Publications by authors named "Anna R Hemnes"

142 Publications

TORREY, a Phase 2 study to evaluate the efficacy and safety of inhaled seralutinib for the treatment of pulmonary arterial hypertension.

Pulm Circ 2021 Oct-Dec;11(4):20458940211057071. Epub 2021 Nov 11.

Justus-Liebig-University Giessen, Giessen, Germany.

Aberrant kinase signaling that involves platelet-derived growth factor receptor (PDGFR) α/β, colony stimulating factor 1 receptor (CSF1R), and stem cell factor receptor (c-KIT) pathways may be responsible for vascular remodeling in pulmonary arterial hypertension. Targeting these specific pathways may potentially reverse the pathological inflammation, cellular proliferation, and fibrosis associated with pulmonary arterial hypertension progression. Seralutinib (formerly known as GB002) is a novel, potent, clinical stage inhibitor of PDGFRα/β, CSF1R, and c-KIT delivered via inhalation that is being developed for patients with pulmonary arterial hypertension. Here, we report on an ongoing Phase 2 randomized, double-blind, placebo-controlled trial (NCT04456998) evaluating the efficacy and safety of seralutinib in subjects with World Health Organization Group 1 Pulmonary Hypertension who are classified as Functional Class II or III. A total of 80 subjects will be enrolled and randomized to receive either study drug or placebo for 24 weeks followed by an optional 72-week open-label extension study. The primary endpoint is the change from baseline to Week 24 in pulmonary vascular resistance by right heart catheterization. The secondary endpoint is the change in distance from baseline to Week 24 achieved in the 6-min walk test. A computerized tomography sub-study will examine the effect of seralutinib on pulmonary vascular remodelling. A separate heart rate monitoring sub-study will examine the effect of seralutinib on cardiac effort during the 6-min walk test.
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http://dx.doi.org/10.1177/20458940211057071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591655PMC
November 2021

Pulmonary Hypertension: A New Vascular Complication of Diabetes?

Chest 2021 Sep 17. Epub 2021 Sep 17.

Atlanta VA Medical Center, Decatur, GA; Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA. Electronic address:

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http://dx.doi.org/10.1016/j.chest.2021.09.005DOI Listing
September 2021

Diagnosis and Treatment of Right Heart Failure in Pulmonary Vascular Diseases: A National Heart, Lung, and Blood Institute Workshop.

Circ Heart Fail 2021 06 15;14(6). Epub 2021 Jun 15.

Division of Lung Diseases, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD.

Right ventricular dysfunction is a hallmark of advanced pulmonary vascular, lung parenchymal, and left heart disease, yet the underlying mechanisms that govern (mal)adaptation remain incompletely characterized. Owing to the knowledge gaps in our understanding of the right ventricle (RV) in health and disease, the National Heart, Lung, and Blood Institute (NHLBI) commissioned a working group to identify current challenges in the field. These included a need to define and standardize normal RV structure and function in populations; access to RV tissue for research purposes and the development of complex experimental platforms that recapitulate the environment; and the advancement of imaging and invasive methodologies to study the RV within basic, translational, and clinical research programs. Specific recommendations were provided, including a call to incorporate precision medicine and innovations in prognosis, diagnosis, and novel RV therapeutics for patients with pulmonary vascular disease.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375628PMC
June 2021

Metabolics of PH - an update.

Curr Opin Pulm Med 2021 09;27(5):329-334

Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Purpose Of Review: While there has been a longstanding interest in metabolic disease in pulmonary hypertension, publications in the last several years have translated basic science findings to human disease and even led to recently published studies of metabolic therapy in pulmonary arterial hypertension that are discussed here.

Recent Findings: Progress has been made in four key areas including mechanisms of insulin resistance in pulmonary arterial hypertension, the role of obesity in pulmonary vascular disease, novel clinical trials targeting metabolism in pulmonary hypertension, and the role of metabolism in chronic thromboembolic pulmonary hypertension.

Summary: : Insulin resistance in pulmonary arterial hypertension is primarily in the lipid axis. There are systemic manifestations of insulin resistance including right ventricular lipotoxicity. Obesity is associated with elevation of right ventricular systolic pressure even in a healthy population and therapies in pulmonary arterial hypertension that target metabolism hold promise for improving exercise, right ventricular function, and visceral adiposity. Finally, there are emerging data that chronic thromboembolic pulmonary hypertension is similarly characterized by metabolic alterations, though the specific metabolites may be different from pulmonary arterial hypertension.
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http://dx.doi.org/10.1097/MCP.0000000000000794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373799PMC
September 2021

NHLBI-CMREF Workshop Report on Pulmonary Vascular Disease Classification: JACC State-of-the-Art Review.

J Am Coll Cardiol 2021 04;77(16):2040-2052

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

The National Heart, Lung, and Blood Institute and the Cardiovascular Medical Research and Education Fund held a workshop on the application of pulmonary vascular disease omics data to the understanding, prevention, and treatment of pulmonary vascular disease. Experts in pulmonary vascular disease, omics, and data analytics met to identify knowledge gaps and formulate ideas for future research priorities in pulmonary vascular disease in line with National Heart, Lung, and Blood Institute Strategic Vision goals. The group identified opportunities to develop analytic approaches to multiomic datasets, to identify molecular pathways in pulmonary vascular disease pathobiology, and to link novel phenotypes to meaningful clinical outcomes. The committee suggested support for interdisciplinary research teams to develop and validate analytic methods, a national effort to coordinate biosamples and data, a consortium of preclinical investigators to expedite target evaluation and drug development, longitudinal assessment of molecular biomarkers in clinical trials, and a task force to develop a master clinical trials protocol for pulmonary vascular disease.
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http://dx.doi.org/10.1016/j.jacc.2021.02.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065203PMC
April 2021

A Mobile Health Intervention to Increase Physical Activity in Pulmonary Arterial Hypertension.

Chest 2021 Sep 17;160(3):1042-1052. Epub 2021 Apr 17.

Division of Cardiovascular Medicine and Vanderbilt Translational and Clinical Cardiovascular Research Center, Nashville, TN. Electronic address:

Background: Supervised exercise training improves outcomes in patients with pulmonary arterial hypertension (PAH). The effect of an unsupervised activity intervention has not been tested.

Research Question: Can a text-based mobile health intervention increase step counts in patients with PAH?

Study Design And Methods: We performed a randomized, parallel arm, single-blind clinical trial. We randomized patients to usual care or a text message-based intervention for 12 weeks. The intervention arm received three automated text messages per day with real-time step count updates and encouraging messages rooted in behavioral change theory. Individual step targets increased by 20% every 4 weeks. The primary end point was mean week 12 step counts. Secondary end points included the 6-min walk test, quality of life, right ventricular function, and body composition.

Results: Among 42 randomized participants, the change in raw steps between baseline and week 12 was higher in the intervention group (1,409 steps [interquartile range, -32 to 2,220] vs -149 steps [interquartile range, -1,010 to 735]; P = .02), which persisted after adjustment for age, sex, baseline step counts, and functional class (model estimated difference, 1,250 steps; P = .03). The intervention arm took a higher average number of steps on all days between days 9 and 84 (P < .05, all days). There was no difference in week 12 six-minute walk distance. Analysis of secondary end points suggested improvements in the emPHasis-10 score (adjusted change, -4.2; P = .046), a reduction in visceral fat volume (adjusted change, -170 mL; P = .023), and nearly significant improvement in tricuspid annular plane systolic excursion (model estimated difference, 1.2 mm; P = .051).

Interpretation: This study demonstrated the feasibility of an automated text message-based intervention to increase physical activity in patients with PAH. Additional studies are warranted to examine the effect of the intervention on clinical outcomes.

Clinical Trial Registration: ClinicalTrials.gov; No. NCT03069716; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2021.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449004PMC
September 2021

Integrative Omics to Characterize and Classify Pulmonary Vascular Disease.

Clin Chest Med 2021 03 12;42(1):195-205. Epub 2021 Jan 12.

Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, T1218 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232, USA.

Advances in high-throughput biotechnologies have facilitated omics profiling, a key component of precision phenotyping, in patients with pulmonary vascular disease. Omics provides comprehensive information pertaining to genes, transcripts, proteins, and metabolites. The resulting omics big datasets may be integrated for more robust results and are amenable to analysis using machine learning or newer analytical methodologies, such as network analysis. Results from fully integrated multi-omics datasets combined with clinical data are poised to provide novel insight into pulmonary vascular disease as well as diagnose the presence of disease and prognosticate outcomes.
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http://dx.doi.org/10.1016/j.ccm.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875152PMC
March 2021

Patient and disease characteristics of the first 500 patients with pulmonary arterial hypertension treated with selexipag in real-world settings from SPHERE.

J Heart Lung Transplant 2021 04 15;40(4):279-288. Epub 2021 Jan 15.

Tufts Medical Center, Boston, Massachusetts.

Background: Selexipag is a selective oral prostacyclin receptor agonist indicated for pulmonary arterial hypertension (PAH) treatment. SelexiPag: tHe usErs dRug rEgistry (SPHERE) (NCT03278002) is collecting data from selexipag-treated patients in real-world clinical practice to elucidate and describe the clinical characteristics, outcomes, and dosing/titration regimens of patients treated with selexipag in routine clinical practice.

Methods: SPHERE is a United States (US)-based, ongoing, multicenter, prospective observational study (target N = 800). This study enrolls patients who are either newly initiated on selexipag (≤60 days before enrollment) or were previously receiving selexipag with documentation of dose titration at study enrollment. Data collection for the study occurs at routine clinic visits. In this paper, we report on the first 500 patients enrolled.

Results: Median follow-up was 17.8 months; 77.6% of patients completed the planned 18 months follow-up, and 22.4% discontinued early from the study. At diagnosis, 94.8% of patients had PAH (World Health Organization [WHO] Group 1), most commonly idiopathic (49.2%) and connective tissue disease associated (26.4%). Most patients (72.4%) initiated selexipag more than 60 days before enrollment. At initiation, 31.0% of patients had WHO functional class (FC) II disease, and 49.6% had WHO FC II or III disease. In addition, 55.0% of patients were receiving double therapy (most commonly an endothelin receptor antagonist plus phosphodiesterase type 5 inhibitor [42.3%]), whereas 30.6% were receiving monotherapy. Despite most patients already receiving PAH-specific therapy, at selexipag initiation, 67.2% (336 of 500) were at intermediate risk, and 9.6% (48 of 500) were at high risk of 1-year mortality. Risk scores remained stable in ∼55% of patients and improved in ∼20% at the end of the study. In total, 72.2% of patients had at least 1 adverse event (AE), and 37.6% reported a serious AE. The median selexipag maintenance dose was 1,200 µg twice daily (interquartile range: 800-1,600 µg twice daily).

Conclusions: Real-world, US-based patients with PAH initiating selexipag typically have WHO FC II/III disease and are at intermediate risk, despite receiving PAH-specific treatment. Selexipag was prescribed as part of a combination regimen in most patients. The study identified no unexpected adverse effects.
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http://dx.doi.org/10.1016/j.healun.2021.01.006DOI Listing
April 2021

Treatment of right ventricular dysfunction and heart failure in pulmonary arterial hypertension.

Cardiovasc Diagn Ther 2020 Oct;10(5):1659-1674

Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Translational and Clinical Cardiovascular Research Center, Nashville, TN, USA.

Right heart dysfunction and failure is the principal determinant of adverse outcomes in patients with pulmonary arterial hypertension (PAH). In addition to right ventricular (RV) dysfunction, systemic congestion, increased afterload and impaired myocardial contractility play an important role in the pathophysiology of RV failure. The behavior of the RV in response to the hemodynamic overload is primarily modulated by the ventricular interaction and its coupling to the pulmonary circulation. The presentation can be acute with hemodynamic instability and shock or chronic producing symptoms of systemic venous congestion and low cardiac output. The prognostic factors associated with poor outcomes in hospitalized patients include systemic hypotension, hyponatremia, severe tricuspid insufficiency, inotropic support use and the presence of pericardial effusion. Effective therapeutic management strategies involve identification and effective treatment of the triggering factors, improving cardiopulmonary hemodynamics by optimization of volume to improve diastolic ventricular interactions, improving contractility by use of inotropes, and reducing afterload by use of drugs targeting pulmonary circulation. The medical therapies approved for PAH act primarily on the pulmonary vasculature with secondary effects on the right ventricle. Mechanical circulatory support as a bridge to transplantation has also gained traction in medically refractory cases. The current review was undertaken to summarize recent insights into the evaluation and treatment of RV dysfunction and failure attributable to PAH.
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http://dx.doi.org/10.21037/cdt-20-348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666956PMC
October 2020

Molecular mechanisms of right ventricular dysfunction in pulmonary arterial hypertension: focus on the coronary vasculature, sex hormones, and glucose/lipid metabolism.

Cardiovasc Diagn Ther 2020 Oct;10(5):1522-1540

Division of Allergy, Pulmonology and Critical Care, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Pulmonary arterial hypertension (PAH) is a rare, life-threatening condition characterized by dysregulated metabolism, pulmonary vascular remodeling, and loss of pulmonary vascular cross-sectional area due to a variety of etiologies. Right ventricular (RV) dysfunction in PAH is a critical mediator of both long-term morbidity and mortality. While combinatory oral pharmacotherapy and/or intravenous prostacyclin aimed at decreasing pulmonary vascular resistance (PVR) have improved clinical outcomes, there are currently no treatments that directly address RV failure in PAH. This is, in part, due to the incomplete understanding of the pathogenesis of RV dysfunction in PAH. The purpose of this review is to discuss the current understanding of key molecular mechanisms that cause, contribute and/or sustain RV dysfunction, with a special focus on pathways that either have led to or have the potential to lead to clinical therapeutic intervention. Specifically, this review discusses the mechanisms by which vessel loss and dysfunctional angiogenesis, sex hormones, and metabolic derangements in PAH directly contribute to RV dysfunction. Finally, this review discusses limitations and future areas of investigation that may lead to novel understanding and therapeutic interventions for RV dysfunction in PAH.
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http://dx.doi.org/10.21037/cdt-20-404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666935PMC
October 2020

Mechanistic Phase II Clinical Trial of Metformin in Pulmonary Arterial Hypertension.

J Am Heart Assoc 2020 11 10;9(22):e018349. Epub 2020 Nov 10.

Division of Allergy, Pulmonary and Critical Care Medicine Vanderbilt University Medical Center Nashville TN.

Background Metabolic dysfunction is highly prevalent in pulmonary arterial hypertension (PAH) and likely contributes to both pulmonary vascular disease and right ventricular (RV) failure in part because of increased oxidant stress. Currently, there is no cure for PAH and human studies of metabolic interventions, generally well tolerated in other diseases, are limited in PAH. Metformin is a commonly used oral antidiabetic that decreases gluconeogenesis, increases fatty acid oxidation, and reduces oxidant stress and thus may be relevant to PAH. Methods and Results We performed a single-center, open-label 8-week phase II trial of up to 2 g/day of metformin in patients with idiopathic or heritable PAH with the co-primary end points of safety, including development of lactic acidosis and study withdrawal, and plasma oxidant stress markers. Exploratory end points included RV function via echocardiography, plasma metabolomic analysis performed before and after metformin therapy, and RV triglyceride content by magnetic resonance spectroscopy in a subset of 9 patients. We enrolled 20 patients; 19/20 reached the target dose and all completed the study protocol. There was no clinically significant lactic acidosis or change in oxidant stress markers. Metformin did not change 6-minute walk distance but did significantly improve RV fractional area change (23±8% to 26±6%, =0.02), though other echocardiographic parameters were unchanged. RV triglyceride content decreased in 8/9 patients (3.2±1.8% to 1.6±1.4%, =0.015). In an exploratory metabolomic analysis, plasma metabolomic correlates of ≥50% reduction in RV lipid included dihydroxybutyrate, acetylputrescine, hydroxystearate, and glucuronate (<0.05 for all). In the entire cohort, lipid metabolites were among the most changed by metformin. Conclusions Metformin therapy was safe and well tolerated in patients with PAH in this single-arm, open-label phase II study. Exploratory analyses suggest that metformin may be associated with improved RV fractional area change and, in a subset of patients, reduced RV triglyceride content that correlated with altered lipid and glucose metabolism markers. Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT01884051.
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http://dx.doi.org/10.1161/JAHA.120.018349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763730PMC
November 2020

Expression of a Human Caveolin-1 Mutation in Mice Drives Inflammatory and Metabolic Defect-Associated Pulmonary Arterial Hypertension.

Front Med (Lausanne) 2020 11;7:540. Epub 2020 Sep 11.

Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.

In 2012, mutations in Cav1 were found to be the driving mutation in several cases of heritable pulmonary arterial hypertension (PAH). These mutations replaced the last 21 amino acids of Cav1 with a novel 22-amino-acid sequence. Because previously only Cav1 knockouts had been studied in the context of PAH, examining the effects of this novel mutation holds promise for new understanding of the role of Cav1 in disease etiology. The new 22 amino acids created by the human mutation were knocked into the native mouse Cav1 locus. The mice underwent hemodynamic, energy balance, and inflammatory measurements, both at baseline and after being stressed with either a metabolic or an inflammatory challenge [low-dose lipopolysaccharide (LPS)]. To metabolically challenge the mice, they were injected with streptozotocin (STZ) and fed a high-fat diet for 12 weeks. Very little mutant protein was found (roughly 2% of wild-type by mass spectrometry), probably because of degradation after failure to traffic from the endoplasmic reticulum. The homozygous mutants developed a mild, low-penetrance PAH similar to that described previously in knockouts, and neither baseline nor metabolic nor inflammatory stress resulted in pressures above normal in heterozygous animals. The homozygous mutants had increased lean mass and worsened oral glucose tolerance, as previously described in knockouts. Novel findings include the preservation of Cav2 and accessory proteins in the liver and the kidney, while they are lost with homozygous Cav1 mutation in the lungs. We also found that the homozygous mutants had a significantly lower tolerance to voluntary spontaneous exercise than the wild-type mice, with the heterozygous mice at an intermediate level. The mutants also had higher circulating monocytes, with both heterozygous and homozygous animals having higher pulmonary MCP1 and MCP5 proteins. The heterozygous animals also lost weight at an LPS challenge level at which the wild-type mice continued to gain weight. The Cav1 mutation identified in human patients in 2012 is molecularly similar to a knockout of Cav1. It results in not only metabolic deficiencies and mild pulmonary hypertension, as expected, but also an inflammatory phenotype and reduced spontaneous exercise.
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http://dx.doi.org/10.3389/fmed.2020.00540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516012PMC
September 2020

Influence of Body Weight and Diabetes Mellitus in Patients With Pulmonary Hypertension.

Am J Cardiol 2020 11 15;134:130-137. Epub 2020 Aug 15.

Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Atlanta VA Health Care System, Department of Veterans Affairs, Decatur, Georgia.

Pulmonary hypertension (PH) is a complex condition that arises due to pulmonary vascular disease, heart disease, lung disease, chronic thromboembolism, or several rare causes. Regardless of underlying cause, PH increases mortality, yet there are no directed treatments for the most common forms of PH due to left heart or lung disease. Because metabolic factors have been implicated in the pathogenesis of PH, we used a large administrative cohort to assess diabetes and weight, potentially modifiable risk factors, on PH outcome. We analyzed 110,495 veterans diagnosed with PH from January 1, 2003 to September 30, 2015 in the Veterans Health Affairs system. Veterans with PH survived an average of 3.88 [IQR 3.85, 3.92] years after PH diagnosis. Diabetes occurred in 36% and increased risk of death by 31% (95% confidence interval 28% to 33%, multivariate adjusted). Higher body mass index was associated with lower mortality in a J-shaped pattern with highest risk in underweight and normal weight veterans. Improved survival in obesity has been referred to as the obesity paradox in heart failure and other diseases. These data show that lower weight and diabetes are strong risk factors for mortality in PH. Our results underscore the importance of systemic conditions on outcome in PH.
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http://dx.doi.org/10.1016/j.amjcard.2020.07.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572794PMC
November 2020

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

Hepatology 2021 02 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115214PMC
February 2021

Six-minute walk distance in healthy young adults.

Respir Med 2020 Apr - May;165:105933. Epub 2020 Mar 19.

Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: The 6-min walk test (6MWT) is a commonly used clinical assessment of exercise capacity in patients with cardiopulmonary or neuromuscular disease, but normal values are lacking for young adults, who are frequent subjects of testing.

Methods: In a two-center study, 272 young adults, ages 18-50, underwent American Thoracic Society protocolized 6-min walk testing, and 56 underwent repeat testing. A linear regression model was developed based on anthropomorphic data. This model was compared to existing prediction equations.

Results: Median 6MWD for the cohort was 637 m (IQR 584-686 m) and was not significantly impacted by age. This is in contrast to existing equations extrapolated from older subjects that predict increasing 6MWD in younger subjects. We found weak correlation of 6MWD with height, weight, BMI, and resting heart rate. Heart rate at completion correlated most strongly with 6MWD (rho 0.53 p < 0.0001). Repeat 6MWD was surprisingly variable, with a median difference between tests of 32.5 ± 31.9 m. Established reference equations performed poorly in this population, largely because age has much less effect on 6MWD in this group than in older adults.

Conclusions: Established reference equations should be reconfigured to include data from young adults, as age has minimal effect on 6MWD in this population. Heart rate response may be a valuable measure of effort in normal subjects. Six-minute walk distance, as with pulmonary function and exercise testing, should have predictive equations across the spectrum of age to allow for accurate assessment of exercise limitation.
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http://dx.doi.org/10.1016/j.rmed.2020.105933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174378PMC
January 2021

Authors' reply: role of natriuretic peptide receptor C signalling in obesity-induced heart failure with preserved ejection fraction with pulmonary hypertension.

Pulm Circ 2020 Jan-Mar;10(1):2045894020910979. Epub 2020 Mar 13.

Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

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http://dx.doi.org/10.1177/2045894020910979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074514PMC
March 2020

A multifaceted investigation into molecular associations of chronic thromboembolic pulmonary hypertension pathogenesis.

JRSM Cardiovasc Dis 2020 Jan-Dec;9:2048004020906994. Epub 2020 Feb 13.

Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, USA.

Purpose: Chronic thromboembolic pulmonary hypertension is characterized by incomplete thrombus resolution following acute pulmonary embolism, leading to pulmonary hypertension and right ventricular dysfunction. Conditions such as thrombophilias, dysfibrinogenemias, and inflammatory states have been associated with chronic thromboembolic pulmonary hypertension, but molecular mechanisms underlying this disease are poorly understood. We sought to characterize the molecular and functional features associated with chronic thromboembolic pulmonary hypertension using a multifaceted approach.

Methods: We utilized functional assays to compare clot lysis times between chronic thromboembolic pulmonary hypertension patients and multiple controls. We then performed immunohistochemical characterization of tissue from chronic thromboembolic pulmonary hypertension, pulmonary arterial hypertension, and healthy controls, and examined RNA expression patterns of cultured lymphocytes and pulmonary arterial specimens. We then confirmed RNA expression changes using immunohistochemistry, immunofluorescence, and Western blotting in pulmonary arterial tissue.

Results: Clot lysis times in chronic thromboembolic pulmonary hypertension patients are similar to multiple controls. Chronic thromboembolic pulmonary hypertension endarterectomized tissue has reduced expression of both smooth muscle and endothelial cell markers. RNA expression profiles in pulmonary arteries and peripheral blood lymphocytes identified differences in RNA transcript levels related to inflammation and growth factor signaling, which we confirmed using immunohistochemistry. Gene expression data also suggested significant alterations in metabolic pathways, and immunofluorescence and Western blot experiments confirmed that unglycosylated CD36 and adiponectin expression were increased in chronic thromboembolic pulmonary hypertension versus controls.

Conclusions: Our data do not support impaired clot lysis underlying chronic thromboembolic pulmonary hypertension, but did demonstrate distinct molecular patterns present both in peripheral blood and in pathologic specimens of chronic thromboembolic pulmonary hypertension patients suggesting that altered metabolism may play a role in chronic thromboembolic pulmonary hypertension pathogenesis.
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http://dx.doi.org/10.1177/2048004020906994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019411PMC
February 2020

Comprehensive Diagnostic Evaluation of Cardiovascular Physiology in Patients With Pulmonary Vascular Disease: Insights From the PVDOMICS Program.

Circ Heart Fail 2020 03 24;13(3):e006363. Epub 2020 Feb 24.

Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Department of Medicine (F.P.R.).

Background: Invasive hemodynamic evaluation through right heart catheterization plays an essential role in the diagnosis, categorization, and risk stratification of patients with pulmonary hypertension.

Methods: Subjects enrolled in the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) program undergo an extensive invasive hemodynamic evaluation that includes repeated measurements at rest and during several provocative physiological challenges. It is a National Institutes of Health/National Heart, Lung, and Blood Institute initiative to reclassify pulmonary hypertension groups based on clustered phenotypic and phenomic characteristics. At a subset of centers, participants also undergo an invasive cardiopulmonary exercise test to assess changes in hemodynamics and gas exchange during exercise.

Conclusions: When coupled with other physiological testing and blood -omic analyses involved in the PVDOMICS study, the comprehensive right heart catheterization protocol described here holds promise to clarify the diagnosis and clustering of pulmonary hypertension patients into cohorts beyond the traditional 5 World Symposium on Pulmonary Hypertension groups. This article will describe the methods applied for invasive hemodynamic characterization in the PVDOMICS program. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02980887.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046052PMC
March 2020

Biomarker-specific differences between transpulmonary and peripheral arterial-venous blood sampling in patients with pulmonary hypertension.

Biomarkers 2020 Mar 9;25(2):131-136. Epub 2020 Jan 9.

Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

: Transpulmonary biomarkers may provide insight into pulmonary hypertension (PH) pathophysiology, but require cardiac catheterization. We investigated whether the peripheral arterial-venous ratio (PR) could substitute for the transpulmonary ratio (TPR). Blood from the pulmonary artery (PA), pulmonary arterial wedge (PAW), peripheral venous, and peripheral arterial positions was analysed for ET-1, NT-pro-BNP and cAMP levels in subjects with no PH ( = 18) and PH due to left heart disease (PH-LHD), which included combined pre- and post-capillary PH (Cpc-PH;  = 7) and isolated post-capillary PH (Ipc-PH;  = 9). Bland-Altman comparisons were made between peripheral venous and PA samples and between peripheral arterial and PAW samples. TPR was defined as [PAW]/[PA]. For ET-1, Bland-Altman analysis indicated negative bias (-24%) in peripheral arterial compared to PAW concentration and positive bias (23%) in peripheral venous compared to PA concentration. There was <10% absolute bias for NT-pro-BNP and cAMP. For ET-1, there was no difference in PR between Cpc-PH and Ipc-PH (0.87 ± 0.4 0.94 ± 0.6,  = 0.8), whereas there was a difference in TPR (2.2 ± 1.1 1.1 ± 0.2,  < 0.05). In PH-LHD, peripheral samples may be inadequate surrogates for transpulmonary samples, particularly when measuring mediators with prominent pulmonary secretion or clearance, such as ET-1.
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http://dx.doi.org/10.1080/1354750X.2019.1710256DOI Listing
March 2020

Natriuretic peptide receptor C contributes to disproportionate right ventricular hypertrophy in a rodent model of obesity-induced heart failure with preserved ejection fraction with pulmonary hypertension.

Pulm Circ 2019 Oct-Dec;9(4):2045894019878599. Epub 2019 Dec 18.

Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Heart failure with preserved ejection fraction (HFpEF) currently has no therapies that improve mortality. Right ventricular dysfunction and pulmonary hypertension are common in HFpEF, and thought to be driven by obesity and metabolic syndrome. Thus, we hypothesized that an animal model of obesity-induced HFpEF with pulmonary hypertension would provide insight into the pathogenesis of right ventricular failure in HFpEF. Two strains of mice, one susceptible (AKR) and one resistant (C3H) to obesity-induced HFpEF, were fed high fat (60% fat) or control diet for 0, 2, or 20 weeks and evaluated by cardiac catheterization and echocardiography for development of right ventricular dysfunction, pulmonary hypertension, and HFpEF. AKR, but not C3H, mice developed right ventricular dysfunction, pulmonary hypertension, and HFpEF. , which antagonizes beneficial natriuretic peptide signaling, was found in RNA sequencing to be the most differentially upregulated gene in the right ventricle, but not left ventricle or lung, of AKR mice that developed pulmonary hypertension and HFpEF. Overexpression of in H9C2 cells increased basal cell size and increased expression of hypertrophic genes, and . In conclusion, we have shown that contributes to right ventricular modeling in obesity-induced pulmonary hypertension-HFpEF by increasing cardiomyocyte hypertrophy. may represent a promising therapeutic target for right ventricular dysfunction in pulmonary hypertension-HFpEF.
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http://dx.doi.org/10.1177/2045894019895452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923530PMC
December 2019

Metabolic syndrome, neurohumoral modulation, and pulmonary arterial hypertension.

Br J Pharmacol 2020 04 18;177(7):1457-1471. Epub 2020 Feb 18.

Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Pulmonary vascular disease, including pulmonary arterial hypertension (PAH), is increasingly recognized to be affected by systemic alterations including up-regulation of the renin-angiotensin-aldosterone system and perturbations to metabolic pathways, particularly glucose and fat metabolism. There is increasing preclinical and clinical data that each of these pathways can promote pulmonary vascular disease and right heart failure and are not simply disease markers. More recently, trials of therapeutics aimed at neurohormonal activation or metabolic dysfunction are beginning to shed light on how interventions in these pathways may affect patients with PAH. This review will focus on underlying mechanistic data that supports neurohormonal activation and metabolic dysfunction in the pathogenesis of PAH and right heart failure as well as discussing early translational data in patients with PAH.
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http://dx.doi.org/10.1111/bph.14968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060367PMC
April 2020

dysfunction impairs insulin signaling and glucose homeostasis in cardiomyocytes.

Am J Physiol Lung Cell Mol Physiol 2020 02 18;318(2):L429-L441. Epub 2019 Dec 18.

Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.

Insulin resistance and right ventricular (RV) dysfunction are associated with lipotoxicity in heritable forms of pulmonary arterial hypertension (PAH), commonly due to mutations in bone morphogenetic protein receptor type 2 (BMPR2). How BMPR2 dysfunction in cardiomyocytes alters glucose metabolism and the response of these cells to insulin are unknown. We hypothesized that BMPR2 mutation in cardiomyocytes alters glucose-supported mitochondrial respiration and impairs cellular responses to insulin, including glucose and lipid uptake. We performed metabolic assays, immunofluorescence and Western analysis, RNA profiling, and radioactive isotope uptake studies in H9c2 cardiomyocyte cell lines with and without patient-derived BMPR2 mutations (mutant cells), with and without insulin. Unlike control cells, BMPR2 mutant cardiomyocytes have reduced metabolic plasticity as indicated by reduced mitochondrial respiration with increased mitochondrial superoxide production. These mutant cells show enhanced baseline phosphorylation of insulin-signaling protein as indicated by increased Akt, AMPK, and acetyl-CoA carboxylase phosphorylation that may negatively influence fatty acid oxidation and enhance lipid uptake, and are insulin insensitive. Furthermore, mutant cells demonstrate an increase in milk fat globule-EGF factor-8 protein (MFGE8), which influences the insulin-signaling pathway by phosphorylating Akt via phosphatidylinositol 3-kinase and mammalian target of rapamycin. In conclusion, BMPR2 mutant cardiomyocytes have reduced metabolic plasticity and fail to respond to glucose. These cells have enhanced baseline insulin-signaling pattern favoring insulin resistance with failure to augment this pattern in response to insulin. BMPR2 mutation possibly blunts glucose uptake and enhances lipid uptake in these cardiomyocytes. The MFGE8-driven signaling pathway may suggest a new mechanism underlying RV lipotoxicity in PAH.
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http://dx.doi.org/10.1152/ajplung.00555.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052666PMC
February 2020

Association of Mild Echocardiographic Pulmonary Hypertension With Mortality and Right Ventricular Function.

JAMA Cardiol 2019 11;4(11):1112-1121

Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: Current guidelines recommend evaluation for echocardiographically estimated right ventricular systolic pressure (RVSP) greater than 40 mm Hg; however, this threshold does not capture all patients at risk.

Objectives: To determine if mild echocardiographic pulmonary hypertension (ePH) is associated with reduced right ventricular (RV) function and increased risk of mortality.

Design, Setting, And Participants: In this cohort study, electronic health record data of patients who were referred for echocardiography at Vanderbilt University Medical Center, Nashville, Tennessee, from March 1997 to February 2014 and had recorded estimates of RVSP values were studied. Data were analyzed from February 2017 to May 2019.

Exposures: Mild ePH was defined as an RVSP value of 33 to 39 mm Hg. Right ventricular function was assessed using tricuspid annular plane systolic excursion (TAPSE), and RV-pulmonary arterial coupling was measured using the ratio of TAPSE to RVSP.

Main Outcomes And Measures: Associations of mild ePH with mortality adjusted for relevant covariates were examined using Cox proportional hazard models with restricted cubic splines.

Results: Of the 47 784 included patients, 26 758 of 47 771 (56.0%) were female and 6040 of 44 763 (13.5%) were black, and the mean (SD) age was 59 (18) years. Patients with mild ePH had worse RV function compared with those with no ePH (mean [SD] TAPSE, 2.0 [0.6] cm vs 2.2 [0.5] cm; P < .001) and nearly double the prevalence of RV dysfunction (32.6% [92 of 282] vs 16.7% [170 of 1015]; P < .001). Compared with patients with RVSP less than 33 mm Hg, those with mild ePH also had reduced RV-pulmonary arterial coupling (mean [SD] ratio of TAPSE to RVSP, 0.55 [0.18] mm/mm Hg vs 0.93 [0.39] mm/mm Hg; P < .001). An increase in adjusted mortality began at an RVSP value of 27 mm Hg (hazard ratio, 1.32; 95% CI, 1.02-1.70). Female sex was associated with increased mortality risk at any given RVSP value.

Conclusions And Relevance: Mild ePH was associated with RV dysfunction and worse RV-pulmonary arterial coupling in a clinical population seeking care. Future studies are needed to identify patients with mild ePH who are susceptible to adverse outcomes.
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http://dx.doi.org/10.1001/jamacardio.2019.3345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751783PMC
November 2019

Moment on the Lips, a Lifetime on the Lungs?: Improving Models of Group 2 Pulmonary Hypertension.

Circ Res 2019 08 1;125(4):467-469. Epub 2019 Aug 1.

Divison of Allergy, Pulmonary and Critical Care Medicine (A.R.H.), Vanderbilt University Medical Center, TN.

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http://dx.doi.org/10.1161/CIRCRESAHA.119.315478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746245PMC
August 2019

Echocardiographic Detection of Occult Diastolic Dysfunction in Pulmonary Hypertension After Fluid Challenge.

J Am Heart Assoc 2019 09 31;8(17):e012504. Epub 2019 Aug 31.

Division of Cardiology Department of Medicine Vanderbilt University Medical Center Nashville TN.

Background Identification of occult diastolic dysfunction often requires invasive right heart catheterization with provocative maneuvers such as fluid challenge. Non-invasive predictors of occult diastolic dysfunction have not been identified. We hypothesized that echocardiographic measures of diastolic function are associated with occult diastolic dysfunction identified at catheterization. Methods and Results We retrospectively examined hemodynamic and echocardiographic data from consecutive patients referred for right heart catheterization with fluid challenge from 2009 to 2017. A replication cohort of 52 patients who prospectively underwent simultaneous echocardiography and right heart catheterization before and after fluid challenge at Monaldi Hospital, Naples, Italy. In the retrospective cohort of 126 patients (83% female, 56+14 years), 27/126 (21%) had occult diastolic dysfunction. After adjusting for tricuspid regurgitant velocity and left atrial volume index, E velocity (odds ratio 1.8, 95% CI 1.1-2.9, P=0.01) and E/e' (odds ratio 1.9, 95% CI 1.1-3, P=0.005) were associated with occult diastolic dysfunction with an optimal threshold of E/e' >8.6 for occult diastolic dysfunction (sensitivity 70%, specificity 64%). In the prospective cohort, 5/52 (10%) patients had diastolic dysfunction after fluid challenge. Resting E/e' (odds ratio 8.75, 95% CI 2.3-33, P=0.001) and E velocity (odds ratio 7.7, 95% CI 2-29, P=0.003) remained associated with occult diastolic dysfunction with optimal threshold of E/e' >8 (sensitivity 73%, specificity 90%). Conclusions Among patients referred for right heart catheterization with fluid challenge, E velocity and E/e' are associated with occult diastolic dysfunction after fluid challenge. These findings suggest that routine echocardiographic measurements may help identify patients like to have occult diastolic dysfunction non-invasively.
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http://dx.doi.org/10.1161/JAHA.119.012504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755835PMC
September 2019

Approach to a patient with pulmonary hypertension.

J Geriatr Cardiol 2019 Jun;16(6):478-481

Division of Cardiovascular Diseases, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.

Pulmonary hypertension is a common clinical condition that can complicate various cardiac and respiratory abnormalities. Interest in pulmonary hypertension has grown remarkably among the scientific community in the last decade. It is now clear based on the scientific advances have paved the way in understanding the effects of abnormal pulmonary hemodynamics development and its antecedent consequences on the right heart in reducing the quality of life and survival of the patient.
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http://dx.doi.org/10.11909/j.issn.1671-5411.2019.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612612PMC
June 2019

High rates of medication adherence in patients with pulmonary arterial hypertension: An integrated specialty pharmacy approach.

PLoS One 2019 6;14(6):e0217798. Epub 2019 Jun 6.

Vanderbilt Specialty Pharmacy Services, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.

Phosphodiesterase-5 inhibitors (PDE-5I) have demonstrated improvement in disease symptoms and quality of life for patients with pulmonary arterial hypertension (PAH). Despite these benefits, reported adherence to PDE-5I therapy is sub-optimal. Clinical pharmacists at an integrated practice site are in a unique position to mitigate barriers related to PAH therapy including medication adherence and costs. The primary objective of this study was to assess medication adherence to PDE-5I therapy within an integrated care model at an academic institution. The secondary objective was to assess the impact of out-of-pocket (OOP) cost, frequency of dosing, adverse events (AE) and PAH-related hospitalizations on medication adherence. We performed a retrospective cohort analysis of adult patients with PAH who were prescribed PDE-5I therapy by the center's outpatient pulmonary clinic and who received medication management through the center's specialty pharmacy. We defined optimal medication adherence as proportion of days covered (PDC) ≥ 80%. Clinical data including AEs and PAH-related hospitalizations were extracted from the electronic medical record, and financial data from pharmacy claims. Of the 131 patients meeting inclusion criteria, 94% achieved optimal adherence of ≥ 80% PDC. In this study population, 47% of patients experienced an AE and 27% had at least one hospitalization. The median monthly OOP cost was $0.62. Patients with PDC<80% were more likely to report an AE compared to patients with PDC≥ 80% (p = 0.002). Hospitalization, OOP cost, and frequency of dosing were not associated with adherence in this cohort. Patients receiving PDE-5I therapy through an integrated model achieved high adherence rates and low OOP costs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217798PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553732PMC
February 2020

CD44 and xCT: The Silver Bullet for Endothelial-to-Mesenchymal Transition in Pulmonary Arterial Hypertension?

Am J Respir Cell Mol Biol 2019 Sep;61(3):281-283

Department of MedicineVanderbilt University Medical CenterNashville, Tennessee.

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http://dx.doi.org/10.1165/rcmb.2019-0135EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839931PMC
September 2019

Human PAH is characterized by a pattern of lipid-related insulin resistance.

JCI Insight 2019 Jan 10;4(1). Epub 2019 Jan 10.

Cardiovascular Medicine Division, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Background: Pulmonary arterial hypertension (PAH) is a deadly disease of the small pulmonary vasculature with an increased prevalence of insulin resistance (IR). Insulin regulates both glucose and lipid homeostasis. We sought to quantify glucose- and lipid-related IR in human PAH, testing the hypothesis that lipoprotein indices are more sensitive indices of IR in PAH.

Methods: Oral glucose tolerance testing in PAH patients and triglyceride-matched (TG-matched) controls and proteomic, metabolomics, and lipoprotein analyses were performed in PAH and controls. Results were validated in an external cohort and in explanted human PAH lungs.

Results: PAH patients were similarly glucose intolerant or IR by glucose homeostasis metrics compared with control patients when matched for the metabolic syndrome. Using the insulin-sensitive lipoprotein index, TG/HDL ratio, PAH patients were more commonly IR than controls. Proteomic and metabolomic analysis demonstrated separation between PAH and controls, driven by differences in lipid species. We observed a significant increase in long-chain acylcarnitines, phosphatidylcholines, insulin metabolism-related proteins, and in oxidized LDL receptor 1 (OLR1) in PAH plasma in both a discovery and validation cohort. PAH patients had higher lipoprotein axis-related IR and lipoprotein-based inflammation scores compared with controls. PAH patient lung tissue showed enhanced OLR1 immunostaining within plexiform lesions and oxidized LDL accumulation within macrophages.

Conclusions: IR in PAH is characterized by alterations in lipid and lipoprotein homeostasis axes, manifest by elevated TG/HDL ratio, and elevated circulating medium- and long-chain acylcarnitines and lipoproteins. Oxidized LDL and its receptor OLR1 may play a role in a proinflammatory phenotype in PAH.

Funding: NIH DK096994, HL060906, UL1 RR024975-01, UL1 TR000445-06, DK020593, P01 HL108800-01A1, and UL1 TR002243; American Heart Association 13FTF16070002.
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http://dx.doi.org/10.1172/jci.insight.123611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485674PMC
January 2019
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