high density lipoprotein cholesterol and outcomes in chronic thromboembolic pulmonary hypertension.

PLoS One 2018 29;13(5):e0197700. Epub 2018 May 29.

Department of Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.

Background: High Density Lipoprotein Cholesterol (HDL-C) has various anti-inflammatory, anti-atherogenic, anti-oxidant and anti-coagulant properties that improve vascular function. The utility of HDL-C as a biomarker of severity and predictor of survival was described in patients with pulmonary arterial hypertension (PAH). No prior study has assessed the utility of HDL-C in patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH).

Objectives: We aim to measure HDL-C levels in CTEPH patients and compare it to those in PAH patients and controls and determine HDL-C associations with markers of disease severity, hemodynamics and mortality in CTEPH.

Methods: We retrospectively included patients with CTEPH, identified from the Cleveland Clinic Pulmonary Hypertension Registry. All patients had right heart catheterization (RHC) and imaging studies consistent with CTEPH. We collected demographics, co-morbidities, baseline laboratory data including plasma HDL-C, six-minute walk test (6MWT), echocardiography and RHC. HDL-C levels were compared to a cohort of patients with cardiovascular risk factors and a previously published PAH cohort.

Results: HDL-C levels were available for 90 patients with CTEPH (age: 57.4±13.9 years; female 40%), 69 patients with PAH (age: 46.7±12.8 years; female 90%) and 254 control subjects (age: 56.7±13 years; female 48%). HDL-C levels in CTEPH patients were lower compared to controls and higher compared to PAH patients (median, IQR: CTEPH: 44, 34-57 mg/dl; PAH: 35.3, 29-39 mg/dl; Control: 49, 40-60 mg/dl; p < 0.01 for both pairwise comparisons). In CTEPH, higher HDL-C was associated with decreased prevalence of right ventricular dilation on echocardiography (p = 0.02). 57 patients with CTEPH underwent pulmonary thromboendarterectomy, higher HDL-C was associated with a larger decrement in postoperative pulmonary vascular resistance (PVR) (r = 0.37, p = 0.049). HDL-C was not associated with mortality or other markers of disease severity.

Conclusions: HDL-C levels in CTEPH patients were lower compared to control subjects, but higher compared to PAH patients. Higher HDL-C in CTEPH was associated with less right ventricular dilation and greater decrement in postoperative PVR. These data suggest that HDL-C may be a useful marker of small vessel disease in CTEPH.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197700PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973565PMC
December 2018

Serum Chloride Levels Track With Survival in Patients With Pulmonary Arterial Hypertension.

Chest 2018 09 24;154(3):541-549. Epub 2018 Apr 24.

Department of Pulmonary, Allergy and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH. Electronic address:

Background: Serum chloride is an important homeostatic biomarker in left heart failure, with significant prognostic implications. The impact of serum chloride in the long-term survival of patients with pulmonary arterial hypertension (PAH) is unknown. We tested whether serum chloride levels are associated with long-term survival in patients with PAH.

Methods: We included patients with idiopathic or heritable PAH who had a basic metabolic panel performed at the time of their diagnostic right heart catheterization. Laboratory results were recorded both at diagnosis and 6-month follow-up.

Results: We included 277 patients, mean age 51 ± 18 years and 73% women, of whom 254 had a follow-up electrolyte determination at 6 months. Serum chloride was 102.9 ± 3.9 mM/L at diagnosis. A serum chloride ≤ 100 mM/L was noted in 65 (24%) and 53 (21%) patients at diagnosis and 6 months, respectively. Patients with serum chloride ≤ 100 mM/L at 6 months tracked with increase mortality when adjusted by age, sex, pulmonary vascular resistance, diuretics or prostacyclin analogs usage, and serum creatinine and sodium at 6 months (hazard ratio, 1.83; 95% CI, 1.11-3.00). This group of patients was older, with decreased functional capacity, had worse renal function, took more diuretics, had higher pulmonary artery wedge pressure but lower mean pulmonary artery pressure, transpulmonary gradient, and pulmonary vascular resistance.

Conclusions: Serum chloride at 6 months from the PAH diagnosis is a strong and independent predictor of mortality in patients with idiopathic or heritable PAH, even after adjusting serum sodium, renal function, diuretic, and prostacyclin analog usage.
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http://dx.doi.org/10.1016/j.chest.2018.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130326PMC
September 2018