76 results on '"Bull TM"'
Search Results
2. Age-related differences in hemodynamics and functional status in pulmonary arterial hypertension: Baseline results from the Pulmonary Hypertension Association Registry
- Author
-
DesJardin, Jacqueline T., primary, Kolaitis, Nicholas A., additional, Kime, Noah, additional, Kronmal, Richard A., additional, Benza, Raymond L., additional, Elwing, Jean M., additional, Lammi, Matthew R., additional, McConnell, John W., additional, Presberg, Kenneth W., additional, Sager, Jeffrey S., additional, Shlobin, Oksana A., additional, De Marco, Teresa, additional, Allen, Roblee, additional, Badesch, David, additional, Bakshi, Sahil, additional, Bartolome, Sonja, additional, Bull, TM, additional, Burger, Charles D, additional, Cadaret, Linda M, additional, Chakinala, Murali, additional, Duncan, Michael, additional, Eggert, Michael, additional, Feldman, Jeremy, additional, Fineman, Jeff, additional, Foley, Raymond J., additional, Ford, Hubert James, additional, Frantz, Robert P, additional, Grinnan, Daniel, additional, Hemnes, Anna R, additional, Hirsch, Russel, additional, Horn, Evelyn M, additional, Ivy, D Dunbar, additional, Kawut, Steven M, additional, Klinger, James R, additional, Leary, Peter J, additional, Mathai, Stephen C, additional, Mazimba, Sula, additional, Parikh, Kishan S, additional, Presberg, Kenneth W, additional, Raina, Amresh, additional, Ramani, Gautam, additional, Robinson, Jeffrey C, additional, Rosenzweig, Erika B, additional, Runo, James R, additional, Ryan, John J, additional, Sager, Jeffrey S, additional, Shlobin, Oksana A, additional, Simon, Marc A, additional, Swisher, John W, additional, Thenappan, Thenappan, additional, Varghese, Nidhy P, additional, Ventetuolo, Corey E, additional, White, R. James, additional, Williamson, Timothy, additional, Yung, Delphine, additional, Zamanian, Roham T, additional, and Zwicke, Dianne L, additional
- Published
- 2020
- Full Text
- View/download PDF
3. Clinical use of extended-release oral treprostinil in the treatment of pulmonary arterial hypertension
- Author
-
Pugliese SC and Bull TM
- Subjects
lcsh:Internal medicine ,Oral Treprostinil Pulmonary Arterial Hypertension Selexipeg ,lcsh:RC31-1245 - Abstract
Steven C Pugliese,1 Todd M Bull1,2 1Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, 2UCD Pulmonary Vascular Disease Center, Division of Pulmonary Sciences and Critical Care Medicine and Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA Abstract: The development of parenteral prostacyclin therapy marked a dramatic breakthrough in the treatment of pulmonary arterial hypertension (PAH). Intravenous (IV) epoprostenol was the first PAH specific therapy and to date, remains the only treatment to demonstrate a mortality benefit. Because of the inherent complexities and risks of treating patients with continuous infusion IV therapy, there is great interest in the development of an oral prostacyclin analog that could mimic the benefits of IV therapy. Herein, we highlight the development of oral prostacyclin therapy, focusing on oral treprostinil, the only US Food and Drug Administration approved oral prostacyclin. Recent Phase III clinical trials have shown the drug to improve exercise tolerance in treatment-naïve PAH patients, but not patients on background oral therapy. Oral treprostinil appears to be most efficacious at higher doses, but its side effect profile and complexities with dosing complicate its use. While oral treprostinil’s current therapeutic role in PAH remains unclear, ongoing studies of this class of medication should help clarify their role in the treatment of PAH. Keywords: oral treprostinil, pulmonary arterial hypertension, selexipag
- Published
- 2016
4. Gene Microarray Expression Analysis of Peripheral Blood Cells in Scleroderma-Associated Pulmonary Hypertension.
- Author
-
Risbano, MG, primary, Meadows, CA, additional, Coldren, CD, additional, DeSilva, WL, additional, Geraci, MW, additional, and Bull, TM, additional
- Published
- 2009
- Full Text
- View/download PDF
5. Growth-Differentiation Factor-15 in Scleroderma Associated Pulmonary Hypertension.
- Author
-
Risbano, MG, primary, Meadows, CA, additional, Geraci, MW, additional, Zhang, L, additional, Tuder, TM, additional, and Bull, TM, additional
- Published
- 2009
- Full Text
- View/download PDF
6. Prostacyclin prevents pulmonary endothelial cell apoptosis induced by cigarette smoke.
- Author
-
Nana-Sinkam SP, Lee JD, Sotto-Santiago S, Stearman RS, Keith RL, Choudhury Q, Cool C, Parr J, Moore MD, Bull TM, Voelkel NF, Geraci MW, Nana-Sinkam, S Patrick, Lee, Jong Deog, Sotto-Santiago, Sylk, Stearman, Robert S, Keith, Robert L, Choudhury, Qamrul, Cool, Carlyne, and Parr, Jane
- Abstract
Rationale: Impaired endothelial cell-dependent vasodilation, inflammation, apoptosis, and proliferation are manifestations of endothelial dysfunction in chronic obstructive pulmonary disease (COPD). Prostacyclin (PGI(2)) is a major product of the cyclooxygenase pathway with potent vasodilatory and antimitogenic properties and may be relevant to endothelial dysfunction in COPD.Objectives: To determine if PGI(2) expression is altered in smoking-related lung disease and if it may be protective in COPD-associated endothelial dysfunction.Methods: We evaluated, by immunohistochemistry, Western blotting, and polymerase chain reaction, human emphysema tissue compared with normal tissue for expression of prostacyclin synthase (PGI(2)S). We examined the effects of cigarette smoke extract (CSE) and aldehyde components on eicosanoid expression in primary human pulmonary microvascular endothelial cells. Finally, we used a murine model of lung-specific PGI(2)S overexpression and in vitro studies to determine if PGI(2) expression has protective effects on cigarette smoke-induced endothelial apoptosis.Measurements and Main Results: Human emphysema lung tissue exhibited lower PGI(2)S expression within the pulmonary endothelium than in normal lung. In vitro studies demonstrated that CSE, and in particular the alpha,beta unsaturated aldehyde acrolein, suppressed PGI(2)S gene expression, whereas CSE significantly induced the upstream mediators COX-2 and cytosolic phospholipase A2 in human pulmonary microvascular endothelial cells. Mice with lung-specific PGI(2)S overexpression exhibited less endothelial apoptosis after chronic smoke exposure. In vitro, iloprost exhibited protective effects on CSE-induced apoptosis.Conclusions: PGI(2) has protective effects in the pulmonary vasculature after acute and chronic cigarette smoke exposure. An imbalance in eicosanoid expression may be important to COPD-associated endothelial dysfunction. [ABSTRACT FROM AUTHOR]- Published
- 2007
- Full Text
- View/download PDF
7. Gene microarray analysis of peripheral blood cells in pulmonary arterial hypertension.
- Author
-
Bull TM, Coldren CD, Moore M, Sotto-Santiago SM, Pham DV, Nana-Sinkam SP, Voelkel NF, and Geraci MW
- Abstract
The importance of genetic predisposition, inflammation, and autoimmune mechanisms in the development of pulmonary arterial hypertension (PAH) is becoming increasingly clear. We hypothesized that the analysis of gene expression profiles from peripheral blood mononuclear cells would distinguish patients with PAH from normal volunteers. We also hypothesized that a subset of genes would discriminate between patients with idiopathic PAH and pulmonary hypertension related to secondary causes. Mononuclear cells were isolated from 15 patients diagnosed with PAH and 6 normal control subjects. Microarray expression was performed, and the expression profiles were analyzed for consistent and predictive differences in gene expression. We identified a signature set of 106 genes that discriminated with high certainty (p < or = 0.002) between patients with PAH and normal individuals. The results of the microarray analysis were retrospectively and prospectively confirmed by quantitative polymerase chain reaction for 2 of the 106 genes. Supervised clustering analysis generated a list of differentially expressed genes between patients with idiopathic and secondary causes of pulmonary hypertension. Microarray expression profiling of peripheral blood cells can discriminate between patients with PAH and normal volunteers. These findings may have important implications toward diagnosis, screening, and pathogenesis of this disease. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
8. Expression of human herpesvirus 8 in primary pulmonary hypertension.
- Author
-
Cool CD, Rai PR, Yeager ME, Hernandez-Saavedra D, Serls AE, Bull TM, Geraci MW, Brown KK, Routes JM, Tuder RM, and Voelkel NF
- Published
- 2003
9. The effects of oxygenation on acute vasodilator challenge in pulmonary arterial hypertension.
- Author
-
Rockstrom MD, Jin Y, Peterson RA, Hountras P, Badesch D, Gu S, Park B, Messenger J, Forbes LM, Cornwell WK 3rd, and Bull TM
- Abstract
Identification of long-term calcium channel blocker (CCB) responders with acute vasodilator challenge is critical in the evaluation of patients with pulmonary arterial hypertension. Currently there is no standardized approach for use of supplemental oxygen during acute vasodilator challenge. In this retrospective analysis of patients identified as acute vasoresponders, treated with CCBs, all patients had hemodynamic measurements in three steps: (1) at baseline; (2) with 100% fractional inspired oxygen; and (3) with 100% fractional inspired oxygen plus inhaled nitric oxide (iNO). Those meeting the definition of acute vasoresponsiveness only after first normalizing for the effects of oxygen in step 2 were labeled "iNO Responders." Those who met the definition of acute vasoresponsiveness from a combination of the effects of 100% FiO
2 and iNO were labeled "oxygen responders." Survival, hospitalization for decompensated right heart failure, duration of CCB monotherapy, and functional data were collected. iNO responders, when compared to oxygen responders, had superior survival (100% vs. 50.1% 5-year survival, respectively), fewer hospitalizations for acute decompensated right heart failure (0% vs. 30.4% at 1 year, respectively), longer duration of CCB monotherapy (80% vs. 52% at 1 year, respectively), and superior 6-min walk distance. Current guidelines for acute vasodilator testing do not standardize oxygen coadministration with iNO. This study demonstrates that adjusting for the effects of supplemental oxygen before assessing for acute vasoresponsiveness identifies a cohort with superior functional status, tolerance of CCB monotherapy, and survival while on long-term CCB therapy., Competing Interests: We have no financial disclosures or conflicts of interest to report., (© 2024 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)- Published
- 2024
- Full Text
- View/download PDF
10. Reduced mortality associated with pulmonary embolism response team consultation for intermediate and high-risk pulmonary embolism: a retrospective cohort study.
- Author
-
Gardner TA, Fuher A, Longino A, Sink EM, Jurica J, Park B, Lindquist J, Bull TM, and Hountras P
- Abstract
Background: The management of acute pulmonary embolism (PE) has become increasingly complex with the expansion of advanced therapeutic options, resulting in the development and widespread adoption of multidisciplinary Pulmonary Embolism Response Teams (PERTs). Much of the literature evaluating the impact of PERTs has been limited by pre- postimplementation study design, leading to confounding by changes in global practice patterns over time, and has yielded mixed results. To address this ambiguity, we conducted a retrospective cohort study to evaluate the impact of the distinct exposures of PERT availability and direct PERT consultation., Methods: At a single tertiary center, we conducted propensity-matched analyses of hospitalized patients with intermediate or high-risk PE. To assess the impact of PERT availability, we evaluated the changes in 30-day mortality, hospital length of stay (HLOS), time to therapeutic anticoagulation (TAC), in-hospital bleeding complications, and use of advanced therapies between the two years preceding and following PERT implementation. To evaluate the impact of direct PERT consultation, we conducted the same analyses in the post-PERT era, comparing patients who did and did not receive PERT consultation., Results: Six hundred eighty four patients were included, of which 315 were pre-PERT patients. Of the 367 postPERT patients, 201 received PERT consultation. For patients who received PERT consultation, we observed a significant reduction in 30-day mortality (5% vs 20%, OR 0.38, p = 0.0024), HLOS. (-5.4 days, p < 0.001), TAC (-0.25 h, p = 0.041), and in-hospital bleeding (OR 0.28, p = 0.011). These differences were not observed evaluating the impact of PERT presence in pre-vs postimplementation eras., Conclusions: We observed a significant reduction in 30-day mortality, hospital LOS, TAC, and in-hospital bleeding complications for patients who received PERT consultation without an observed difference in these metrics when comparing the pre- vs post-implementation eras. This suggests the benefits stem from direct PERT involvement rather than the mere existence of PERT. Our data supports that PERT consultation may provide benefit to patients with acute intermediate or high-risk PE and can be achieved without a concomitant increase in advanced therapies., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
11. Characterization of pulmonary arterial stiffness using cardiac MRI.
- Author
-
Cain MT, Schäfer M, Park S, Barker AJ, Vargas D, Stenmark KR, Yu YA, Bull TM, Ivy DD, and Hoffman JRH
- Subjects
- Humans, Cardiac Catheterization methods, Predictive Value of Tests, Pulmonary Artery, Magnetic Resonance Imaging, Ventricular Function, Right, Vascular Stiffness, Hypertension, Pulmonary diagnostic imaging
- Abstract
Pulmonary arterial stiffness (PAS) is a pathologic hallmark of all types of pulmonary hypertension (PH). Cardiac MRI (CMR), a gold-standard imaging modality for the evaluation of pulmonary flow, biventricular morphology and function has been historically reserved for the longitudinal clinical follow-up, PH phenotyping purposes, right ventricular evaluation, and research purposes. Over the last two decades, numerous indices combining invasive catheterization and non-invasive CMR have been utilized to phenotype the character and severity of PAS in different types of PH and to assess its clinically prognostic potential with encouraging results. Many recent studies have demonstrated a strong role of CMR derived PAS markers in predicting long-term clinical outcomes and improving currently gold standard risk assessment provided by the REVEAL calculator. With the utilization of a machine learning strategies, strong diagnostic and prognostic performance of CMR reported in multicenter studies, and ability to detect PH at early stages, the non-invasive assessment of PAS is on verge of routine clinical utilization. In this review, we focus on appraising important CMR studies interrogating PAS over the last 20 years, describing the benefits and limitations of different PAS indices, and their pathophysiologic relevance to pulmonary vascular remodeling. We also discuss the role of CMR and PAS in clinical surveillance and phenotyping of PH, and the long-term future goal to utilize PAS as a biomarker to aid with more targeted therapeutic management., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)
- Published
- 2024
- Full Text
- View/download PDF
12. 4D-Flow MRI intracardiac flow analysis considering different subtypes of pulmonary hypertension.
- Author
-
Cain MT, Schäfer M, Ross LK, Ivy DD, Mitchell MB, Fenster BE, Bull TM, Barker AJ, Vargas D, and Hoffman JRH
- Abstract
Intracardiac flow hemodynamic patterns have been considered to be an early sign of diastolic dysfunction. In this study we investigated right ventricular (RV) diastolic dysfunction between patients with pulmonary arterial hypertension (PAH) and pulmonary hypertension with chronic lung disease (PH-CLD) via 4D-Flow cardiac MRI (CMR). Patients underwent prospective, comprehensive CMR for function and size including 4D-Flow CMR protocol for intracardiac flow visualization and analysis. RV early filling phase and peak atrial phase vorticity (E-vorticity and A-vorticity) values were calculated in all patients. Patients further underwent comprehensive Doppler and tissue Doppler evaluation for the RV diastolic dysfunction. In total 13 patients with PAH, 15 patients with PH-CLD, and 10 control subjects underwent the 4D-Flow CMR and echocardiography evaluation for RV diastolic dysfunction. Reduced E-vorticity differentiated PAH and PH-CLD from healthy controls (both p < 0.01) despite the same Doppler E values. E-vorticity was further decreased in PAH patients when compared to PH-CLD group ( p < 0.05) with similar Doppler and tissue Doppler markers of diastolic dysfunction. A-vorticity was decreased in both PAH and PH-CLD groups compared to controls but with no difference between the disease groups. E-vorticity correlated with ejection fraction ( R = 0.60, p < 0.001), end-systolic volume ( R = 0.50, p = 0.001), stroke volume ( R = 0.42, p = 0.007), and cardiac output ( R = 0.30, p = 0.027). Intracardiac flow analysis using 4D-Flow CMR derived vorticity is a sensitive method to differentiate diastolic dysfunction in patients with different PH etiology and similar Doppler echocardiography profile., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)
- Published
- 2023
- Full Text
- View/download PDF
13. Exercise Testing in the Risk Assessment of Pulmonary Hypertension.
- Author
-
Forbes LM, Bull TM, Lahm T, Make BJ, and Cornwell WK 3rd
- Subjects
- Humans, Exercise Test methods, Pulmonary Circulation, Risk Assessment, Ventricular Function, Right physiology, Hypertension, Pulmonary, Ventricular Dysfunction, Right etiology, Ventricular Dysfunction, Right complications
- Abstract
Topic Importance: Right ventricular dysfunction in pulmonary hypertension (PH) contributes to reduced exercise capacity, morbidity, and mortality. Exercise can unmask right ventricular dysfunction not apparent at rest, with negative implications for prognosis., Review Findings: Among patients with pulmonary vascular disease, right ventricular afterload may increase during exercise out of proportion to increases observed among healthy individuals. Right ventricular contractility must increase to match the demands of increased afterload to maintain ventricular-arterial coupling (the relationship between contractility and afterload) and ultimately cardiac output. Impaired right ventricular contractile reserve leads to ventricular-arterial uncoupling, preventing cardiac output from increasing during exercise and limiting exercise capacity. Abnormal pulmonary vascular response to exercise can signify early pulmonary vascular disease and is associated with increased mortality. Impaired right ventricular contractile reserve similarly predicts poor outcomes, including reduced exercise capacity and death. Exercise provocation can be used to assess pulmonary vascular response to exercise and right ventricular contractile reserve. Noninvasive techniques (including cardiopulmonary exercise testing, transthoracic echocardiography, and cardiac MRI) as well as invasive techniques (including right heart catheterization and pressure-volume analysis) may be applied selectively to the screening, diagnosis, and risk stratification of patients with suspected or established PH. Further research is required to determine the role of exercise stress testing in the management of pulmonary vascular disease., Summary: This review describes the current understanding of clinical applications of exercise testing in the risk assessment of patients with suspected or established PH., (Copyright © 2023 American College of Chest Physicians. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
14. Right Ventricular Response to Acute Hypoxia among Healthy Humans.
- Author
-
Forbes LM, Bull TM, Lahm T, Lawley JS, Hunter K, Levine BD, Lovering A, Roach RC, Subudhi AW, and Cornwell WK 3rd
- Subjects
- Humans, Heart Ventricles, Ventricular Function, Right physiology, Hypoxia, Hypertension, Pulmonary
- Published
- 2023
- Full Text
- View/download PDF
15. Pulmonary artery compliance in different forms of pulmonary hypertension.
- Author
-
McCormick A, Krishnan A, Badesch D, Benza RL, Bull TM, De Marco T, Feldman J, Hemnes AR, Hirsch R, Horn E, Kennedy J, Mathai SC, McConnell W, Pugliese SC, Sager JS, Shlobin OA, Simon MA, and Lammi MR
- Subjects
- Adult, Humans, Pulmonary Artery surgery, Retrospective Studies, Familial Primary Pulmonary Hypertension, Hypertension, Pulmonary, Pulmonary Arterial Hypertension
- Abstract
Objective: Pulmonary artery compliance (PAC), estimated as stroke volume (SV) divided by pulmonary artery pulse pressure (PP), may be a predictor of survival in pulmonary arterial hypertension (PAH). Resistance-compliance (RC) time, the product of PAC and pulmonary vascular resistance, is reported to be a physiological constant. We investigated if differences in PAC and RC time exist between pulmonary hypertension (PH) subgroups and examined whether PAC is an independent predictor of transplant-free survival in PAH., Methods: This was a retrospective analysis of adult PAH (n=532) and chronic thromboembolic PH (CTEPH, n=84) patients enrolled in the US Pulmonary Hypertension Association Registry from 2015 to 2019. PAC and RC time were compared between PH subgroups (connective tissue disease-PAH (CTD-PAH), idiopathic/heritable-PAH (i/h-PAH), drug/toxin-PAH (d/t-PAH)). Cox proportional hazards models were constructed for transplant-free survival, adjusting for REVEAL 2.0 risk score., Results: There were no differences in estimated PAC between PAH subgroups, nor between PAH and CTEPH. RC time was shorter in CTEPH compared with PAH (median 0.55 (IQR 0.45-0.64) vs 0.62 (0.52-0.73) s, p<0.0001). RC time was shortest in CTD-PAH when compared with i/h-PAH and d/t-PAH ((0.59±0.18) vs (0.65±0.20) vs (0.73±0.25) s, p=0.0001). PAC was associated with transplant-free survival (HR 0.72, 95% CI 0.55 to 0.94, p=0.02) but was not an independent predictor of outcome after adjustment for REVEAL 2.0 score., Conclusion: PAC was similar between PH groups and was not an independent predictor of transplant-free survival in PAH. RC time was different between PH subgroups, challenging RC time constancy., Trial Registration Number: NCT04071327., Competing Interests: Competing interests: ARH: consultant for Bayer, Janssen, United Therapeutics, GossamerBio and Complexa. Holds stock in Tenax Therapeutics. MAS: research support from Novartis. Haemodyanamic core lab for Aadi. Consulting/scientific advisory board for Janssen, Acceleron, Liquidia, Bial, Impulse Dynamics. OAS: consultant and speaker for United Therapeutics, Johnson and Johnson, and Bayer. JSS: research grants from Janssen, PhaseBio, Reata, Bayer, United Therapeutics and Covance. Consultant for Janssen, Bayer and United Therapeutics. TDM: consultant for Actelion/Johnson and Johnson, United Therapeutic, SCIOS-Bial and TrioHealth. Advisory Boards for Altevant and Liquidia; MRL: dlinical trial participation with Gilead, Actelion/Janssen, Bayer, United Therapeutics, Altavant and Acceleron (all funds to the institution)., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
- Full Text
- View/download PDF
16. Rivaroxaban for Prevention of Thrombotic Events, Hospitalization, and Death in Outpatients With COVID-19: A Randomized Clinical Trial.
- Author
-
Piazza G, Spyropoulos AC, Hsia J, Goldin M, Towner WJ, Go AS, Bull TM, Weng S, Lipardi C, Barnathan ES, and Bonaca MP
- Subjects
- Humans, Rivaroxaban adverse effects, Outpatients, Hemorrhage chemically induced, Hemorrhage drug therapy, Hospitalization, Anticoagulants adverse effects, COVID-19, Thrombosis epidemiology, Thrombosis prevention & control
- Abstract
Background: COVID-19 (coronavirus disease 2019) is associated with heightened risks of venous and arterial thrombosis and hospitalization due to respiratory failure. To assess whether prophylactic anticoagulation can safely reduce the frequency of venous and arterial thrombosis, hospitalization, and death in nonhospitalized patients with symptomatic COVID-19 and at least one thrombosis risk factor, we conducted the PREVENT-HD double-blind, placebo-controlled randomized trial (A Study of Rivaroxaban to Reduce the Risk of Major Venous and Arterial Thrombotic Events, Hospitalization and Death in Medically Ill Outpatients With Acute, Symptomatic COVID-19] Infection)., Methods: PREVENT-HD was conducted between August 2020 and April 2022 at 14 US integrated health care delivery networks. A virtual trial design used remote informed consent and clinical monitoring and facilitated data collection through electronic health record integration with a cloud-based research platform. Nonhospitalized patients with symptomatic COVID-19 and at least one thrombosis risk factor were enrolled and randomly assigned to either 10 mg of oral rivaroxaban or placebo daily for 35 days. The primary efficacy outcome was time to first occurrence of a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic arterial embolism, hospitalization, or death through day 35. The principal safety end point was International Society on Thrombosis and Hemostasis critical-site or fatal bleeding. The last study visit was on day 49., Results: The study was terminated prematurely because of enrollment challenges and a lower-than-expected blinded pooled event rate. A total of 1284 patients underwent randomization with complete accrual of primary events through May 2022. No patients were lost to follow-up. The primary efficacy outcome occurred in 22 of 641 in the rivaroxaban group and 19 of 643 in the placebo group (3.4% versus 3.0%; hazard ratio, 1.16 [95% CI, 0.63-2.15]; P =0.63). No patient in either group experienced critical-site or fatal bleeding. One patient receiving rivaroxaban had a major bleed., Conclusions: The study was terminated prematurely after enrollment of 32% of planned accrual because of recruitment challenges and lower-than-expected event rate. Rivaroxaban prescribed for 35 days in nonhospitalized patients with symptomatic COVID-19 at risk for thrombosis did not appear to reduce a composite end point of venous and arterial thrombotic events, hospitalization, and death., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT04508023., Competing Interests: Disclosures Dr Piazza has received research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific Corp, as well as consulting fees from Bristol-Myers Squibb/Pfizer Alliance, Boston Scientific Corp, Janssen, NAMSA, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen. Dr Spyropoulos has received research support from Boehringer Ingelheim and Janssen and consulting fees from Janssen, Bristol-Meyer Squibb/Pfizer Alliance, Sanofi, Alexion, Boehringer Ingelheim, Bayer, and Roche Diagnostics. Drs Hsia and Bonaca receive salary support from Colorado Prevention Center, a nonprofit academic research organization affiliated with the University of Colorado that receives research grant/consulting funding from Abbott, Agios, Alexion Pharma, Alnylam, Amgen, Angionetics, Anthos, ARCA Biopharma, Array, AstraZeneca, Atentiv, Audentes, Bayer, Better Therapeutics, Brigham and Women’s Hospital, Bristol-Myers Squibb, Cardiol Therapeutics, CellResearch, Cook Medical, Cook, Cook Regentec, CSL Behring, Eidos Therapeutics, EP Trading Co, Esperion Therapeutics, Everly Health, Faraday, Fortress Biotech, HDL Therapeutics, Heartflow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, MedPace, Medtronic, Moderna, Novate Medical, NovoNordisk, Pfizer, PhaseBio, Prairie Education and Research, Prothena Biosciences, Regeneron, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, University of Pittsburgh, Worldwide Clinical Trials, Wraser, and Yale Cardiovascular Research Group. Dr Hsia also reports owning AstraZeneca stock. Dr Goldin reports research support and consulting honoraria from Janssen. Dr Towner receives research grant support paid to his institution from Pfizer, Moderna, Gilead, ViiV, GSK, Janssen, and Merck. Dr Go has received research grants through his institution from Bristol-Myers Squibb/Pfizer Alliance, Janssen, Novartis, National Heart, Lung and Blood Institute, National Institute of Diabetes, Digestive and Kidney Diseases, and the Patient Centered Outcomes Research Institute. Dr Bull receives consulting fees from United Therapeutics, Liquidia, and Bayer. Dr Bonaca receives support from the American Heart Association Strategically Focused Research Network under awards 18SFRN3390085 (Brigham and Women’s Hospital–Dartmouth-Hitchcock Strategically Focused Research Network Center) and 18SFRN33960262 (Brigham and Women’s Hospital–Dartmouth-Hitchcock Clinical Project). Dr Bonaca also reports stock in Medtronic and Pfizer. Drs Weng, Lipardi, and Barnathan are employees of Janssen Research and Development.
- Published
- 2023
- Full Text
- View/download PDF
17. Erratum: Health disparities and treatment approaches in portopulmonary hypertension and idiopathic pulmonary arterial hypertension: An analysis of the Pulmonary Hypertension Association Registry.
- Author
-
DuBrock HM, Burger CD, Bartolome SD, Feldman JP, Ivy DD, Rosenzweig EB, Sager JS, Presberg KW, Mathai SC, Lammi MR, Klinger JR, Eggert M, De Marco T, Elwing JM, Badesch D, Bull TM, Cadaret LM, Ramani G, Thenappan T, Ford HJ, Al-Naamani N, Simon MA, Mazimba S, Runo JR, Chakinala M, Horn EM, Ryan JJ, Frantz RP, and Krowka MJ
- Abstract
[This corrects the article DOI: 10.1177/20458940211020913.]., (© 2022 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)
- Published
- 2022
- Full Text
- View/download PDF
18. INSPIRE: Safety and tolerability of inhaled Yutrepia (treprostinil) in pulmonary arterial hypertension (PAH).
- Author
-
Hill NS, Feldman JP, Sahay S, Benza RL, Preston IR, Badesch D, Frantz RP, Patel S, Galloway A, and Bull TM
- Abstract
The INSPIRE trial was a Phase 3, open-label, multicenter trial (LTI-301) that enrolled patients with pulmonary arterial hypertension (PAH) ≥ 18 years of age who transitioned to Yutrepia from nebulized treprostinil (Transition) or added Yutrepia to prostacyclin naïve patients on ≤2 nonprostacyclin oral therapies. The objectives of the trial were to evaluate the safety and tolerability of Yutrepia (dry-powder formulation of treprostinil) in patients with PAH. The primary safety measures were the incidence of adverse events (AEs) and serious AEs. Exploratory efficacy measures were also assessed during the trial. Transition patients initiated Yutrepia at a dose comparable to their nebulized treprostinil dose while prostacyclin naïve patients received 26.5-mcg QID; up-titration in 26.5-mcg increments was permitted for both groups. A total of 121 patients were enrolled, of which 29 patients discontinued from the trial, with the most common reason being AEs. Eighty percent of the Transition group and 96% of the prostacyclin naïve group titrated to a dose ≥79.5 mcg QID at Day 360, respectively, with one patient achieving a dose of 212-mcg QID. The most common AEs were cough, headache, upper respiratory tract infection, dyspnea, dizziness, throat irritation, diarrhea, chest discomfort, fatigue, and nasopharyngitis. Most of these events were considered treatment-related though mild to moderate in severity and expected for prostacyclin therapy administered by inhalation. In an evaluation of exploratory efficacy measures, patients remained stable or improved over the 1 year of treatment. Yutrepia was found to be a convenient, safe, and well-tolerated inhaled prostacyclin treatment option for PAH patients., Competing Interests: N. S. H.: Liquidia and Aerovate, consulting fees; Altavant, lectures, presentations, speakers bureaus, manuscript writing, and/or educational events; Liquidia, expert testimony; Liquidia, support for attending meetings and/or travel; Merck and United Therapeutics, data safety monitoring board or advisory board. J. P. F.: Liquidia, advisory board. S. S.: ACCP CHEST and United Therapeutics, research grants; Liquidia, steering committee; Gossamer Bio, United Therapeutics, and Bayer, advisor; Bayer, United Therapeutics, and Johnson & Johnson, speaker; Johnson & Johnson, planned patent; Bayer, advisory board; GSK, endpoint adjudication committee. R. L. B.: Bayer, Abbot, United Therapeutics, Abbott, Gossamer Bio, and Acceleron, consulting fees; Society of Heart and Lung Transplantation and the Pulmonary Vascular Disease Institute, leadership and/or fiduciary role. I. R. P.: Janssen, United Therapeutics, PhaseBio, and Tenax, research grants and/or contracts; Altavant, Janssen, United Therapeutics, and Liquidia, consulting fees; Medscape and Med on the Go, lectures, presentations, speakers bureaus, manuscript writing and/or educational events; Bayer, expert testimony; Altavant, Janssen, United Therapeutics, and Liquidia, data safety monitoring or advisory board; ISHLT, leadership or fiduciary role. D. B.: Acceleron, Arena/United Therapeutics, Altavant, Actelion/Janssen/Johnson & Johnson, Ikaria, Reata, Complexa Liquidia, and Merck, research grants; Acceleron, Altavant, Bayer, Merck, and Liquidia, consulting fees; Practice Point Communications, lectures, presentations, speakers bureaus, manuscript writing and/or educational events; Bayer, expert testimony; United Therapeutics, data safety or advisory board; USPHSR (United States Pulmonary Hypertension Scientific Registry), leadership or fiduciary role; Johnson & Johnson, stock or stock options. R. P. F.: NHLBI, research grant; Up to Date, royalties or licenses; Janssen, Liquidia, Shouti, Altavant, Gossamer Bio, Bayer, and Tenax, consulting fees; United Therapeutics, France Foundation, and Janssen, lectures, presentations, speakers bureaus, manuscript writing and/or educational events; Janssen and Liquidia, data safety or advisory board; Tenax, stock or stock options. S. P.: Liquidia, employee, stock or stock options. A. G.: Liquidia, employee, attending meetings and/or travel patents, and stock or stock options. T. M. B.: Bayer, research grant; Liquidia and Bayer, steering committee and consulting fees; NHLBI and MESA, data safety and/or advisory board., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)
- Published
- 2022
- Full Text
- View/download PDF
19. Corrigendum for health-related quality of life and hospitalizations in chronic thromboembolic pulmonary hypertension versus idiopathic pulmonary arterial hypertension: And analysis from the Pulmonary Hypertension Association Registry.
- Author
-
Minhas J, Narasimmal SP, Bull TM, De Marco T, Mc Connell JW, Lammi MR, Thenappan T, Feldman JP, Sager JS, Badesch DB, Ryan JJ, Grinnan DC, Zwicke D, Horn EM, Elwing JM, Moss JE, Eggert M, Shlobin OA, Frantz RP, Bartolome SD, Mathai SC, Mazimba S, Pugliese SC, and Al-Naamani N
- Abstract
[This corrects the article DOI: 10.1177/20458940211053196.]., (© 2022 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)
- Published
- 2022
- Full Text
- View/download PDF
20. Mortality in Pulmonary Arterial Hypertension in the Modern Era: Early Insights From the Pulmonary Hypertension Association Registry.
- Author
-
Chang KY, Duval S, Badesch DB, Bull TM, Chakinala MM, De Marco T, Frantz RP, Hemnes A, Mathai SC, Rosenzweig EB, Ryan JJ, and Thenappan T
- Subjects
- Adult, Familial Primary Pulmonary Hypertension, Female, Humans, Male, Middle Aged, Proportional Hazards Models, Registries, Survival Rate, United States epidemiology, Hypertension, Pulmonary, Pulmonary Arterial Hypertension diagnosis
- Abstract
Background Current mortality data for pulmonary arterial hypertension (PAH) in the United States are based on registries that enrolled patients prior to 2010. We sought to determine mortality in PAH in the modern era using the PHAR (Pulmonary Hypertension Association Registry). Methods and Results We identified all adult patients with PAH enrolled in the PHAR between September 2015 and September 2020 (N=935). We used Kaplan-Meier survival analysis and Cox proportional hazards models to assess mortality at 1, 2, and 3 years. Patients were stratified based on disease severity by 3 validated risk scores. In treatment-naïve patients, we compared survival based on initial treatment strategy. The median age was 56 years (44-68 years), and 76% were women. Of the 935 patients, 483 (52%) were ≤6 months from PAH diagnosis. There were 121 deaths (12.9%) during a median follow-up time of 489 days (281-812 days). The 1-, 2-, and 3-year mortality was 8% (95% CI, 6%-10%), 16% (95% CI, 13%-19%), and 21% (95% CI, 17%-25%), respectively. When stratified into low-, intermediate-, and high-risk PAH, the mortality at 1, 2, and 3 years was 1%, 4% to 6%, and 7% to 11% for low risk; 7% to 8%, 11% to 16%, and 18% to 20% for intermediate risk; and 12% to 19%, 22% to 38%, and 28% to 55% for high risk, respectively. In treatment-naïve patients, initial combination therapy was associated with better 1-year survival (adjusted hazard ratio, 0.43 [95% CI, 0.19-0.95]; P =0.037). Conclusions Mortality in the intermediate- and high-risk patients with PAH remains unacceptably high in the PHAR, suggesting the importance for early diagnosis, aggressive use of available therapies, and the need for better therapeutics.
- Published
- 2022
- Full Text
- View/download PDF
21. Peripheral Blood Inflammation Profile of Patients with Pulmonary Arterial Hypertension Using the High-Throughput Olink Proteomics Platform.
- Author
-
Mickael C, Kheyfets VO, Langouët-Astrié C, Lee MH, Sanders LA, Trentin CO, Sweatt AJ, Zamanian RT, Bull TM, Stenmark K, Graham BB, and Tuder RM
- Subjects
- Familial Primary Pulmonary Hypertension, Humans, Inflammation, Proteomics, Pulmonary Arterial Hypertension
- Published
- 2022
- Full Text
- View/download PDF
22. Physical Activity and Its Association with Traditional Outcome Measures in Pulmonary Arterial Hypertension.
- Author
-
Minhas J, Shou H, Hershman S, Zamanian R, Ventetuolo CE, Bull TM, Hemnes A, Chakinala MM, Mathai S, Al-Naamani N, Ellenberg S, Matura LA, Kawut SM, and Shcherbina A
- Subjects
- Cross-Sectional Studies, Exercise, Female, Humans, Outcome Assessment, Health Care, Quality of Life, Pulmonary Arterial Hypertension
- Abstract
Rationale: Limitation of physical activity is a common presenting complaint for patients with pulmonary arterial hypertension (PAH). Physical activity is thought to be determined by cardiopulmonary function, yet there are limited data that investigate this relationship. Objectives: We aimed to study the relationship between right ventricular function and daily activity and its impact on health-related quality of life (HRQoL) in PAH. Methods: Baseline data for 55 patients enrolled in PHANTOM (Pulmonary Hypertension and Anastrozole), an ongoing multicenter randomized controlled trial of anastrozole in PAH, were used. Postmenopausal women and men were eligible and underwent 6-minute walk testing and echocardiography and completed HRQoL questionnaires. Each patient wore an accelerometer for 7 days. Multivariable linear regression models were used to study the association between tricuspid annular plane systolic excursion (TAPSE) and vector magnitude counts, and between daily activity and HRQoL. Principal component analysis and K-means clustering were used to identify activity-based phenotypes. K-nearest neighbors classification was applied to an independent cross-sectional cohort from the University of Pennsylvania. Results: The mean age of patients in PHANTOM was 61 years. In total, 67% were women with idiopathic PAH as the most common etiology. A 0.4-cm increase in TAPSE was associated with an increase in daily vector magnitude counts (β: 34,000; 95% confidence interval [CI], 900-67,000; P = 0.004) after adjustment for age, sex, body mass index, etiology of PAH, and wear time. A 1-SD increase in vector magnitude counts was associated with higher 6-minute walk distance (β: 56.1 m; 95% CI, 28.6-83.7; P < 0.001) and lower emPHasis-10 scores (β: -3.3; 95% CI, 0.3-6.4; P = 0.03). Three activity phenotypes, low, medium, and high, were identified. The most active phenotype had greater 6-minute walk distances ( P = 0.001) and lower emPHasis-10 scores ( P = 0.009) after adjustment for age, sex, body mass index, World Health Organization functional class, and parenteral prostacyclin use. Phenotypes of physical activity were reproduced in the second cohort and were independently associated with 6-minute walk distance. Conclusions: Better right ventricular systolic function was associated with increased levels of activity in PAH. Increased daily activity was associated with greater 6-minute walk distance and better HRQoL. Distinct activity-based phenotypes may be helpful in risk stratification of patients with PAH or provide novel endpoints for clinical trials.
- Published
- 2022
- Full Text
- View/download PDF
23. Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19: A Vanguard Multicenter, Rapidly Adaptive, Pragmatic, Randomized Controlled Trial.
- Author
-
Barrett CD, Moore HB, Moore EE, Wang J, Hajizadeh N, Biffl WL, Lottenberg L, Patel PR, Truitt MS, McIntyre RC Jr, Bull TM, Ammons LA, Ghasabyan A, Chandler J, Douglas IS, Schmidt EP, Moore PK, Wright FL, Ramdeo R, Borrego R, Rueda M, Dhupa A, McCaul DS, Dandan T, Sarkar PK, Khan B, Sreevidya C, McDaniel C, Grossman Verner HM, Pearcy C, Anez-Bustillos L, Baedorf-Kassis EN, Jhunjhunwala R, Shaefi S, Capers K, Banner-Goodspeed V, Talmor DS, Sauaia A, and Yaffe MB
- Subjects
- Adolescent, Adult, Aged, COVID-19 blood, COVID-19 epidemiology, Cross-Sectional Studies, Female, Fibrinolytic Agents administration & dosage, Follow-Up Studies, Humans, Male, Middle Aged, Partial Thromboplastin Time, Respiratory Insufficiency blood, Respiratory Insufficiency etiology, Retrospective Studies, Thrombosis blood, Thrombosis drug therapy, Treatment Outcome, Young Adult, COVID-19 complications, Pandemics, Respiratory Insufficiency drug therapy, SARS-CoV-2, Thrombosis complications, Tissue Plasminogen Activator administration & dosage
- Abstract
Background: Pulmonary vascular microthrombi are a proposed mechanism of COVID-19 respiratory failure. We hypothesized that early administration of tissue plasminogen activator (tPA) followed by therapeutic heparin would improve pulmonary function in these patients., Research Question: Does tPA improve pulmonary function in severe COVID-19 respiratory failure, and is it safe?, Study Design and Methods: Adults with COVID-19-induced respiratory failure were randomized from May14, 2020 through March 3, 2021, in two phases. Phase 1 (n = 36) comprised a control group (standard-of-care treatment) vs a tPA bolus (50-mg tPA IV bolus followed by 7 days of heparin; goal activated partial thromboplastin time [aPTT], 60-80 s) group. Phase 2 (n = 14) comprised a control group vs a tPA drip (50-mg tPA IV bolus, followed by tPA drip 2 mg/h plus heparin 500 units/h over 24 h, then heparin to maintain aPTT of 60-80 s for 7 days) group. Patients were excluded from enrollment if they had not undergone a neurologic examination or cross-sectional brain imaging within the previous 4.5 h to rule out stroke and potential for hemorrhagic conversion. The primary outcome was Pao
2 to Fio2 ratio improvement from baseline at 48 h after randomization. Secondary outcomes included Pao2 to Fio2 ratio improvement of > 50% or Pao2 to Fio2 ratio of ≥ 200 at 48 h (composite outcome), ventilator-free days (VFD), and mortality., Results: Fifty patients were randomized: 17 in the control group and 19 in the tPA bolus group in phase 1 and eight in the control group and six in the tPA drip group in phase 2. No severe bleeding events occurred. In the tPA bolus group, the Pao2 to Fio2 ratio values were significantly (P < .017) higher than baseline at 6 through 168 h after randomization; the control group showed no significant improvements. Among patients receiving a tPA bolus, the percent change of Pao2 to Fio2 ratio at 48 h (16.9% control [interquartile range (IQR), -8.3% to 36.8%] vs 29.8% tPA bolus [IQR, 4.5%-88.7%]; P = .11), the composite outcome (11.8% vs 47.4%; P = .03), VFD (0.0 [IQR, 0.0-9.0] vs 12.0 [IQR, 0.0-19.0]; P = .11), and in-hospital mortality (41.2% vs 21.1%; P = .19) did not reach statistically significant differences when compared with those of control participants. The patients who received a tPA drip did not experience benefit., Interpretation: The combination of tPA bolus plus heparin is safe in severe COVID-19 respiratory failure. A phase 3 study is warranted given the improvements in oxygenation and promising observations in VFD and mortality., Trial Registry: ClinicalTrials.gov; No.: NCT04357730; URL: www., Clinicaltrials: gov., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
24. Double Trouble: Airflow and Pulmonary Vascular Obstruction.
- Author
-
Lee MH, Graham BB, and Bull TM
- Subjects
- Forced Expiratory Volume, Humans, Airway Obstruction etiology
- Published
- 2021
- Full Text
- View/download PDF
25. Pulmonary Arterial Hypertension and Intraductal Papillary Mucinous Neoplasms of the Pancreas: A Novel Association?
- Author
-
Lee MH, Doran J, Bang TJ, Hohsfield R, Hountras P, Boddie G, Wagh MS, Badesch D, and Bull TM
- Subjects
- Adenocarcinoma, Mucinous complications, Adenocarcinoma, Mucinous diagnostic imaging, Cholangiopancreatography, Magnetic Resonance, Female, Humans, Male, Pancreatic Intraductal Neoplasms complications, Pancreatic Intraductal Neoplasms diagnostic imaging, Pancreatic Neoplasms complications, Pancreatic Neoplasms diagnostic imaging, Pulmonary Arterial Hypertension complications, Vascular Resistance, Adenocarcinoma, Mucinous therapy, Pancreatic Intraductal Neoplasms therapy, Pancreatic Neoplasms therapy, Pulmonary Arterial Hypertension therapy
- Published
- 2021
- Full Text
- View/download PDF
26. Clotting and COVID-19.
- Author
-
Bull TM
- Subjects
- Anticoagulants, Blood Coagulation, Critical Illness, Humans, SARS-CoV-2, COVID-19
- Published
- 2021
- Full Text
- View/download PDF
27. Health disparities and treatment approaches in portopulmonary hypertension and idiopathic pulmonary arterial hypertension: an analysis of the Pulmonary Hypertension Association Registry.
- Author
-
DuBrock HM, Burger CD, Bartolome SD, Feldman JP, Ivy DD, Rosenzweig EB, Sager JS, Presberg KW, Mathai SC, Lammi MR, Klinger JR, Eggert M, De Marco T, Elwing JM, Badesch D, Bull TM, Cadaret LM, Ramani G, Thenappan T, Ford HJ, Al-Naamani N, Simon MA, Mazimba S, Runo JR, Chakinala M, Horn EM, Ryan JJ, Frantz RP, and Krowka MJ
- Abstract
Compared to idiopathic pulmonary arterial hypertension (IPAH), patients with portopulmonary hypertension (POPH) have worse survival. Health disparities may contribute to these differences but have not been studied. We sought to compare socioeconomic factors in patients with POPH and IPAH and to determine whether socioeconomic status and/or POPH diagnosis were associated with treatment and health-care utilization. We performed a cross-sectional study of adults enrolled in the Pulmonary Hypertension Association Registry. Patients with IPAH (n = 344) and POPH (n = 57) were compared. Compared with IPAH, patients with POPH were less likely to be college graduates (19.6% vs. 34.9%, p = 0.02) and more likely to be unemployed (54.7% vs. 30.5%, p < 0.001) and have an annual household income below poverty level (45.7% vs. 19.0%, p < 0.001). Patients with POPH had similar functional class, quality of life, 6-min walk distance, and mean pulmonary arterial pressure with a higher cardiac index. Compared with IPAH, patients with POPH were less likely to receive combination therapy (46.4% vs. 62.2%, p = 0.03) and endothelin receptor antagonists (28.6% vs. 55.1%, p < 0.001) at enrollment with similar treatment at follow-up. Patients with POPH had more emergency department visits (1.7 ± 2.1 vs. 0.9 ± 1.2, p = 0.009) and hospitalizations in the six months preceding enrollment (1.5 ± 2.1 vs. 0.8 ± 1.1, p = 0.02). Both POPH diagnosis and lower education level were independently associated with a higher number of emergency department visits. Compared to IPAH, patients with POPH have lower socioeconomic status, are less likely to receive initial combination therapy and endothelin receptor antagonists but have similar treatment at follow-up, and have increased health-care utilization., (© The Author(s) 2021.)
- Published
- 2021
- Full Text
- View/download PDF
28. Estrogen Signaling and Portopulmonary Hypertension: The Pulmonary Vascular Complications of Liver Disease Study (PVCLD2).
- Author
-
Al-Naamani N, Krowka MJ, Forde KA, Krok KL, Feng R, Heresi GA, Dweik RA, Bartolome S, Bull TM, Roberts KE, Austin ED, Hemnes AR, Patel MJ, Oh JK, Lin G, Doyle MF, Denver N, Andrew R, MacLean MR, Fallon MB, and Kawut SM
- Subjects
- Aged, Aromatase metabolism, Case-Control Studies, Cytochrome P-450 CYP1B1 genetics, Cytochrome P-450 CYP1B1 metabolism, Echocardiography, End Stage Liver Disease blood, End Stage Liver Disease genetics, End Stage Liver Disease metabolism, Estrogen Receptor alpha genetics, Estrogen Receptor alpha metabolism, Estrogens blood, Estrogens urine, Female, Humans, Hypertension, Portal blood, Hypertension, Portal metabolism, Hypertension, Portal urine, Hypertension, Pulmonary blood, Hypertension, Pulmonary metabolism, Hypertension, Pulmonary urine, Liver Function Tests, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies, Signal Transduction genetics, Vascular Resistance genetics, Aromatase genetics, End Stage Liver Disease complications, Estrogens metabolism, Hypertension, Portal genetics, Hypertension, Pulmonary genetics
- Abstract
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
-5 , 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., (© 2020 by the American Association for the Study of Liver Diseases.)- Published
- 2021
- Full Text
- View/download PDF
29. Impact of Proactive Integrated Care on Chronic Obstructive Pulmonary Disease.
- Author
-
Koff PB, Min SJ, Freitag TJ, Diaz DLP, James SS, Voelkel NF, Linderman DJ, Diaz Del Valle F, Zakrajsek JK, Albert RK, Bull TM, Beck A, Stelzner TJ, Ritzwoller DP, Kveton CM, Carwin S, Ghosh M, Keith RL, Westfall JM, and Vandivier RW
- Abstract
Background: Up to 50% of chronic obstructive pulmonary disease (COPD) patients do not receive recommended care for COPD. To address this issue, we developed Proactive Integrated Care (Proactive iCare), a health care delivery model that couples integrated care with remote monitoring., Methods: We conducted a prospective, quasi-randomized clinical trial in 511 patients with advanced COPD or a recent COPD exacerbation, to test whether Proactive iCare impacts patient-centered outcomes and health care utilization. Patients were allocated to Proactive iCare (n=352) or Usual Care ( =159) and were examined for changes in quality of life using the St George's Respiratory Questionnaire (SGRQ), symptoms, guideline-based care, and health care utilization., Findings: Proactive iCare improved total SGRQ by 7-9 units ( p < 0.0001), symptom SGRQ by 9 units ( p <0.0001), activity SGRQ by 6-7 units (p <0.001) and impact SGRQ by 7-11 units ( p <0.0001) at 3, 6 and 9 months compared with Usual Care. Proactive iCare increased the 6-minute walk distance by 40 m ( p <0.001), reduced annual COPD-related urgent office visits by 76 visits per 100 participants (p <0.0001), identified unreported exacerbations, and decreased smoking ( p =0.01). Proactive iCare also improved symptoms, the b ody mass index-airway o bstruction- d yspnea- e xercise tolerance (BODE) index and oxygen titration ( p <0.05). Mortality in the Proactive iCare group (1.1%) was not significantly different than mortality in the Usual Care group (3.8%; p =0.08)., Interpretation: Linking integrated care with remote monitoring improves the lives of people with advanced COPD, findings that may have been made more relevant by the coronavirus 2019 (COVID-19) pandemic., Competing Interests: RWV, PBK, SJM, DLPD, TJF, SSJ, NFV, DJL, AB, TJS, DPR, CMK, SC, RLK and JMW received funding from the Colorado Cancer, Cardiovascular Disease and Chronic Pulmonary Disease Prevention, Early Detection and Treatment Program (CCPD). RWV and MG received funding from the National Institutes of Health. PBK worked for Robert Bosch Healthcare from 2010 to 2015 and for Philips Healthcare from 2015 to 2017, after the study was completed. RKA, FDV, JKZ and TMB had no conflicts of interest., (JCOPDF © 2021.)
- Published
- 2021
- Full Text
- View/download PDF
30. Inferior Vena Cava Filters: Past, Present, and Future.
- Author
-
Marron RM, Rali P, Hountras P, and Bull TM
- Subjects
- Humans, Venous Thromboembolism therapy, Endovascular Procedures adverse effects, Endovascular Procedures methods, Procedures and Techniques Utilization trends, Vena Cava Filters classification, Vena Cava Filters trends
- Abstract
Inferior vena cava (IVC) filters have existed as a treatment option for VTE for decades. Advances in medical technology have provided physicians with several options for devices that can be placed on either a permanent or temporary basis; however, there are limited data from randomized, controlled trials on the appropriate use of IVC filters. This contemporary review summarizes the history of IVC filters and the types that are available in clinical practice. It reviews the literature on the use of IVC filters and discusses the indications that professional societies have endorsed for their use. In addition, it outlines the complications of IVC filter placement and future research directions., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
31. Advanced therapies for pulmonary embolism.
- Author
-
Hountras P and Bull TM
- Subjects
- Acute Disease, Embolectomy, Humans, Patient Care Team, Practice Guidelines as Topic, Thrombectomy, Vena Cava Filters, Extracorporeal Membrane Oxygenation, Fibrinolytic Agents therapeutic use, Pulmonary Embolism therapy, Thrombolytic Therapy
- Abstract
Purpose of Review: Treatment options for managing patients with acute pulmonary embolism are rapidly evolving. In this review, we discuss the supporting evidence and implementation strategies for these advanced therapeutic modalities., Recent Findings: We review the recent data supporting systemic and catheter directed thrombolytic therapies, mechanical embolectomy, use of extracorporeal membrane oxygen support, and pulmonary embolism response teams in managing patients with acute pulmonary embolism. We discuss the major professional society recommendations regarding their implementation., Summary: A review of advanced therapies for pulmonary embolism.
- Published
- 2020
- Full Text
- View/download PDF
32. Unusual Case of Acquired Hypoxemia Following Left Ventricular Assist Device Implantation.
- Author
-
Purohit SN, Lee PJ, Strobel AL, Desai AA, Marsala MT, Bull TM, Brieke A, Vargas D, Kay JD, and Altman NL
- Subjects
- Extracorporeal Membrane Oxygenation methods, Heart Failure diagnosis, Heart Ventricles surgery, Humans, Hypoxia diagnosis, Male, Middle Aged, Treatment Outcome, Heart Failure physiopathology, Heart-Assist Devices adverse effects, Hypoxia etiology, Hypoxia surgery
- Published
- 2020
- Full Text
- View/download PDF
33. The role of pulmonary arterial hypertension-targeted therapy in systemic sclerosis.
- Author
-
Lee MH and Bull TM
- Subjects
- Humans, Hypertension, Pulmonary complications, Hypertension, Pulmonary therapy, Scleroderma, Systemic complications, Scleroderma, Systemic therapy
- Abstract
Pulmonary arterial hypertension, categorized as group 1 pulmonary hypertension by the World Health Organization classification system, represents a major complication of systemic sclerosis resulting from pulmonary vascular involvement of the disease. The high mortality seen in systemic sclerosis-associated pulmonary arterial hypertension is likely due to the impairment of right ventricular systolic function and the coexistence of other non-group-1 pulmonary hypertension phenotypes that may negatively impact clinical response to pulmonary arterial hypertension-targeted therapy. This review highlights two areas of recent advances regarding the management of systemic sclerosis patients with pulmonary hypertension: the tolerability of pulmonary arterial hypertension-targeted therapy in the presence of mild to moderate interstitial lung disease and the potential clinical significance of the antifibrotic effect of soluble guanylate cyclase stimulators demonstrated in preclinical studies., Competing Interests: Competing interests: TMB has received grant support from and has served as a consultant for Bayer Pharmaceuticals. MHL declares that he has no competing interests.No competing interests were disclosed.No competing interests were disclosed., (Copyright: © 2019 Lee MH and Bull TM.)
- Published
- 2019
- Full Text
- View/download PDF
34. Exercise-Induced Pulmonary Hypertension: Translating Pathophysiological Concepts Into Clinical Practice.
- Author
-
Naeije R, Saggar R, Badesch D, Rajagopalan S, Gargani L, Rischard F, Ferrara F, Marra AM, D' Alto M, Bull TM, Saggar R, Grünig E, and Bossone E
- Subjects
- Cardiac Catheterization, Humans, Hypertension, Pulmonary etiology, Pulmonary Circulation physiology, Risk Factors, Exercise physiology, Exercise Test adverse effects, Hypertension, Pulmonary physiopathology, Pulmonary Wedge Pressure physiology, Vascular Resistance physiology
- Abstract
Exercise stress testing of the pulmonary circulation for the diagnosis of latent or early-stage pulmonary hypertension (PH) is gaining acceptance. There is emerging consensus to define exercise-induced PH by a mean pulmonary artery pressure > 30 mm Hg at a cardiac output < 10 L/min and a total pulmonary vascular resistance> 3 Wood units at maximum exercise, in the absence of PH at rest. Exercise-induced PH has been reported in association with a bone morphogenetic receptor-2 gene mutation, in systemic sclerosis, in left heart conditions, in chronic lung diseases, and in chronic pulmonary thromboembolism. Exercise-induced PH is a cause of decreased exercise capacity, may precede the development of manifest PH in a proportion of patients, and is associated with a decreased life expectancy. Exercise stress testing of the pulmonary circulation has to be dynamic and rely on measurements of the components of the pulmonary vascular equation during, not after exercise. Noninvasive imaging measurements may be sufficiently accurate in experienced hands, but suffer from lack of precision, so that invasive measurements are required for individual decision-making. Exercise-induced PH is caused either by pulmonary vasoconstriction, pulmonary vascular remodeling, or by increased upstream transmission of pulmonary venous pressure. This differential diagnosis is clinical. Left heart disease as a cause of exercise-induced PH can be further ascertained by a pulmonary artery wedge pressure above or below 20 mm Hg at a cardiac output < 10 L/min or a pulmonary artery wedge pressure-flow relationship above or below 2 mm Hg/L/min during exercise., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
35. Diagnostic workup, etiologies and management of acute right ventricle failure : A state-of-the-art paper.
- Author
-
Vieillard-Baron A, Naeije R, Haddad F, Bogaard HJ, Bull TM, Fletcher N, Lahm T, Magder S, Orde S, Schmidt G, and Pinsky MR
- Subjects
- Adult, Aged, Aged, 80 and over, Critical Illness, Female, Humans, Male, Middle Aged, Heart Ventricles physiopathology, Ventricular Dysfunction, Right diagnosis, Ventricular Dysfunction, Right physiopathology, Ventricular Dysfunction, Right therapy
- Abstract
Introduction: This is a state-of-the-art article of the diagnostic process, etiologies and management of acute right ventricular (RV) failure in critically ill patients. It is based on a large review of previously published articles in the field, as well as the expertise of the authors., Results: The authors propose the ten key points and directions for future research in the field. RV failure (RVF) is frequent in the ICU, magnified by the frequent need for positive pressure ventilation. While no universal definition of RVF is accepted, we propose that RVF may be defined as a state in which the right ventricle is unable to meet the demands for blood flow without excessive use of the Frank-Starling mechanism (i.e. increase in stroke volume associated with increased preload). Both echocardiography and hemodynamic monitoring play a central role in the evaluation of RVF in the ICU. Management of RVF includes treatment of the causes, respiratory optimization and hemodynamic support. The administration of fluids is potentially deleterious and unlikely to lead to improvement in cardiac output in the majority of cases. Vasopressors are needed in the setting of shock to restore the systemic pressure and avoid RV ischemia; inotropic drug or inodilator therapies may also be needed. In the most severe cases, recent mechanical circulatory support devices are proposed to unload the RV and improve organ perfusion CONCLUSION: RV function evaluation is key in the critically-ill patients for hemodynamic management, as fluid optimization, vasopressor strategy and respiratory support. RV failure may be diagnosed by the association of different devices and parameters, while echocardiography is crucial.
- Published
- 2018
- Full Text
- View/download PDF
36. Enhancing Insights into Pulmonary Vascular Disease through a Precision Medicine Approach. A Joint NHLBI-Cardiovascular Medical Research and Education Fund Workshop Report.
- Author
-
Newman JH, Rich S, Abman SH, Alexander JH, Barnard J, Beck GJ, Benza RL, Bull TM, Chan SY, Chun HJ, Doogan D, Dupuis J, Erzurum SC, Frantz RP, Geraci M, Gillies H, Gladwin M, Gray MP, Hemnes AR, Herbst RS, Hernandez AF, Hill NS, Horn EM, Hunter K, Jing ZC, Johns R, Kaul S, Kawut SM, Lahm T, Leopold JA, Lewis GD, Mathai SC, McLaughlin VV, Michelakis ED, Nathan SD, Nichols W, Page G, Rabinovitch M, Rich J, Rischard F, Rounds S, Shah SJ, Tapson VF, Lowy N, Stockbridge N, Weinmann G, and Xiao L
- Subjects
- Education, Humans, National Heart, Lung, and Blood Institute (U.S.), United States, Hypertension, Pulmonary therapy, Precision Medicine methods
- Abstract
The Division of Lung Diseases of the NHLBI and the Cardiovascular Medical Education and Research Fund held a workshop to discuss how to leverage the anticipated scientific output from the recently launched "Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics" (PVDOMICS) program to develop newer approaches to pulmonary vascular disease. PVDOMICS is a collaborative, protocol-driven network to analyze all patient populations with pulmonary hypertension to define novel pulmonary vascular disease (PVD) phenotypes. Stakeholders, including basic, translational, and clinical investigators; clinicians; patient advocacy organizations; regulatory agencies; and pharmaceutical industry experts, joined to discuss the application of precision medicine to PVD clinical trials. Recommendations were generated for discussion of research priorities in line with NHLBI Strategic Vision Goals that include: (1) A national effort, involving all the stakeholders, should seek to coordinate biosamples and biodata from all funded programs to a web-based repository so that information can be shared and correlated with other research projects. Example programs sponsored by NHLBI include PVDOMICS, Pulmonary Hypertension Breakthrough Initiative, the National Biological Sample and Data Repository for PAH, and the National Precision Medicine Initiative. (2) A task force to develop a master clinical trials protocol for PVD to apply precision medicine principles to future clinical trials. Specific features include: (a) adoption of smaller clinical trials that incorporate biomarker-guided enrichment strategies, using adaptive and innovative statistical designs; and (b) development of newer endpoints that reflect well-defined and clinically meaningful changes. (3) Development of updated and systematic variables in imaging, hemodynamic, cellular, genomic, and metabolic tests that will help precisely identify individual and shared features of PVD and serve as the basis of novel phenotypes for therapeutic interventions.
- Published
- 2017
- Full Text
- View/download PDF
37. TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension.
- Author
-
Kumar R, Mickael C, Kassa B, Gebreab L, Robinson JC, Koyanagi DE, Sanders L, Barthel L, Meadows C, Fox D, Irwin D, Li M, McKeon BA, Riddle S, Dale Brown R, Morgan LE, Evans CM, Hernandez-Saavedra D, Bandeira A, Maloney JP, Bull TM, Janssen WJ, Stenmark KR, Tuder RM, and Graham BB
- Subjects
- Animals, Antigens, Ly metabolism, Basic Helix-Loop-Helix Transcription Factors metabolism, Cattle, Humans, Hypertension, Pulmonary genetics, Hypertension, Pulmonary immunology, Hypoxia pathology, Lung blood supply, Lung metabolism, Lung pathology, Mice, Inbred C57BL, Monocytes metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Signal Transduction, Th2 Cells immunology, Thrombospondin 1 blood, Thrombospondin 1 genetics, Bone Marrow Cells metabolism, Hypertension, Pulmonary etiology, Hypertension, Pulmonary parasitology, Hypoxia complications, Schistosoma physiology, Thrombospondin 1 metabolism, Transforming Growth Factor beta metabolism
- Abstract
Pulmonary arterial hypertension (PAH) is an obstructive disease of the precapillary pulmonary arteries. Schistosomiasis-associated PAH shares altered vascular TGF-β signalling with idiopathic, heritable and autoimmune-associated etiologies; moreover, TGF-β blockade can prevent experimental pulmonary hypertension (PH) in pre-clinical models. TGF-β is regulated at the level of activation, but how TGF-β is activated in this disease is unknown. Here we show TGF-β activation by thrombospondin-1 (TSP-1) is both required and sufficient for the development of PH in Schistosoma-exposed mice. Following Schistosoma exposure, TSP-1 levels in the lung increase, via recruitment of circulating monocytes, while TSP-1 inhibition or knockout bone marrow prevents TGF-β activation and protects against PH development. TSP-1 blockade also prevents the PH in a second model, chronic hypoxia. Lastly, the plasma concentration of TSP-1 is significantly increased in subjects with scleroderma following PAH development. Targeting TSP-1-dependent activation of TGF-β could thus be a therapeutic approach in TGF-β-dependent vascular diseases.
- Published
- 2017
- Full Text
- View/download PDF
38. Long-Term Health Outcomes in High-Altitude Pulmonary Hypertension.
- Author
-
Robinson JC, Abbott C, Meadows CA, Roach RC, Honigman B, and Bull TM
- Subjects
- Adolescent, Aged, Cohort Studies, Colorado, Female, Follow-Up Studies, Health Surveys, Humans, Male, Middle Aged, Altitude, Altitude Sickness physiopathology, Hypertension, Pulmonary physiopathology, Patient Outcome Assessment, Time Factors
- Abstract
Robinson, Jeffrey C., Cheryl Abbott, Christina A. Meadows, Robert C. Roach, Benjamin Honigman, and Todd M. Bull. Long-term health outcomes in high-altitude pulmonary hypertension. High Alt Med Biol. 18:61-66, 2017., Background: High-altitude pulmonary hypertension (HAPH) is one of several known comorbidities that effect populations living at high altitude, but there have been no studies looking at long-term health consequences of HAPH. We aimed to determine whether HAPH during adolescence predisposes to significant pulmonary hypertension (PH) later in life, as well as identify how altitude exposure and HAPH correlate with functional class and medical comorbidities., Methods: We utilized a previously published cohort of 28 adolescents from Leadville, Colorado, that underwent right heart catheterization at 10,150 ft (3094 m) in 1962, with many demonstrating PH as defined by resting mean pulmonary arterial pressure ≥25 mmHg. We located participants of the original study and had living subjects complete demographic and health surveys to assess for the presence of PH and other medical comorbidities, along with current functional status., Results: Seventy-five percent of the individuals who participated in the original study were located. Those with HAPH in the past were more prone to have exertional limitation corresponding to WHO functional class >1. Fifty-five years following the original study, we found no significant differences in prevalence of medical comorbidities, including PH, among those with and without HAPH in their youth., Conclusions: Surveyed individuals did not report significant PH, but those with HAPH in their youth were more likely to report functional limitation. With a significant worldwide population living at moderate and high altitudes, further study of long-term health consequences is warranted.
- Published
- 2017
- Full Text
- View/download PDF
39. Steps forward in the treatment of pulmonary arterial hypertension: latest developments and clinical opportunities.
- Author
-
Badlam JB and Bull TM
- Abstract
Pulmonary arterial hypertension (PAH) is a chronic disease that results in narrowing of the small pre-capillary pulmonary arteries leading to elevation of pulmonary artery pressure and pulmonary vascular resistance, subsequent right ventricular failure, and if unchecked, death. Advances in the treatment of PAH over the last two decades have markedly improved survival. These improvements reflect a combination of changes in treatments, improved patient care strategies, and varying disease phenotypes in the PAH population. Currently approved therapies for PAH are directed at the recognized abnormalities within the pulmonary vasculature and include endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, and prostacyclin pathway agents. Most of these drugs have been approved on the basis of short-term trials that mainly demonstrated improvements in exercise capacity. More recently, long-term, event-driven trials of novel drugs have been performed, demonstrating new efficacy parameters. There have also been exciting advances in the understanding of right heart failure pathophysiology in PAH that have the potential to inspire the development of right ventricular targeted therapy and continued discoveries in the heterogeneity of disease and response to treatment has great potential for developing more 'personalized' therapeutic options. In this article, we review the current available data regarding the management of PAH, with an emphasis on the pharmacologic therapies and discussion of novel therapeutic directions for the treatment of this fatal disease., Competing Interests: Conflict of interest statement: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
- Published
- 2017
- Full Text
- View/download PDF
40. Speckle Tracking Echocardiography to Evaluate for Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease.
- Author
-
Rice JL, Stream AR, Fox DL, Geraci MW, Vandivier RW, Dorosz JL, and Bull TM
- Subjects
- Blood Pressure, Cardiac Catheterization, Female, Humans, Hypertension, Pulmonary complications, Male, Middle Aged, Pulmonary Disease, Chronic Obstructive physiopathology, ROC Curve, Retrospective Studies, Systole, Vascular Resistance, Ventricular Dysfunction, Right complications, Ventricular Dysfunction, Right physiopathology, Echocardiography methods, Hypertension, Pulmonary diagnostic imaging, Pulmonary Disease, Chronic Obstructive complications, Ventricular Dysfunction, Right diagnostic imaging
- Abstract
Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD), increasing morbidity and mortality. Current echocardiographic measures have poor predictive value for the diagnosis of PH in COPD. Right ventricular (RV) strain obtained by speckle tracking echocardiography (STE) is a measure of myocardial deformation which correlates with RV function and survival in subjects with pulmonary arterial hypertension. We hypothesized that RV strain measurements would be feasible and correlate with invasive hemodynamic measurements in patients with COPD. Retrospective analysis of RV strain values from subjects with severe COPD with echocardiogram within 48 hours of right heart catheterization was performed. First, 54 subjects were included in the analysis. Right ventricular systolic pressure (RVSP) and RV strain could be estimated in 31% and 57%, respectively. Then, 61% had RV-focused apical views, and of those, RV strain could be obtained for 94%. RV free wall strain correlated with PVR (r = 0.41, p = 0.02). Subjects with pulmonary vascular resistance (PVR) > 3 Wood units (WU) had less negative (worse) RV free wall strain values than those with PVR ≤ 3 WU, with a median strain of -20 (-23, -12) versus -23 (-29, -15), p < 0.05. A receiver operating characteristic curve demonstrated an RV free wall strain of > -23 to be 92% sensitive and 44% specific for identifying PVR > 3 WU (AUC 0.71). RV strain estimates are feasible in the majority of subjects with severe COPD. RV strain correlates with PVR and may improve screening for PH in subjects with COPD.
- Published
- 2016
- Full Text
- View/download PDF
41. Right Ventricular Longitudinal Strain Is Depressed in a Bovine Model of Pulmonary Hypertension.
- Author
-
Bartels K, Brown RD, Fox DL, Bull TM, Neary JM, Dorosz JL, Fonseca BM, and Stenmark KR
- Subjects
- Animals, Animals, Newborn, Biomechanical Phenomena, Cardiac Catheterization, Cattle, Disease Models, Animal, Hypertension, Pulmonary etiology, Hypertension, Pulmonary physiopathology, Hypoxia complications, Magnetic Resonance Imaging, Male, Predictive Value of Tests, Stress, Mechanical, Time Factors, Ventricular Dysfunction, Right etiology, Ventricular Dysfunction, Right physiopathology, Echocardiography, Doppler, Color, Hypertension, Pulmonary diagnostic imaging, Myocardial Contraction, Ventricular Dysfunction, Right diagnostic imaging, Ventricular Function, Right
- Abstract
Background: Pulmonary hypertension and resulting right ventricular (RV) dysfunction are associated with significant perioperative morbidity and mortality. Although echocardiography permits real-time, noninvasive assessment of RV function, objective and comparative measures are underdeveloped, and appropriate animal models to study their utility are lacking. Longitudinal strain analysis is a novel echocardiographic method to quantify RV performance. Herein, we hypothesized that peak RV longitudinal strain would worsen in a bovine model of pulmonary hypertension compared with control animals., Methods: Newborn Holstein calves were randomly chosen for induction of pulmonary hypertension versus control conditions. Pulmonary hypertension was induced by exposing animals to 14 days of hypoxia (equivalent to 4570 m above sea level or 430 mm Hg barometric pressure). Control animals were kept at ambient pressure/normoxia. At the end of the intervention, transthoracic echocardiography was performed in awake calves. Longitudinal wall strain was analyzed from modified apical 4-chamber views focused on the RV. Comparisons between measurements in hypoxic versus nonhypoxic conditions were performed using Student t test for independent samples and unequal variances., Results: After 14 days at normoxic versus hypoxic conditions, 15 calves were examined with echocardiography. Pulmonary hypertension was confirmed by right heart catheterization and associated with reduced RV systolic function. Mean systolic strain measurements were compared in normoxia-exposed animals (n = 8) and hypoxia-exposed animals (n = 7). Peak global systolic longitudinal RV strain after hypoxia worsened compared to normoxia (-10.5% vs -16.1%, P = 0.0031). Peak RV free wall strain also worsened after hypoxia compared to normoxia (-9.6% vs -17.3%, P = 0.0031). Findings from strain analysis were confirmed by measurement of tricuspid annular peak systolic excursion., Conclusions: Peak longitudinal RV strain detected worsened RV function in animals with hypoxia-induced pulmonary hypertension compared with control animals. This relationship was demonstrated in the transthoracic echocardiographic 4-chamber view independently for the RV free wall and for the combination of the free and septal walls. This innovative model of bovine pulmonary hypertension may prove useful to compare different monitoring technologies for the assessment of early events of RV dysfunction. Further studies linking novel RV imaging applications with mechanistic and therapeutic approaches are needed.
- Published
- 2016
- Full Text
- View/download PDF
42. [New trial designs and potential therapies for pulmonary artery hypertension].
- Author
-
Gomberg-Maitland M, Bull TM, Saggar R, Barst RJ, Elgazayerly A, Fleming TR, Grimminger F, Rainisio M, Stewart DJ, Stockbridge N, Ventura C, Ghofrani AH, and Rubin LJ
- Abstract
A greater understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary artery hypertension (PAH) has led to significant advances, but the disease remains fatal. Treatment options are neither universally available nor always effective, underscoring the need for development of novel therapies and therapeutic strategies. Clinical trials to date have provided evidence of efficacy, but were limited in evaluating the scope and duration of treatment effects. Numerous potential targets in varied stages of drug development exist, in addition to novel uses of familiar therapies. The pursuit of gene and cell-based therapy continues, and device use to help acute deterioration and chronic management is emerging. This rapid surge of drug development has led to multicenter pivotal clinical trials and has resulted in novel ethical and global clinical trial I concerns. This paper will provide an overview of the opportunities and challenges that await the development of novel treatments for PAH. (J Am Coil Cardiol 2013;62:D82-91) ©2013 by the American College of Cardiology Foundation.
- Published
- 2014
43. Timed response to inhaled nitric oxide in pulmonary hypertension.
- Author
-
Hunt JM, Risbano MG, Messenger JC, Carroll J, Badesch D, Lowes BD, Casserly IP, Kay J, and Bull TM
- Published
- 2014
- Full Text
- View/download PDF
44. New trial designs and potential therapies for pulmonary artery hypertension.
- Author
-
Gomberg-Maitland M, Bull TM, Saggar R, Barst RJ, Elgazayerly A, Fleming TR, Grimminger F, Rainisio M, Stewart DJ, Stockbridge N, Ventura C, Ghofrani AH, and Rubin LJ
- Subjects
- Animals, Clinical Trials as Topic methods, Familial Primary Pulmonary Hypertension, Humans, Clinical Trials as Topic trends, Drug Discovery trends, Hypertension, Pulmonary diagnosis, Hypertension, Pulmonary therapy, Research Design trends
- Abstract
A greater understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary artery hypertension (PAH) has led to significant advances, but the disease remains fatal. Treatment options are neither universally available nor always effective, underscoring the need for development of novel therapies and therapeutic strategies. Clinical trials to date have provided evidence of efficacy, but were limited in evaluating the scope and duration of treatment effects. Numerous potential targets in varied stages of drug development exist, in addition to novel uses of familiar therapies. The pursuit of gene and cell-based therapy continues, and device use to help acute deterioration and chronic management is emerging. This rapid surge of drug development has led to multicenter pivotal clinical trials and has resulted in novel ethical and global clinical trial concerns. This paper will provide an overview of the opportunities and challenges that await the development of novel treatments for PAH., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
45. Outcomes of noncardiac, nonobstetric surgery in patients with PAH: an international prospective survey.
- Author
-
Meyer S, McLaughlin VV, Seyfarth HJ, Bull TM, Vizza CD, Gomberg-Maitland M, Preston IR, Barberà JA, Hassoun PM, Halank M, Jaïs X, Nickel N, Hoeper MM, and Humbert M
- Subjects
- Aged, Anesthesia adverse effects, Familial Primary Pulmonary Hypertension, Female, Humans, International Cooperation, Male, Middle Aged, Perioperative Period, Postoperative Complications, Prospective Studies, Risk Factors, Surveys and Questionnaires, Treatment Outcome, Hypertension, Pulmonary physiopathology, Hypertension, Pulmonary surgery
- Abstract
We conducted an international, prospective, 3-year questionnaire-based survey among 11 pulmonary hypertension centres to assemble data from patients with pulmonary arterial hypertension (PAH) undergoing noncardiac and nonobstetric surgery. Data were collected between July 2007 and June 2010 from 114 patients with PAH (70% female, mean age 57 years) who underwent major surgery. At the time of surgery, 43% were in functional class III/IV. 82% of the interventions were performed under general anaesthesia and 18% under spinal anaesthesia. Major complications occurred in seven (6.1%) of the patients, of whom four died, resulting in an overall perioperative mortality rate of 3.5%. The mortality rate was 15% (two out of 13) in emergency procedures, compared with 2% (two out of 101) in nonemergency procedures (p=0.01). Risk factors for major complications were an elevated right atrial pressure (OR 1.1, 95% CI 1.0-1.3; p=0.01), a 6-min walking distance <399 m at the last preoperative assessment (OR 2.2, 95% CI 1.1-3.7; p=0.04), the perioperative use of vasopressors (OR 1.5, 95% CI 1.2-2.7; p=0.03) and the need for emergency surgery (OR 2.4, 95% CI 1.4-3.6; p=0.01). Major surgery in patients with PAH continues to be a high-risk procedure, particularly when emergency interventions are needed.
- Published
- 2013
- Full Text
- View/download PDF
46. Growth differentiation factor-15 and prognosis in acute respiratory distress syndrome: a retrospective cohort study.
- Author
-
Clark BJ, Bull TM, Benson AB, Stream AR, Macht M, Gaydos J, Meadows C, Burnham EL, and Moss M
- Subjects
- Adult, Biomarkers blood, Catheterization, Swan-Ganz, Female, Fluid Therapy, Humans, Male, Middle Aged, Prognosis, Pulmonary Artery physiopathology, Respiratory Distress Syndrome mortality, Respiratory Distress Syndrome physiopathology, Respiratory Distress Syndrome therapy, Retrospective Studies, Growth Differentiation Factor 15 blood, Respiratory Distress Syndrome blood
- Abstract
Introduction: We sought to determine whether higher levels of the novel biomarker growth differentiation factor-15 (GDF-15) are associated with poor outcomes and the presence of pulmonary vascular dysfunction (PVD) in patients with acute respiratory distress syndrome (ARDS)., Methods: We conducted a retrospective cohort study in patients enrolled in the Acute Respiratory Distress Syndrome Network Fluid and Catheter Treatment (FACT) Trial. Patients enrolled in the FACT Trial who received a pulmonary artery catheter (PAC), had plasma available from the same study day and sufficient hemodynamic data to determine the presence of PVD were included. Logistic regression was used to determine the association between GDF-15 level and 60-day mortality., Results: Of the 513 patients enrolled in the FACT Trial assigned to receive a PAC, 400 were included in this analysis. Mortality at 60 days was significantly higher in patients whose GDF-15 levels were in the third (28%) or fourth (49%) quartile when compared to patients with GDF-15 levels in the first quartile (12%) (P <0.001). Adjusting for severity of illness measured by APACHE III score, the odds of death for patients with GDF-15 levels in the fourth quartile when compared to the first quartile was 4.26 (95% CI 2.18, 10.92, P <0.001). When added to APACHE III alone for prediction of 60-day mortality, GDF-15 levels increased the area under the receiver operating characteristic curve from 0.72 to 0.77. At an optimal cutoff of 8,103 pg/mL, the sensitivity and specificity of GDF-15 for predicting 60-day mortality were 62% (95% CI 53%, 71%) and 76% (95% CI 71%, 81%), respectively. Levels of GDF-15 were not useful in identifying the presence of PVD, as defined by hemodynamic measurements obtained by a PAC., Conclusions: In patients with ARDS, higher levels of GDF-15 are significantly associated with poor outcome but not PVD.
- Published
- 2013
- Full Text
- View/download PDF
47. Mechanics and mechanisms of pulmonary hypertension: An introduction to the 55(th) annual Thomas L. Petty Aspen Lung Conference.
- Author
-
Bull TM and Stenmark KR
- Published
- 2013
- Full Text
- View/download PDF
48. Experiences with treprostinil in the treatment of pulmonary arterial hypertension.
- Author
-
Stream AR and Bull TM
- Subjects
- Antihypertensive Agents administration & dosage, Antihypertensive Agents pharmacology, Drug Approval, Drug Delivery Systems, Drug Stability, Drug Storage, Epoprostenol administration & dosage, Epoprostenol pharmacology, Epoprostenol therapeutic use, Europe, Familial Primary Pulmonary Hypertension, Humans, Hypertension, Pulmonary physiopathology, United States, Antihypertensive Agents therapeutic use, Epoprostenol analogs & derivatives, Hypertension, Pulmonary drug therapy
- Abstract
Pulmonary arterial hypertension (PAH) is a chronic condition of elevated pulmonary arterial pressures with associated increases in pulmonary vascular resistance leading to right ventricular failure, which was almost uniformly fatal prior to the introduction of pulmonary hypertension specific therapy. Systemic prostacyclin analogs are the first PAH-specific therapies to be made available and are typically recommended as first-line therapy for subjects with severe disease. Treprostinil is a newer prostacyclin analog similar to epoprostenol in its mechanism of action and relative efficacy with the advantage of a longer half life in human serum and room temperature stability. It is unique in that it is available in multiple formulations for alternative routes of delivery, including subcutaneous, intravenous and inhalational routes. Additionally, oral treprostinil is currently under investigation. Both subcutaneous and intravenous forms of treprostinil have demonstrated efficacy in short-term clinical trials and are currently approved for use in subjects with PAH and New York Heart Association functional class (NYHA FC) II-IV symptoms in the USA and for subjects with NYHA FC III and IV in Europe. Inhaled treprostinil has also demonstrated efficacy in short-term clinical trials primarily as add-on therapy and is currently approved for use in subjects with PAH and NYHA FC III-IV symptoms in the USA and Europe. The different formulations of treprostinil have significantly increased the treatment options and opportunities for treatment of patients with PAH.
- Published
- 2012
- Full Text
- View/download PDF
49. Loss-of-function thrombospondin-1 mutations in familial pulmonary hypertension.
- Author
-
Maloney JP, Stearman RS, Bull TM, Calabrese DW, Tripp-Addison ML, Wick MJ, Broeckel U, Robbins IM, Wheeler LA, Cogan JD, and Loyd JE
- Subjects
- Binding Sites, Cell Growth Processes genetics, Cells, Cultured, Cohort Studies, Conserved Sequence, DNA-Binding Proteins metabolism, Endothelial Cells metabolism, Familial Primary Pulmonary Hypertension, Female, Humans, Introns, Male, Myocytes, Smooth Muscle metabolism, Polymorphism, Genetic, Protein Binding, Pulmonary Artery metabolism, RNA Splicing genetics, Sp1 Transcription Factor metabolism, Transcription Factors metabolism, Transforming Growth Factor beta metabolism, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Hypertension, Pulmonary genetics, Hypertension, Pulmonary metabolism, Mutation, Missense
- Abstract
Most patients with familial pulmonary arterial hypertension (FPAH) carry mutations in the bone morphogenic protein receptor 2 gene (BMPR2). Yet carriers have only a 20% risk of disease, suggesting that other factors influence penetrance. Thrombospondin-1 (TSP1) regulates activation of TGF-β and inhibits endothelial and smooth muscle cell proliferation, pathways coincidentally altered in pulmonary arterial hypertension (PAH). To determine whether a subset of FPAH patients also have mutations in the TSP1 gene (THBS1) we resequenced the type I repeats of THBS1 encoding the TGF-β regulation and cell growth inhibition domains in 60 FPAH probands, 70 nonfamilial PAH subjects, and in large control groups. We identified THBS1 mutations in three families: a novel missense mutation in two (Asp362Asn), and an intronic mutation in a third (IVS8+255 G/A). Neither mutation was detected in population controls. Mutant 362Asn TSP1 had less than half of the ability of wild-type TSP1 to activate TGF-β. Mutant 362Asn TSP1 also lost the ability to inhibit growth of pulmonary arterial smooth muscle cells and was over threefold less effective at inhibiting endothelial cell growth. The IVS8+255 G/A mutation decreased and/or eliminated local binding of the transcription factors SP1 and MAZ but did not affect RNA splicing. These novel mutations implicate THBS1 as a modifier gene in FPAH. These THBS1 mutations have implications in the genetic evaluation of FPAH patients. However, since FPAH is rare, these data are most relevant as evidence for the importance of TSP1 in pulmonary vascular homeostasis. Further examination of THBS1 in the pathogenesis of PAH is warranted.
- Published
- 2012
- Full Text
- View/download PDF
50. Practical approach to screening for scleroderma-associated pulmonary arterial hypertension.
- Author
-
Fischer A, Bull TM, and Steen VD
- Subjects
- Humans, Physical Examination, Risk Factors, Hypertension, Pulmonary diagnosis, Hypertension, Pulmonary etiology, Scleroderma, Systemic complications
- Published
- 2012
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.