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A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension.
Hemnes AR, Rathinasabapathy A, Austin EA, Brittain EL, Carrier EJ, Chen X, Fessel JP, Fike CD, Fong P, Fortune N, Gerszten RE, Johnson JA, Kaplowitz M, Newman JH, Piana R, Pugh ME, Rice TW, Robbins IM, Wheeler L, Yu C, Loyd JE, West J
(2018) Eur Respir J 51:
MeSH Terms: Adult, Aged, Animals, Biomarkers, Cytokines, Female, Gene Expression, Humans, Hypertension, Pulmonary, Male, Middle Aged, Peptidyl-Dipeptidase A, Pilot Projects, Proof of Concept Study, Proto-Oncogene Proteins, Pulmonary Artery, Receptors, G-Protein-Coupled, Superoxide Dismutase, Swine, Vascular Resistance
Show Abstract · Added March 26, 2019
Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1-7) (Ang-(1-7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1-7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2-4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.
Copyright ©ERS 2018.
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20 MeSH Terms
The relationship between pulmonary artery wedge pressure and pulmonary blood volume derived from contrast echocardiography: A proof-of-concept study.
Monahan K, Lenihan D, Brittain EL, Saliba L, Piana RN, Robison LL, Hudson MM, Armstrong GT
(2018) Echocardiography 35: 1266-1270
MeSH Terms: Adult, Blood Volume, Cardiac Catheterization, Echocardiography, Female, Humans, Male, Middle Aged, Pulmonary Artery, Pulmonary Wedge Pressure, Reproducibility of Results
Show Abstract · Added June 7, 2018
BACKGROUND - Pulmonary transit time (PTT) obtained from contrast echocardiography is a marker of global cardiopulmonary function. Pulmonary blood volume (PBV), derived from PTT, may be a noninvasive surrogate for left-sided filling pressures, such as pulmonary artery wedge pressure (PAWP). We sought to assess the relationship between PBV obtained from contrast echocardiography and PAWP.
METHODS - Participants were adult survivors of childhood cancer that had contrast echocardiography performed nearly simultaneously with right-heart catheterization. PTT was derived from time-intensity curves of contrast passage through the right ventricle (RV) and left atrium (LA). PBV relative to overall stroke volume (rPBV) was estimated from the product of PTT and heart rate during RV-LA transit. PAWP was obtained during standard right-heart catheterization. The Spearman correlation coefficient was used to assess the relationship between rPBV and PAWP.
RESULTS - The study population consisted of 7 individuals who had contrast echocardiography and right-heart catheterization within 3 hours of each other. There was a wide range of right atrial (1-17 mm Hg), mean pulmonary artery (18-42 mm Hg), and PAW pressures (4-26 mm Hg) as well as pulmonary vascular resistance (<1-6 Wood Units). We observed a statistically significant correlation between rPBV and PAWP (r = .85; P = .02).
CONCLUSION - Relative PBV derived from contrast echocardiography correlates with PAWP. If validated in larger studies, rPBV could potentially be used as an alternative to invasively determine left-sided filling pressure.
© 2018 Wiley Periodicals, Inc.
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11 MeSH Terms
Diabetes Mellitus Associates with Increased Right Ventricular Afterload and Remodeling in Pulmonary Arterial Hypertension.
Whitaker ME, Nair V, Sinari S, Dherange PA, Natarajan B, Trutter L, Brittain EL, Hemnes AR, Austin ED, Patel K, Black SM, Garcia JGN, Yuan Md PhD JX, Vanderpool RR, Rischard F, Makino A, Bedrick EJ, Desai AA
(2018) Am J Med 131: 702.e7-702.e13
MeSH Terms: Diabetes Mellitus, Female, Heart Ventricles, Humans, Hypertension, Pulmonary, Male, Pulmonary Artery, Retrospective Studies, Risk Factors, Ventricular Dysfunction, Right, Ventricular Remodeling
Show Abstract · Added June 7, 2018
BACKGROUND - Diabetes mellitus is associated with left ventricular hypertrophy and dysfunction. Parallel studies have also reported associations between diabetes mellitus and right ventricular dysfunction and reduced survival in patients with pulmonary arterial hypertension. However, the impact of diabetes mellitus on the pulmonary vasculature has not been well characterized. We hypothesized that diabetes mellitus and hyperglycemia could specifically influence right ventricular afterload and remodeling in patients with Group I pulmonary arterial hypertension, providing a link to their known susceptibility to right ventricular dysfunction.
METHODS - Using an adjusted model for age, sex, pulmonary vascular resistance, and medication use, associations of fasting blood glucose, glycated hemoglobin, and the presence of diabetes mellitus were evaluated with markers of disease severity in 162 patients with pulmonary arterial hypertension.
RESULTS - A surrogate measure of increased pulmonary artery stiffness, elevated pulmonary arterial elastance (P = .012), along with reduced log(pulmonary artery capacitance) (P = .006) were significantly associated with the presence of diabetes mellitus in patients with pulmonary arterial hypertension in a fully adjusted model. Similar associations between pulmonary arterial elastance and capacitance were noted with both fasting blood glucose and glycated hemoglobin. Furthermore, right ventricular wall thickness on echocardiography was greater in pulmonary arterial hypertension patients with diabetes, supporting the link between right ventricular remodeling and diabetes.
CONCLUSION - Cumulatively, these data demonstrate that an increase in right ventricular afterload, beyond pulmonary vascular resistance alone, may influence right ventricular remodeling and provide a mechanistic link between the susceptibility to right ventricular dysfunction in patients with both diabetes mellitus and pulmonary arterial hypertension.
Copyright © 2018 Elsevier Inc. All rights reserved.
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11 MeSH Terms
Redefining pulmonary hypertension.
Maron BA, Brittain EL, Choudhary G, Gladwin MT
(2018) Lancet Respir Med 6: 168-170
MeSH Terms: Arterial Pressure, Diagnostic Errors, Humans, Hypertension, Pulmonary, Pulmonary Artery, Reference Standards, Respiratory Function Tests
Added June 7, 2018
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7 MeSH Terms
Increased Echocardiographic Pulmonary Pressure in HIV-infected and -uninfected Individuals in the Veterans Aging Cohort Study.
Brittain EL, Duncan MS, Chang J, Patterson OV, DuVall SL, Brandt CA, So-Armah KA, Goetz M, Akgun K, Crothers K, Zola C, Kim J, Gibert C, Pisani M, Morris A, Hsue P, Tindle HA, Justice A, Freiberg M
(2018) Am J Respir Crit Care Med 197: 923-932
MeSH Terms: Adult, Aged, Aging, Cohort Studies, Comorbidity, Echocardiography, Female, HIV Infections, Humans, Hypertension, Pulmonary, Male, Middle Aged, Prevalence, Prospective Studies, Pulmonary Artery, Risk Factors, United States, Veterans
Show Abstract · Added February 7, 2018
RATIONALE - The epidemiology and prognostic impact of increased pulmonary pressure among HIV-infected individuals in the antiretroviral therapy era is not well described.
OBJECTIVES - To examine the prevalence, clinical features, and outcomes of increased echocardiographic pulmonary pressure in HIV-infected and -uninfected individuals.
METHODS - This study evaluated 8,296 veterans referred for echocardiography with reported pulmonary artery systolic pressure (PASP) estimates from the Veterans Aging Cohort study, an observational cohort of HIV-infected and -uninfected veterans matched by age, sex, race/ethnicity, and clinical site. The primary outcome was adjusted mortality by HIV status.
MEASUREMENTS AND MAIN RESULTS - PASP was reported in 2,831 HIV-infected and 5,465 HIV-uninfected veterans (follow-up [mean ± SD], 3.8 ± 2.6 yr). As compared with uninfected veterans, HIV-infected veterans with HIV viral load greater than 500 copies/ml (odds ratio, 1.27; 95% confidence interval [CI], 1.05-1.54) and those with CD4 cell count less than 200 cells/μl (odds ratio, 1.28; 95% CI, 1.02-1.60) had a higher prevalence of PASP greater than or equal to 40 mm Hg. As compared with uninfected veterans with a PASP less than 40 mm Hg, HIV-infected veterans with a PASP greater than or equal to 40 mm Hg had an increased risk of death (adjusted hazard ratio, 1.78; 95% CI, 1.57-2.01). This risk persisted even among participants without prevalent comorbidities (adjusted hazard ratio, 3.61; 95% CI, 2.17-6.01). The adjusted risk of mortality in HIV-infected veterans was higher at all PASP values than in uninfected veterans, including at values currently considered to be normal.
CONCLUSIONS - HIV-infected people with high HIV viral loads or low CD4 cell counts have a higher prevalence of increased PASP than uninfected people. Mortality risk in HIV-infected veterans increases at lower values of PASP than previously recognized and is present even among those without prevalent comorbidities. These findings may inform clinical decision-making regarding screening and surveillance of pulmonary hypertension in HIV-infected individuals.
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18 MeSH Terms
Prognostic Effect and Longitudinal Hemodynamic Assessment of Borderline Pulmonary Hypertension.
Assad TR, Maron BA, Robbins IM, Xu M, Huang S, Harrell FE, Farber-Eger EH, Wells QS, Choudhary G, Hemnes AR, Brittain EL
(2017) JAMA Cardiol 2: 1361-1368
MeSH Terms: Aged, Blood Pressure, Cardiac Catheterization, Cohort Studies, Echocardiography, Female, Hemodynamics, Humans, Hypertension, Pulmonary, Logistic Models, Longitudinal Studies, Male, Middle Aged, Mortality, Prognosis, Proportional Hazards Models, Pulmonary Artery, Pulmonary Wedge Pressure, Retrospective Studies, Survival Rate, United States
Show Abstract · Added June 7, 2018
Importance - Pulmonary hypertension (PH) is diagnosed by a mean pulmonary arterial pressure (mPAP) value of at least 25 mm Hg during right heart catheterization (RHC). While several studies have demonstrated increased mortality in patients with mPAP less than that threshold, little is known about the natural history of borderline PH.
Objective - To test the hypothesis that patients with borderline PH have decreased survival compared with patients with lower mPAP and frequently develop overt PH and to identify clinical correlates of borderline PH.
Design, Setting, and Participants - Retrospective cohort study from 1998 to 2014 at Vanderbilt University Medical Center, comprising all patients undergoing routine RHC for clinical indication. We extracted demographics, clinical data, invasive hemodynamics, echocardiography, and vital status for all patients. Patients with mPAP values of 18 mm Hg or less, 19 to 24 mm Hg, and at least 25 mm Hg were classified as reference, borderline PH, and PH, respectively.
Exposures - Mean pulmonary arterial pressure.
Main Outcome and Measures - Our primary outcome was all-cause mortality after adjusting for clinically relevant covariates in a Cox proportional hazards model. Our secondary outcome was the diagnosis of overt PH in patients initially diagnosed with borderline PH. Both outcomes were determined prior to data analysis.
Results - We identified 4343 patients (mean [SD] age, 59 [15] years, 51% women, and 86% white) among whom the prevalence of PH and borderline PH was 62% and 18%, respectively. Advanced age, features of the metabolic syndrome, and chronic heart and lung disease were independently associated with a higher likelihood of borderline PH compared with reference patients in a logistic regression model. After adjusting for 34 covariates in a Cox proportional hazards model, borderline PH was associated with increased mortality compared with reference patients (hazard ratio, 1.31; 95% CI, 1.04-1.65; P = .001). The hazard of death increased incrementally with higher mPAP, without an observed threshold. In the 70 patients with borderline PH who underwent a repeated RHC, 43 (61%) had developed overt PH, with a median increase in mPAP of 5 mm Hg (interquartile range, -1 to 11 mm Hg; P < .001).
Conclusions and Relevance - Borderline PH is common in patients undergoing RHC and is associated with significant comorbidities, progression to overt PH, and decreased survival. Small increases in mPAP, even at values currently considered normal, are independently associated with increased mortality. Prospective studies are warranted to determine whether early intervention or closer monitoring improves clinical outcomes in these patients.
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21 MeSH Terms
Isolation and characterization of endothelial-to-mesenchymal transition cells in pulmonary arterial hypertension.
Suzuki T, Carrier EJ, Talati MH, Rathinasabapathy A, Chen X, Nishimura R, Tada Y, Tatsumi K, West J
(2018) Am J Physiol Lung Cell Mol Physiol 314: L118-L126
MeSH Terms: Animals, Antigens, CD, Cadherins, Cells, Cultured, Endothelium, Vascular, Epithelial-Mesenchymal Transition, Female, Gene Expression Profiling, Humans, Hypertension, Pulmonary, Mice, Mice, Inbred C57BL, Mice, Transgenic, Pulmonary Artery
Show Abstract · Added March 26, 2019
Endothelial-to-mesenchymal transition (EndMT) is a process in which endothelial cells lose polarity and cell-to cell contacts, and undergo a dramatic remodeling of the cytoskeleton. It has been implicated in initiation and progression of pulmonary arterial hypertension (PAH). However, the characteristics of cells which have undergone EndMT cells in vivo have not been reported and so remain unclear. To study this, sugen5416 and hypoxia (SuHx)-induced PAH was established in Cdh5-Cre/Gt(ROSA)26Sor/J double transgenic mice, in which GFP was stably expressed in pan-endothelial cells. After 3 wk of SuHx, flow cytometry and immunohistochemistry demonstrated CD144-negative and GFP-positive cells (complete EndMT cells) possessed higher proliferative and migratory activity compared with other mesenchymal cells. While CD144-positive and α-smooth muscle actin (α-SMA)-positive cells (partial EndMT cells) continued to express endothelial progenitor cell markers, complete EndMT cells were Sca-1-rich mesenchymal cells with high proliferative and migratory ability. When transferred in fibronectin-coated chamber slides containing smooth muscle media, α-SMA robustly expressed in these cells compared with cEndMT cells that were grown in maintenance media. Demonstrating additional paracrine effects, conditioned medium from isolated complete EndMT cells induced enhanced mesenchymal proliferation and migration and increased angiogenesis compared with conditioned medium from resident mesenchymal cells. Overall, these findings show that EndMT cells could contribute to the pathogenesis of PAH both directly, by transformation into smooth muscle-like cells with higher proliferative and migratory potency, and indirectly, through paracrine effects on vascular intimal and medial proliferation.
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MeSH Terms
Echocardiographic Pulmonary Artery Systolic Pressure in the Coronary Artery Risk Development in Young Adults (CARDIA) Study: Associations With Race and Metabolic Dysregulation.
Brittain EL, Nwabuo C, Xu M, Gupta DK, Hemnes AR, Moreira HT, De Vasconcellos HD, Terry JG, Carr JJ, Lima JA
(2017) J Am Heart Assoc 6:
MeSH Terms: African Americans, Age Factors, Blood Pressure, C-Reactive Protein, Cohort Studies, Coronary Artery Disease, Echocardiography, Echocardiography, Doppler, Ethnic Groups, European Continental Ancestry Group, Female, Humans, Hypertension, Hypertension, Pulmonary, Insulin Resistance, Interleukin-6, Intra-Abdominal Fat, Male, Metabolic Syndrome, Middle Aged, Overweight, Pulmonary Artery, Systole, Tissue Survival, Tomography, X-Ray Computed
Show Abstract · Added September 11, 2017
BACKGROUND - The determinants of pulmonary artery systolic pressure (PASP) are not fully understood. It is unknown whether racial differences in PASP exist or if other population characteristics are associated with pulmonary pressure in humans. We examined echocardiographically estimated PASP in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a middle-aged, biracial community-based cohort.
METHODS AND RESULTS - At the CARDIA year-25 examination, 3469 participants underwent echocardiography, including measurement of tricuspid regurgitant jet velocity to estimate PASP. Clinical features, laboratory values, pulmonary function tests, and measurement of adipose depot volume were analyzed for association with PASP. PASP was estimated in 1311 individuals (61% female, 51% white). Older age, higher blood pressure, and higher body mass index were associated with higher PASP. Black race was associated with higher PASP after adjustment for demographics and left and right ventricular function (β 0.94, 95% CI 0.24-1.64; =0.009), but this association was no longer significant after further adjustment for lung volume (β 0.42, 95% CI -0.68 to 0.96; =0.74). Insulin resistance, inflammation (C-reactive protein and interleukin-6), and visceral adipose volume were independently associated with higher PASP after adjustment for relevant covariates. PASP rose with worsening diastolic function (ratio of early transmitral Doppler velocity to average mitral annular tissue Doppler velocity [E/e'] and left atrial volume index).
CONCLUSIONS - In a large biracial cohort of middle-aged adults, we identified associations among black race, insulin resistance, and diastolic dysfunction with higher echocardiographically estimated PASP. Further studies are needed to examine racial differences in PASP and whether insulin resistance directly contributes to pulmonary vascular disease in humans.
© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
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25 MeSH Terms
The Endothelial Prolyl-4-Hydroxylase Domain 2/Hypoxia-Inducible Factor 2 Axis Regulates Pulmonary Artery Pressure in Mice.
Kapitsinou PP, Rajendran G, Astleford L, Michael M, Schonfeld MP, Fields T, Shay S, French JL, West J, Haase VH
(2016) Mol Cell Biol 36: 1584-94
MeSH Terms: Animals, Arterial Pressure, Cell Hypoxia, Disease Models, Animal, Hypertension, Pulmonary, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases, Mice, Mutation, Pulmonary Artery, Signal Transduction, Transcription Factors
Show Abstract · Added March 16, 2016
Hypoxia-inducible factors 1 and 2 (HIF-1 and -2) control oxygen supply to tissues by regulating erythropoiesis, angiogenesis and vascular homeostasis. HIFs are regulated in response to oxygen availability by prolyl-4-hydroxylase domain (PHD) proteins, with PHD2 being the main oxygen sensor that controls HIF activity under normoxia. In this study, we used a genetic approach to investigate the endothelial PHD2/HIF axis in the regulation of vascular function. We found that inactivation of Phd2 in endothelial cells specifically resulted in severe pulmonary hypertension (∼118% increase in right ventricular systolic pressure) but not polycythemia and was associated with abnormal muscularization of peripheral pulmonary arteries and right ventricular hypertrophy. Concurrent inactivation of either Hif1a or Hif2a in endothelial cell-specific Phd2 mutants demonstrated that the development of pulmonary hypertension was dependent on HIF-2α but not HIF-1α. Furthermore, endothelial HIF-2α was required for the development of increased pulmonary artery pressures in a model of pulmonary hypertension induced by chronic hypoxia. We propose that these HIF-2-dependent effects are partially due to increased expression of vasoconstrictor molecule endothelin 1 and a concomitant decrease in vasodilatory apelin receptor signaling. Taken together, our data identify endothelial HIF-2 as a key transcription factor in the pathogenesis of pulmonary hypertension.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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12 MeSH Terms
Endothelial HIF signaling regulates pulmonary fibrosis-associated pulmonary hypertension.
Bryant AJ, Carrick RP, McConaha ME, Jones BR, Shay SD, Moore CS, Blackwell TR, Gladson S, Penner NL, Burman A, Tanjore H, Hemnes AR, Karwandyar AK, Polosukhin VV, Talati MA, Dong HJ, Gleaves LA, Carrier EJ, Gaskill C, Scott EW, Majka SM, Fessel JP, Haase VH, West JD, Blackwell TS, Lawson WE
(2016) Am J Physiol Lung Cell Mol Physiol 310: L249-62
MeSH Terms: Animals, Cell Proliferation, Cells, Cultured, Endothelial Cells, Endothelium, Vascular, Fibrosis, Hypertension, Pulmonary, Hypoxia, Hypoxia-Inducible Factor 1, Mice, Transgenic, Muscle, Smooth, Vascular, Pulmonary Artery, Vascular Remodeling
Show Abstract · Added February 16, 2016
Pulmonary hypertension (PH) complicating chronic parenchymal lung disease, such as idiopathic pulmonary fibrosis, results in significant morbidity and mortality. Since the hypoxia-inducible factor (HIF) signaling pathway is important for development of pulmonary hypertension in chronic hypoxia, we investigated whether HIF signaling in vascular endothelium regulates development of PH related to pulmonary fibrosis. We generated a transgenic model in which HIF is deleted within vascular endothelial cells and then exposed these mice to chronic intraperitoneal bleomycin to induce PH associated with lung fibrosis. Although no differences in the degree of fibrotic remodeling were observed, we found that endothelial HIF-deficient mice were protected against development of PH, including right ventricle and pulmonary vessel remodeling. Similarly, endothelial HIF-deficient mice were protected from PH after a 4-wk exposure to normobaric hypoxia. In vitro studies of pulmonary vascular endothelial cells isolated from the HIF-targeted mice and controls revealed that endothelial HIF signaling increases endothelial cell expression of connective tissue growth factor, enhances vascular permeability, and promotes pulmonary artery smooth muscle cell proliferation and wound healing ability, all of which have the potential to impact the development of PH in vivo. Taken together, these studies demonstrate that vascular endothelial cell HIF signaling is necessary for development of hypoxia and pulmonary fibrosis associated PH. As such, HIF and HIF-regulated targets represent a therapeutic target in these conditions.
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13 MeSH Terms