Publications by authors named "Richard N Channick"

85 Publications

Results From the United States Chronic Thromboembolic Pulmonary Hypertension Registry: Enrollment Characteristics and 1-Year Follow-up.

Chest 2021 Jun 4. Epub 2021 Jun 4.

Temple University Hospital, Philadelphia, PA.

Background: The United States Chronic Thromboembolic Pulmonary Hypertension Registry (US-CTEPH-R) was designed to characterize the demographic characteristics, evaluation, clinical course, and outcomes of surgical and nonsurgical therapies for patients with chronic thromboembolic pulmonary hypertension.

Research Question: What are the differences in baseline characteristics and 1-year outcomes between operated and nonoperated subjects?

Study Design And Methods: This study describes a multicenter, prospective, longitudinal, observational registry of patients newly diagnosed (< 6 months) with CTEPH. Inclusion criteria required a mean pulmonary artery pressure ≥ 25 mm Hg according to right heart catheterization and radiologic confirmation of CTEPH. Between 2015 and 2018, a total of 750 patients were enrolled and followed up biannually until 2019.

Results: Most patients with CTEPH (87.9%) reported a history of acute pulmonary embolism. CTEPH diagnosis delays were frequent (median, 10 months), and most patients reported World Health Organization functional class 3 status at enrollment with a median mean pulmonary artery pressure of 44 mm Hg. The registry cohort was subdivided into Operable patients undergoing pulmonary thromboendarterectomy (PTE) surgery (n = 566), Operable patients who did not undergo surgery (n = 88), and those who were Inoperable (n = 96). Inoperable patients were older than Operated patients; less likely to be obese; have a DVT history, non-type O blood group, or thrombophilia; and more likely to have COPD or a history of cancer. PTE resulted in a median pulmonary vascular resistance decline from 6.9 to 2.6 Wood units (P < .001) with a 3.9% in-hospital mortality. At 1-year follow-up, Operated patients were less likely treated with oxygen, diuretics, or pulmonary hypertension-targeted therapy compared with Inoperable patients. A larger percentage of Operated patients were World Health Organization functional class 1 or 2 at 1 year (82.9%) compared with the Inoperable (48.2%) and Operable/No Surgery (56%) groups (P < .001).

Interpretation: Differences exist in the clinical characteristics between patients who exhibited operable CTEPH and those who were inoperable, with the most favorable 1-year outcomes in those who underwent PTE surgery.

Clinical Trial Registration: ClinicalTrials.gov; No.: NCT02429284; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2021.05.052DOI Listing
June 2021

Significance of autoimmune disease in severe pulmonary hypertension complicating extensive pulmonary fibrosis: a prospective cohort study.

Pulm Circ 2021 Apr-Jun;11(2):20458940211011329. Epub 2021 May 2.

David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.

The association of autoimmune disease (AI) with transplant-free survival in the setting of Group 3 pulmonary hypertension and pulmonary fibrosis remains unclear. We report cases of severe pulmonary hypertension (mean pulmonary artery pressure ≥35 mmHg right ventricular dysfunction) and extensive pulmonary fibrosis after pulmonary arterial hypertension-specific therapy. We used multivariate regression to determine the clinical variables associated with transplant-free survival. Of 286 screened patients, 55 demonstrated severe pulmonary hypertension and extensive pulmonary fibrosis and were treated with parenteral prostacyclin therapy. The (+)AI subgroup (n = 34), when compared to the (-)AI subgroup (n = 21), was more likely to be female (77% versus 19%) and younger (58.7 ± 12.1 versus 66.0 ± 10.7 years), and revealed lower forced vital capacity (absolute) (1.9 ± 0.7 versus 2.9 ± 1.1 L), higher DCO (% predicted) (31.1 ± 15.2 versus 23.2 ± 8.0), and increased unadjusted transplant-free survival (1 year (84.6 ± 6.3% versus 45 ± 11.1%)), 3 years (71 ± 8.2% versus 28.6 ± 11.9%), and 5 years (47.6 ± 9.6% versus 6.4 ± 8.2%); (p = 0.01)). Transplant-free survival was unchanged after adjusting for age and gender. The pulmonary hemodynamic profiles improved after parenteral prostacyclin therapy, independent of AI status. The baseline variables associated with mortality included age at pulmonary hypertension diagnosis (heart rate (HR) 1.23 (confidence interval (CI) 1.03-1.47); p = 0.02) and presence of AI (HR 0.26 (confidence interval (CI) 0.10-0.70); p < 0.01). Gas exchange was not adversely affected by parenteral prostacyclin therapy. In the setting of Group 3 pulmonary hypertension and pulmonary fibrosis treated with pulmonary arterial hypertension-specific therapy, AI is independently associated with increased transplant-free survival. Pulmonary hypertension/pulmonary fibrosis associated with AI should be considered in future clinical trials of pulmonary arterial hypertension-specific therapy in Group 3 pulmonary hypertension.
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http://dx.doi.org/10.1177/20458940211011329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108092PMC
May 2021

The United States Chronic Thromboembolic Pulmonary Hypertension Registry: Protocol for a Prospective, Longitudinal Study.

JMIR Res Protoc 2021 May 25;10(5):e25397. Epub 2021 May 25.

Division of Cardiology, Temple University, Philadelphia, PA, United States.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare sequela of acute pulmonary embolism that is treatable when recognized. Awareness of this disease has increased with recent advancements in therapeutic options, but delays in diagnosis remain common, and diagnostic and treatment guidelines are often not followed. Data gathered from international registries have improved our understanding of CTEPH, but these data may not be applicable to the US population owing to differences in demographics and medical practice patterns.

Objective: The US CTEPH Registry (US-CTEPH-R) was developed to provide essential information to better understand the demographics, risk factors, evaluation, and treatment of CTEPH in the United States, as well as the short- and long-term outcomes of surgical and nonsurgical therapies in the modern treatment era.

Methods: Thirty sites throughout the United States enrolled 750 subjects in this prospective, longitudinal, observational registry of patients newly diagnosed with CTEPH. Enrollment criteria included a mean pulmonary artery pressure ≥25 mmHg by right heart catheterization and radiologic confirmation of CTEPH by a multidisciplinary adjudication committee. Following enrollment, subjects were followed biannually until the conclusion of the study. Quality of life surveys were administered at enrollment and biannually, and all other testing was at the discretion of the treating clinician. Details regarding surgical therapy, balloon pulmonary angioplasty, and medical therapy were collected at enrollment and at follow-up, as well as information related to health care utilization and survival.

Results: Data from this registry will improve understanding of the demographics, risk factors, and treatment patterns of patients with CTEPH, and the longitudinal impact of therapies on quality of life, health care utilization, and survival.

Conclusions: This manuscript details the methodology and design of the first large, prospective, longitudinal registry of patients with CTEPH in the United States.

Trial Registration: ClinicalTrials.gov NCT02429284; https://www.clinicaltrials.gov/ct2/show/NCT02429284.

International Registered Report Identifier (irrid): DERR1-10.2196/25397.
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http://dx.doi.org/10.2196/25397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188310PMC
May 2021

Vascular Endobronchial Ultrasound in a Patient With Chronic Thromboembolic Pulmonary Hypertension.

J Bronchology Interv Pulmonol 2021 Apr;28(2):e23-e26

Division of Pulmonary, Critical Care, Sleep Medicine, Clinical Immunology and Allergy David Geffen School of Medicine at UCLA Los Angeles, CA.

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http://dx.doi.org/10.1097/LBR.0000000000000713DOI Listing
April 2021

The Pulmonary Embolism Response Team: Why and How?

Semin Respir Crit Care Med 2021 Apr 16;42(2):212-217. Epub 2021 Feb 16.

Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.

Treatment of patients with intermediate and high-risk pulmonary embolism (PE) is a controversial area. Many therapeutic options exist, and deciding on appropriate treatment can be difficult. In addition, multiple specialties are often involved in the care of PE patients. To better organize the response to serious PE patients, several hospitals and academic centers throughout the world have created pulmonary embolism response teams (PERTs). The goal of a PERT is to have a single multidisciplinary team of experts in thromboembolic disease, who can respond rapidly to patients with acute PE, and offer consultation and implementation of the full spectrum of therapeutic options. PERT teams were modeled after rapid response teams and are meant to generate a prompt, patient-specific plan for patients with PE without having to consult multiple individual specialists. Data are emerging demonstrating the value of PERTs in reducing hospital length of stay and, possibly, patient outcomes.
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http://dx.doi.org/10.1055/s-0041-1722963DOI Listing
April 2021

Relationship Between Time From Diagnosis and Morbidity/Mortality in Pulmonary Arterial Hypertension: Results From the Phase III GRIPHON Study.

Chest 2021 Jul 3;160(1):277-286. Epub 2021 Feb 3.

Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Allgemeines Krankenhaus, Vienna, Austria.

Background: Early initiation of pulmonary arterial hypertension (PAH) therapies is associated with improved long-term outcomes, yet data on the early use of prostacyclin pathway agents are limited. In these post hoc analyses of the Prostacyclin (PGI) Receptor Agonist In Pulmonary Arterial Hypertension (GRIPHON) study, the largest randomized controlled trial for PAH to date, the prognostic value of time from diagnosis and its impact on treatment response were examined.

Research Question: How does time from diagnosis impact morbidity/mortality events and response to selexipag treatment in patients with PAH?

Study Design And Methods: The GRIPHON study randomly assigned 1,156 patients with PAH to selexipag or placebo treatment. Patients were categorized post hoc into a time from diagnosis of ≤ 6 months and > 6 months at randomization. Hazard ratios (selexipag vs placebo) were calculated for the primary end point of morbidity/mortality by time from diagnosis using Cox proportional hazard models.

Results: Time from diagnosis was ≤ 6 months in 34.9% and > 6 months in 65.1% of patients. Time from diagnosis was prognostic of morbidity/mortality, with newly diagnosed patients having a poorer long-term outcome than patients diagnosed for longer. Compared with placebo, selexipag reduced the risk of morbidity/mortality in patients with a time from diagnosis of ≤ 6 months and > 6 months, with a more pronounced effect in newly diagnosed patients (hazard ratio, 0.45 [95% CI, 0.33-0.63] and 0.74 [95% CI, 0.57-0.96], respectively; P = .0219 for interaction).

Interpretation: In the GRIPHON study, newly diagnosed PAH patients had a worse prognosis than patients with a longer time from diagnosis. The benefit of selexipag treatment on disease progression was more pronounced in patients treated earlier than in patients treated later.

Trial Registry: ClinicalTrials.gov; No.: NCT01106014; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2021.01.066DOI Listing
July 2021

NEDD9 Is a Novel and Modifiable Mediator of Platelet-Endothelial Adhesion in the Pulmonary Circulation.

Am J Respir Crit Care Med 2021 06;203(12):1533-1545

Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.

Data on the molecular mechanisms that regulate platelet-pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic implications. To identify a hypoxia-sensitive, modifiable mediator of platelet-pulmonary artery endothelial cell adhesion and thrombotic remodeling. Network medicine was used to profile protein-protein interactions in hypoxia-treated human pulmonary artery endothelial cells. Data from liquid chromatography-mass spectrometry and microscale thermophoresis informed the development of a novel antibody (Ab) to inhibit platelet-endothelial adhesion, which was tested in cells from patients with chronic thromboembolic pulmonary hypertension (CTEPH) and three animal models . The protein NEDD9 was identified in the hypoxia thrombosome network . Compared with normoxia, hypoxia (0.2% O) for 24 hours increased HIF-1α (hypoxia-inducible factor-1α)-dependent NEDD9 upregulation . Increased NEDD9 was localized to the plasma-membrane surface of cells from control donors and patients with CTEPH. In endarterectomy specimens, NEDD9 colocalized with the platelet surface adhesion molecule P-selectin. Our custom-made anti-NEDD9 Ab targeted the NEDD9-P-selectin interaction and inhibited the adhesion of activated platelets to pulmonary artery endothelial cells from control donors and from patients with CTEPH . Compared with control mice, platelet-pulmonary endothelial aggregates and pulmonary hypertension induced by ADP were decreased in NEDD9 mice or wild-type mice treated with the anti-NEDD9 Ab, which also decreased chronic pulmonary thromboembolic remodeling . The NEDD9-P-selectin protein-protein interaction is a modifiable target with which to inhibit platelet-pulmonary endothelial adhesion and thromboembolic vascular remodeling, with potential therapeutic implications for patients with disorders of increased hypoxia signaling pathways, including CTEPH.
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http://dx.doi.org/10.1164/rccm.202003-0719OCDOI Listing
June 2021

Sex Differences in Portopulmonary Hypertension.

Chest 2021 01 13;159(1):328-336. Epub 2020 Aug 13.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN.

Background: Portopulmonary hypertension (POPH), pulmonary arterial hypertension that develops in the setting of portal hypertension, can lead to right-sided heart failure and death. Being female is a known risk factor for POPH, but little is known about the effect of sex on clinical manifestations, hemodynamics, treatment response, and survival.

Research Question: We sought to characterize sex differences in clinical characteristics, pulmonary hemodynamics, treatment response, and survival in patients with POPH.

Study Design And Methods: We performed a retrospective cohort study of adult candidates for liver transplant (LT) who had POPH within the Organ Procurement and Transplantation Network database. Females and males were compared. Multivariate regression was performed to assess the association between sex and pulmonary vascular resistance (PVR) and survival. Patients were also stratified by age (50 years) to determine how age modifies the relationship between sex and hemodynamics and survival.

Results: We included 190 adults (103 male, 87 female). Compared with men, women had a lower model for end-stage liver disease (MELD) score (12.1± 4.2 vs 13.8 ± 4.9; P = .01) and were more likely to have autoimmune liver disease. Women had a higher baseline PVR (610.6 ± 366.6 vs 461.0 ± 185.3 dynes-s-cm; P < .001) and posttreatment PVR (244.6 ± 119.5 vs 202.0 ± 87.7 dynes-s-cm; P = .008) and a greater treatment response (ΔPVR) (-359.3 ± 381.9 vs -260.2 ± 177.3 dynes-s-cm; P = .03). In multivariate analysis, female sex (or gender) remained associated with a higher baseline PVR (P = .008). Women and men had overall similar survival (P > .05). When patients were stratified by age, being female was independently associated with worse waiting list survival after adjusting for MELD and PVR in younger patients (HR, 6.61; 95% CI, 1.25-35.08; P = .03) but not in older patients.

Interpretation: Compared with male candidates, female candidates for LT who had POPH had a higher PVR and lower MELD score and were more likely to have autoimmune liver disease. Women and men had similar overall survival, but female sex (or gender) was associated with worse survival in younger patients.
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http://dx.doi.org/10.1016/j.chest.2020.07.081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893306PMC
January 2021

Post-Intensive Care Unit Follow-up of Pulmonary Embolism.

Crit Care Clin 2020 Jul 11;36(3):561-570. Epub 2020 May 11.

Division of Pulmonary and Critical Care, University of California Los Angeles, David Geffen School of Medicine, 650 Charles East Young Drive South, Room 43-229 CHS, Los Angeles, CA 90095-1690, USA. Electronic address:

The post-intensive care unit follow-up of patients hospitalized with pulmonary embolism is crucial to the comprehensive care of these patients. This article discusses the recommended duration of intensive care unit stay after high-intermediate risk or high-risk pulmonary embolism, duration of anticoagulation after venous thromboembolism event, retrieval of inferior vena cava filters, post-hospitalization follow-up and assessment of right ventricular function, and assessment for chronic thromboembolic pulmonary hypertension, chronic thromboembolic disease, and post-pulmonary embolism syndrome.
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http://dx.doi.org/10.1016/j.ccc.2020.03.002DOI Listing
July 2020

Free-Floating Right Atrial Thrombus Removed by Aspiration Thrombectomy under Transesophageal Guidance.

Am J Respir Crit Care Med 2020 07;202(1):e1-e2

Division of Pulmonary, Critical Care, Sleep Medicine, Clinical Immunology and Allergy, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; and.

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http://dx.doi.org/10.1164/rccm.201909-1756IMDOI Listing
July 2020

Risk assessment in pulmonary arterial hypertension: Insights from the GRIPHON study.

J Heart Lung Transplant 2020 04 21;39(4):300-309. Epub 2020 Jan 21.

Department of Respiratory Medicine and German Center of Lung Research, Hannover Medical School, Hannover, Germany.

Background: Approaches to risk assessment in pulmonary arterial hypertension (PAH) include the noninvasive French risk assessment approach (number of low-risk criteria based on the European Society of Cardiology and European Respiratory Society guidelines) and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) 2.0 risk calculator. The prognostic and predictive value of these methods for morbidity/mortality was evaluated in the predominantly prevalent population of GRIPHON, the largest randomized controlled trial in PAH.

Methods: GRIPHON randomized 1,156 patients with PAH to selexipag or placebo. Post-hoc analyses were performed on the primary composite end-point of morbidity/mortality by the number of low-risk criteria (World Health Organization functional class I-II; 6-minute walk distance >440 m; N-terminal pro-brain natriuretic peptide <300 ng/liter) and REVEAL 2.0 risk category. Hazard ratios and 95% confidence intervals were calculated using Cox proportional hazard models.

Results: Both the number of low-risk criteria and the REVEAL 2.0 risk category were prognostic for morbidity/mortality at baseline and any time-point during the study. Patients with 3 low-risk criteria at baseline had a 94% reduced risk of morbidity/mortality compared to patients with 0 low-risk criteria and were all categorized as low-risk by REVEAL 2.0. The treatment effect of selexipag on morbidity/mortality was consistent irrespective of the number of low-risk criteria or the REVEAL 2.0 risk category at any time-point during the study. Selexipag-treated patients were more likely to increase their number of low-risk criteria from baseline to week 26 than placebo-treated patients (odds ratio 1.69, p = 0.0002); similar results were observed for REVEAL 2.0 risk score.

Conclusions: These results support the association between risk profile and long-term outcome and suggest that selexipag treatment may improve risk profile.
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http://dx.doi.org/10.1016/j.healun.2019.12.013DOI Listing
April 2020

Circulating NEDD9 is increased in pulmonary arterial hypertension: A multicenter, retrospective analysis.

J Heart Lung Transplant 2020 04 31;39(4):289-299. Epub 2019 Dec 31.

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: Pulmonary arterial hypertension (PAH) is a highly morbid disease characterized by elevated pulmonary vascular resistance (PVR) and pathogenic right ventricular remodeling. Endothelial expression of the prometastatic protein NEDD9 is increased in fibrotic PAH arterioles, and NEDD9 inhibition decreases PVR in experimental PAH. We hypothesized that circulating NEDD9 is increased in PAH and informs the clinical profile of patients.

Methods: Clinical data and plasma samples were analyzed retrospectively for 242 patients from 5 referral centers (2010-2017): PAH (n = 139; female 82%, 58 [48-67] years), non-PAH pulmonary hypertension (PH) (n = 54; female 56%, 63.4 ± 12.2 years), and dyspnea non-PH controls (n = 36; female 75%, 54.2 ± 14.0 years).

Results: Compared with controls, NEDD9 was increased in PAH by 1.82-fold (p < 0.0001). Elevated NEDD9 correlated with PVR in idiopathic PAH (ρ = 0.42, p < 0.0001, n = 54), connective tissue disease (CTD)-PAH (ρ = 0.53, p < 0.0001, n = 53), and congenital heart disease-PAH (ρ = 0.68, p < 0.0001, n = 10). In CTD-PAH, NEDD9 correlated with 6-minute walk distance (ρ = -0.35, p = 0.028, n = 39). In contrast to the PAH biomarker N-terminal pro-brain natriuretic peptide (n = 38), NEDD9 correlated inversely with exercise pulmonary artery wedge pressure and more strongly with right ventricular ejection fraction (ρ = -0.41, p = 0.006, n = 45) in a mixed population. The adjusted hazard ratio for lung transplant-free survival was 1.12 (95% confidence interval [CI], 1.02-1.22, p = 0.01) and 1.75 (95% CI, 1.12-2.73, p = 0.01) per 1 ng/ml and 5 ng/ml increase in plasma NEDD9, respectively, by Cox proportional hazard model.

Conclusions: In PAH, plasma NEDD9 is increased and associates with key prognostic variables. Prospective studies that include hard end points are warranted to validate NEDD9 as a novel PAH biomarker.
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http://dx.doi.org/10.1016/j.healun.2019.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605895PMC
April 2020

Unilateral Chronic Thromboembolic Pulmonary Disease: A Mimic of Pulmonary Artery Agenesis.

Am J Respir Crit Care Med 2020 05;201(10):e74-e75

Division of Pulmonary, Critical Care and Sleep Medicine, Tufts University School of Medicine, Boston, Massachusetts.

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http://dx.doi.org/10.1164/rccm.201905-0997IMDOI Listing
May 2020

Rebuttal From Drs Channick and Saggar.

Chest 2019 12;156(6):1047-1048

David Geffen School of Medicine at UCLA, Los Angeles, CA.

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http://dx.doi.org/10.1016/j.chest.2019.07.006DOI Listing
December 2019

COUNTERPOINT: Should Initial Combination Therapy Be the Standard of Care in Pulmonary Arterial Hypertension? No.

Chest 2019 12;156(6):1043-1045

David Geffen School of Medicine at UCLA, Los Angeles, CA.

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http://dx.doi.org/10.1016/j.chest.2019.07.004DOI Listing
December 2019

Safety and tolerability of macitentan in the management of pulmonary arterial hypertension: an update.

Drug Healthc Patient Saf 2019 3;11:71-85. Epub 2019 Sep 3.

Division of Pulmonary and Critical Care, University of California Los Angeles Medical Center, Los Angeles, CA 90095, USA.

Macitentan is a medication in the endothelin receptor antagonist class, approved for treatment of pulmonary arterial hypertension in 2013 based on the results of the pivotal SERAPHIN Trial (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome). Macitentan was shown in initial trials to reduce the likelihood of a morbidity/mortality event. Real-world use of this medication additionally reveals a reduced risk of hospitalizations related to pulmonary arterial hypertension, improved health-related quality of life scores, potential clinical utility in other conditions (such as chronic thromboembolic pulmonary hypertension and pulmonary hypertension related to congenital heart disease), and has a similar safety profile as demonstrated in initial trials.
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http://dx.doi.org/10.2147/DHPS.S173050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731963PMC
September 2019

Portopulmonary Hypertension: A Survey of Practice Patterns and Provider Attitudes.

Transplant Direct 2019 Jun 22;5(6):e456. Epub 2019 May 22.

Department of Medicine, Mayo Clinic, Rochester, MN.

Background: The role of liver transplantation (LT) in the management of portopulmonary hypertension (POPH) is poorly understood. The aim of this study was to better understand provider attitudes and practice patterns regarding the management of patients with POPH and to assess the concordance between clinical practice and current guidelines.

Methods: We performed a multicenter survey study of hepatologists and pulmonary hypertension (PH) physicians at US LT centers that performed >50 transplants per year. Survey responses are summarized as number (%). Associations were assessed using a Wilcoxon-rank sum, chi-square, or Fisher exact test, as appropriate.

Results: Seventy-four providers from 35 centers were included. There was marked variability regarding screening practices, management, and attitudes. Forty-two percent responded that POPH nearly always or often improves with LT, and 15.5% reported that POPH rarely or never improves. In contrast to current guidelines, 50.7% agreed that treated POPH should be an indication for LT in patients with compensated cirrhosis. Hepatologists were more likely than PH physicians to agree that POPH should be an indication for LT ( = 0.02). Forty-nine percent of respondents thought that the current POPH Model for End-stage Liver Disease exception criteria should be modified, and management of patients with an elevated mean pulmonary arterial pressure and normal pulmonary vascular resistance differed from current policies.

Conclusions: There is marked variability in provider attitudes and practice patterns regarding the management of POPH. This study highlights the need for prospective studies to inform practice and for improved implementation of practice guidelines in order to standardize care.
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http://dx.doi.org/10.1097/TXD.0000000000000900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553621PMC
June 2019

Use of Endobronchial Ultrasound for Bedside Diagnosis of Acute Pulmonary Embolism in a Critically Ill Patient.

Chest 2019 03;155(3):651-652

Division of Pulmonary, Critical Care, Sleep Medicine, Clinical Immunology and Allergy, David Geffen School of Medicine at UCLA, Los Angeles, CA.

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http://dx.doi.org/10.1016/j.chest.2018.11.013DOI Listing
March 2019

Selexipag treatment for pulmonary arterial hypertension associated with congenital heart disease after defect correction: insights from the randomised controlled GRIPHON study.

Eur J Heart Fail 2019 03 11;21(3):352-359. Epub 2019 Jan 11.

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Bologna University Hospital, Bologna, Italy.

Aims: Patients with pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) after defect correction have a poor prognosis compared with other CHD-PAH patients. Therefore, it is important that these patients are treated as early and effectively as possible. Evidence supporting the use of PAH therapies in patients with corrected CHD-PAH from randomised controlled trials is limited. The purpose of these analyses was to characterise the corrected CHD-PAH patients from the GRIPHON study and examine the response to selexipag.

Methods And Results: Out of the 110 patients diagnosed with corrected CHD-PAH, 55 had atrial septal defects, 38 had ventricular septal defects, 14 had persistent ducti arteriosus, and 3 had defects not further specified. Hazard ratios (HR) and 95% confidence intervals (CI) for the primary composite endpoint were calculated using Cox proportional hazard models. Compared with the non-CHD patients from GRIPHON, patients with corrected CHD-PAH were slightly younger, with a greater proportion being treatment-naive and in World Health Organization functional class I/II. The rate of the primary composite endpoint of morbidity/mortality was lower in patients with corrected CHD-PAH who were treated with selexipag compared with those treated with placebo (HR 0.58; 95% CI 0.25, 1.37). The most common adverse events were those known to be related to selexipag.

Conclusions: These post-hoc analyses of GRIPHON provide valuable information about a large population of patients with corrected CHD-PAH, and suggest that selexipag may delay disease progression and was well-tolerated in patients with corrected CHD-PAH.
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http://dx.doi.org/10.1002/ejhf.1375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607487PMC
March 2019

Risk stratification and medical therapy of pulmonary arterial hypertension.

Eur Respir J 2019 01 24;53(1). Epub 2019 Jan 24.

Cardiovascular Medicine, The University of Michigan, Ann Arbor, MI, USA.

Pulmonary arterial hypertension (PAH) remains a severe clinical condition despite the availability over the past 15 years of multiple drugs interfering with the endothelin, nitric oxide and prostacyclin pathways. The recent progress observed in medical therapy of PAH is not, therefore, related to the discovery of new pathways, but to the development of new strategies for combination therapy and on escalation of treatments based on systematic assessment of clinical response. The current treatment strategy is based on the severity of the newly diagnosed PAH patient as assessed by a multiparametric risk stratification approach. Clinical, exercise, right ventricular function and haemodynamic parameters are combined to define a low-, intermediate- or high-risk status according to the expected 1-year mortality. The current treatment algorithm provides the most appropriate initial strategy, including monotherapy, or double or triple combination therapy. Further treatment escalation is required in case low-risk status is not achieved in planned follow-up assessments. Lung transplantation may be required in most advanced cases on maximal medical therapy.
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http://dx.doi.org/10.1183/13993003.01889-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351343PMC
January 2019

Psychometric Validation of the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Questionnaire: Results of the SYMPHONY Trial.

Chest 2018 10 26;154(4):848-861. Epub 2018 Apr 26.

University of Colorodo Denver, Cardiology/Pulmonary Sciences & Critical Care Medicine, Aurora, CO.

Background: Disease-specific patient-reported outcome (PRO) instruments are important in assessing the impact of disease and treatment. The Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire is the first instrument for quantifying pulmonary arterial hypertension (PAH) symptoms and impacts developed according to the 2009 US Food and Drug Administration PRO guidance; previous qualitative research in patients with PAH supported its initial content validity.

Methods: Content finalization and psychometric validation were conducted by using data from A Study of Macitentan in Pulmonary Arterial Hypertension to Validate the PAH-SYMPACT (SYMPHONY), a single-arm, 16-week trial with macitentan 10 mg in US patients with PAH. Item performance, Rasch analysis, and factor analyses were used to select the final item content of the PRO and to define its domain structure. Internal consistency, test-retest reliability, known-group and construct validity, sensitivity to change, and influence of oxygen on item performance were evaluated.

Results: Data from 278 patients (79% female; mean age: 60 years) were analyzed. Following removal of redundant/misfitting items, the final questionnaire has 11 symptom items across two domains (cardiopulmonary and cardiovascular symptoms) and 11 impact items across two domains (physical and cognitive/emotional impacts). Differential item function analysis confirmed that PRO scoring is unaffected by oxygen use. For all four domains, internal consistency reliability was high (Cronbach's alpha > 0.80), and scores were highly reproducible in stable patients (intraclass correlation coefficient: 0.84-0.94). Correlations with the Cambridge Pulmonary Hypertension Outcome Review questionnaire and the 36-item Medical Outcomes Study Short Form Survey were moderate to high ([r] = 0.34-0.80). The questionnaire differentiated well between patients with varying disease severity levels and was sensitive to improvements in clinician- and patient-reported disease severity.

Conclusions: The Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire is a brief, disease-specific PRO instrument possessing good psychometric properties that can be administered in clinical practice and clinical studies.

Trial Registry: ClinicalTrials.gov; No.: NCT01841762; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2018.04.027DOI Listing
October 2018

Association between six-minute walk distance and long-term outcomes in patients with pulmonary arterial hypertension: Data from the randomized SERAPHIN trial.

PLoS One 2018 28;13(3):e0193226. Epub 2018 Mar 28.

Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.

Background: Patients with pulmonary arterial hypertension who achieve a six-minute walk distance of 380-440 m may have improved prognosis. Using the randomized controlled trial of macitentan in pulmonary arterial hypertension (SERAPHIN), the association between six-minute walk distance and long-term outcomes was explored.

Methods: Patients with six-minute walk distance data at Month 6 were dichotomized as above or below the median six-minute walk distance (400 m) and assessed for future risk of pulmonary arterial hypertension-related death or hospitalization and all-cause death. Additionally, six-minute walk distance values at baseline, Month 6 and the change from baseline to Month 6 were categorized by quartiles. All associations were analyzed by the Kaplan-Meier method using a log-rank test and Cox regression models.

Results: Patients with a six-minute walk distance >400 m vs. ≤400 m at Month 6 have a reduced risk of pulmonary arterial hypertension-related death or hospitalization (hazard ratio 0.48; 95% confidence interval 0.33-0.69). The risk was also lower for patients with higher quartiles of six-minute walk distance at baseline or Month 6 (baseline: hazard ratio [Q4 (>430 m) vs. Q1 (≤300 m)] 0.23; 95% confidence interval 0.15-0.36; Month 6: hazard ratio [Q4 (>455 m) vs. Q1 (≤348 m)] 0.33; 95% confidence interval 0.19-0.55). In contrast, six-minute walk distance changes at Month 6 were not associated with the risk of pulmonary arterial hypertension-related death or hospitalization (p = 0.477). These findings were consistent when adjusted for known confounders. Similar results were observed for the risk of all-cause death up to end of study.

Conclusions: Patients with pulmonary arterial hypertension walking >400 m had better long-term prognosis. Although changes in six-minute walk distance were not associated with long-term outcomes, assessing absolute six-minute walk distance values remains important in the clinical management of patients with pulmonary arterial hypertension.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193226PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873992PMC
June 2018

Pulmonary Arterial Hypertension-Related Morbidity Is Prognostic for Mortality.

J Am Coll Cardiol 2018 02;71(7):752-763

Istituto di Malattie dell'Apparato Cardiovascolare, Università di Bologna, Bologna, Italy.

Background: Registry data suggest that disease progression in pulmonary arterial hypertension (PAH) is indicative of poor prognosis. However, the prognostic relevance of PAH-related morbidity has not been formally evaluated in randomized controlled trials.

Objectives: The purpose of these analyses was to assess the impact of morbidity events on the risk of subsequent mortality using the landmark method and data from the SERAPHIN and GRIPHON studies.

Methods: For each study, the risk of all-cause death up to the end of the study was assessed from the landmark time point (months 3, 6, and 12) according to whether a patient had experienced a primary endpoint morbidity event before the landmark. Each analysis was conducted using data from all patients who were available for survival follow-up at the landmark.

Results: In the SERAPHIN study, on the basis of the 3-month landmark time point, patients who experienced a morbidity event before month 3 had an increased risk of death compared with patients who did not (hazard ratio [HR]: 3.39; 95% confidence interval [CI]: 1.94 to 5.92). In the GRIPHON study, on the basis of the 3-month landmark time point, there was also an increased risk with a HR of 4.48; (95% CI: 2.98 to 6.73). Analyses based on 6-month and 12-month landmarks also showed increased risk in patients who experienced morbidity events, albeit with a reduced HR.

Conclusions: These results demonstrate the prognostic relevance of PAH-related morbidity as defined in the SERAPHIN and GRIPHON studies, highlighting the importance of preventing disease progression in patients with PAH and supporting the clinical relevance of SERAPHIN and GRIPHON morbidity events. (Study of Macitentan [ACT-064992] on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension [SERAPHIN]; NCT00660179; Selexipag [ACT-293987] in Pulmonary Arterial Hypertension [GRIPHON]; NCT01106014).
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http://dx.doi.org/10.1016/j.jacc.2017.12.010DOI Listing
February 2018

Quantifying the learning curve for pulmonary thromboendarterectomy.

J Cardiothorac Surg 2017 Dec 28;12(1):121. Epub 2017 Dec 28.

Division of Thoracic Surgery, Massachusetts General Hospital, 55 Fruit Street, Founders 7, Boston, Massachusetts, 02114, USA.

Background: Pulmonary thromboendarterectomy (PTE) is an effective treatment for chronic thromboembolic pulmonary hypertension (CTEPH), but is a technically challenging operation for cardiothoracic surgeons. Starting a new program allows an opportunity to define a learning curve for PTE.

Methods: A retrospective case review was performed of 134 consecutive PTEs performed from 1998 to 2016 at a single institution. Outcomes were compared using either a two-tailed t-test for continuous variables or a chi-squared test for categorical variables according to experience of the program by terciles (T).

Results: The 30-day mortality was 3.7%. The mean length of hospital stay, length of ICU stay, and duration on a ventilator were 12.6 days, 4.6 days, and 2.0 days, respectively. The mean decrease in systolic pulmonary artery pressure (sPAP) was 41.3 mmHg. Patients with Jamieson type 2 disease had a greater change in mean sPAP than those with type 3 disease (p = 0.039). The mean cardiopulmonary bypass time was 180 min (T1-198 min, T3-159 min, p = <0.001), and the mean circulatory arrest time was 37 min (T1-44 min, T3-31 min, p < 0.001). Plotting circulatory arrest times as a running sum compared to the mean demonstrated 2 inflection points, the first at 22 cases and the second at 95 cases.

Conclusions: PTE is a challenging procedure to learn, and good outcomes are a result of a multi-disciplinary effort to optimize case selection, operative performance, and postoperative care. Approximately 20 cases are needed to become proficient in PTE, and nearly 100 cases are required for more efficient clearing of obstructed pulmonary arteries.
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http://dx.doi.org/10.1186/s13019-017-0686-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747243PMC
December 2017

Temporary treatment interruptions with oral selexipag in pulmonary arterial hypertension: Insights from the Prostacyclin (PGI) Receptor Agonist in Pulmonary Arterial Hypertension (GRIPHON) study.

J Heart Lung Transplant 2018 03 2;37(3):401-408. Epub 2017 Oct 2.

Department of Medicine, University of California, San Diego Medical School, San Diego, California.

Background: Parenteral prostacyclin analogs that target the prostacyclin pathway have been used to treat pulmonary arterial hypertension (PAH) since the 1990s. Abrupt discontinuation of parenteral prostacyclin analogs can be associated with acute deterioration of PAH. Less is known about temporary interruption of oral therapies that target the prostacyclin pathway, such as selexipag.

Methods: We evaluated the frequency, duration, reasons, and consequences of temporary selexipag interruptions among PAH patients enrolled in the Prostacyclin (PGI) Receptor Agonist in Pulmonary Arterial Hypertension (GRIPHON) study. In GRIPHON, patients were randomized to selexipag or placebo and titrated to an individualized highest tolerated dose (200 to 1,600 µg twice daily) over 12 weeks, after which patients entered the maintenance phase. Treatment interruptions were allowed; if the interruption was < 3 days, treatment was restarted at the previous highest tolerated dose; if the interruption was ≥ 3 days, retitration from 200 µg twice daily was required. Descriptive analyses were performed.

Results: At least 1 treatment interruption occurred in 111 of 574 patients (19.3%) in the selexipag group and in 58 of 582 (10.0%) in the placebo group. Baseline characteristics were similar between patients with and without an interruption. Of the 111 patients in whom selexipag was temporarily interrupted, 94 (85%) were receiving background PAH therapy. Adverse events were the most common reason for selexipag interruption. Selexipag interruptions and reinstitution of treatment were well tolerated. There were no episodes of acute deterioration during treatment interruption.

Conclusions: Based on observations from GRIPHON, selexipag interruptions can be expected in clinical practice. However, temporarily interrupting selexipag was well tolerated and manageable.
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http://dx.doi.org/10.1016/j.healun.2017.09.024DOI Listing
March 2018

SERAPHIN haemodynamic substudy: the effect of the dual endothelin receptor antagonist macitentan on haemodynamic parameters and NT-proBNP levels and their association with disease progression in patients with pulmonary arterial hypertension.

Eur Heart J 2017 04;38(15):1147-1155

Department of Pulmonary Circulation and Thromboembolic Diseases, Medical Center for Postgraduate Education, ECZ-Otwock, Poland.

Aims: The effect of macitentan on haemodynamic parameters and NT-proBNP levels was evaluated in pulmonary arterial hypertension (PAH) patients in the SERAPHIN study. Association between these parameters and disease progression, assessed by the primary endpoint (time to first morbidity/mortality event), was explored.

Methods And Results: Of the 742 randomized patients, 187 with right heart catheterization at baseline and month 6 participated in a haemodynamic sub-study. Prespecified endpoints included change from baseline to month 6 in cardiac index (CI), right atrial pressure (RAP), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), mixed-venous oxygen saturation, and NT-proBNP. Exploratory analyses examined associations between CI, RAP, and NT-proBNP and disease progression using the Kaplan-Meier method and Cox regression models. Macitentan improved CI, RAP, mPAP, PVR and NT-proBNP vs. placebo at month 6. Absolute levels of CI, RAP and NT-proBNP at baseline and month 6, but not their changes, were associated with morbidity/mortality events. Patients with CI > 2.5 L/min/m2, RAP < 8 mmHg, or NT-proBNP < 750 fmol/ml at month 6 had a lower risk of morbidity/mortality than those not meeting these thresholds (HR 0.49, 95% CL 0.28-0.86; HR 0.72, 95% CL 0.42-1.22; and HR 0.22, 95% CL 0.15-0.33, respectively).

Conclusions: For all treatment groups, baseline and month 6 values of CI, RAP, and NT-proBNP, but not their changes, were associated with morbidity/mortality events, confirming their relevance in predicting disease progression in patients with PAH. By improving those parameters, macitentan increased the likelihood of reaching threshold values associated with lower risk of morbidity/mortality.
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http://dx.doi.org/10.1093/eurheartj/ehx025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400052PMC
April 2017

Predictors of Waitlist Mortality in Portopulmonary Hypertension.

Transplantation 2017 07;101(7):1609-1615

Department of Medicine, Massachusetts General Hospital Boston, MA USA.

Background: The current Organ Procurement Transplantation Network policy grants Model for End-Stage Liver Disease (MELD) exception points to patients with portopulmonary hypertension (POPH), but potentially important factors, such as severity of liver disease and pulmonary hypertension, are not included in the exception score, and may affect survival. The purpose of this study was to identify significant predictors of waitlist mortality in patients with POPH.

Methods: We performed a retrospective cohort study of patients in the Organ Procurement and Transplantation Network database with hemodynamics consistent with POPH (defined as mean pulmonary arterial pressure >25 mm Hg and pulmonary vascular resistance [PVR] ≥240 dynes·s·cm) who were approved for a POPH MELD exception between 2006 and 2014. Using a Cox proportional hazards model, we identified predictors of waitlist mortality (or removal for clinical deterioration).

Results: One hundred ninety adults were included. Age (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.00-1.08; P = 0.0499), initial native MELD score (HR, 1.11; 95% CI, 1.05-1.17; P < 0.001), and initial PVR (HR, 1.12 per 100 dynes·s·cm; 95% CI, 1.02-1.23; P = 0.02) were the only significant univariate predictors of waitlist mortality and remained significant predictors in a multivariate model, which had a c-statistic of 0.71. PVR and mean pulmonary arterial pressure were not significant predictors of posttransplant mortality.

Conclusions: Both the severity of liver disease and POPH (as assessed by MELD and PVR, respectively) were significantly associated with waitlist, but not posttransplant, mortality in patients with approved MELD exceptions for POPH. Both factors should potentially be included in the POPH MELD exception score to more accurately reflect waitlist mortality risk.
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http://dx.doi.org/10.1097/TP.0000000000001666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481480PMC
July 2017

Macrophage migration inhibitory factor as a novel biomarker of portopulmonary hypertension.

Pulm Circ 2016 Dec;6(4):498-507

Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

Portopulmonary hypertension (POPH) is a poorly understood complication of liver disease associated with significant morbidity and mortality. We sought to identify novel biomarkers of POPH disease presence and severity. We performed a prospective, multicenter, case-control study involving patients with liver disease undergoing right heart catheterization. POPH cases were defined as a mean pulmonary arterial pressure (mPAP) ≥25 mmHg and pulmonary vascular resistance (PVR) >240 dynes˙s˙cm. Plasma samples were collected from the systemic and pulmonary circulation, and antibody microarray was used to identify biomarkers. Characterization and validation of a candidate cytokine, macrophage migration inhibitory factor (MIF), was performed using enzyme-linked immunosorbent assay. Continuous variables were compared using a Mann-Whitney test and correlated with disease severity using Spearman correlation. MIF levels were elevated in both the systemic and pulmonary circulation in patients with POPH compared with controls (median MIF level [interquartile range] in systemic circulation: 46.68 ng/mL [32.31-76.04] vs. 31.19 ng/mL [26.92-42.17], = 0.009; in pulmonary circulation: 49.59 ng/mL [35.90-108.80] vs. 37.78 [21.78-45.53], = 0.002). In patients with POPH, MIF levels were positively correlated with PVR ( = 0.58, = 0.006) and inversely correlated with cardiac output ( = -0.57, = 0.007). MIF >60 ng/mL or tricuspid regurgitation gradient >50 mmHg had a 92% sensitivity and specificity for the diagnosis of POPH, with a positive predictive value of 86% and a negative predictive value of 96%. MIF is a promising novel biomarker of POPH disease presence and severity in patients with liver disease and portal hypertension.
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http://dx.doi.org/10.1086/688489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210057PMC
December 2016