Publications by authors named "Peter J Leary"

54 Publications

Pulmonary Hypertension in the Context of Heart Failure with Preserved Ejection Fraction.

Chest 2021 Aug 12. Epub 2021 Aug 12.

Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, SC USA. Electronic address:

Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure and is frequently associated with pulmonary hypertension (PH). PH-HFpEF may be difficult to distinguish from pre-capillary forms of PH, though this distinction is crucial as therapeutic pathways are divergent for the two conditions. A comprehensive and systematic approach utilizing history, clinical exam, non-invasive and invasive evaluation with and without provocative testing may be necessary for accurate diagnosis and phenotyping. Once diagnosed, PH-HFpEF can be subdivided into isolated post-capillary pulmonary hypertension (IpcPH) and combined post- and pre-capillary pulmonary hypertension (CpcPH) based on the presence or absence of elevated pulmonary vascular resistance (PVR). CpcPH portends a worse prognosis than IpcPH. Despite its association with reduced functional capacity and quality of life, heart failure hospitalizations, and higher mortality, therapeutic options focused on pulmonary hypertension for PH-HFpEF remain limited. In this review, we aim to provide an updated overview on clinical definitions and hemodynamically characterized phenotypes of PH, pathophysiology, therapeutic strategies, and ongoing challenges in this patient population.
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http://dx.doi.org/10.1016/j.chest.2021.08.039DOI Listing
August 2021

Balloon Pulmonary Angioplasty in Chronic Totally Occluded Pulmonary Arteries: Applying Lessons Learned From the Treatment of Coronary Artery Chronic Total Occlusions.

J Invasive Cardiol 2021 Aug;33(8):E632-E639

University of Washington Medical Center, Box 356422, Seattle, WA 98195 USA.

Objectives: This study aims to describe the safety and efficacy of revascularizing chronic total occlusions (CTOs) of the pulmonary arteries with balloon pulmonary angioplasty (BPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH).

Background: BPA has emerged as an effective treatment for CTEPH patients when surgical treatment is not possible. Experience to date has suggested treating CTOs may be associated with excess risk and less procedural success relative to other lesion types.

Methods: This study is a retrospective case series of all BPAs on CTOs for individuals with CTEPH at a single institution. Procedural approach, complications, and success rate over a 6-month period are described.

Results: During the study period, 6 individuals with 15 CTOs were identified and intervened upon during 21 interventions. Success rate for revascularization was 62% per attempt and 87% per lesion. Techniques used for successful intervention include true to true lumen wiring (n = 7) and subintimal dissection re-entry with subintimal tracking and re-entry (n = 3), Stingray balloon (Boston Scientific) assisted re-entry (n = 2), and direct wire re-entry (n = 1). Wire perforations were relatively common and occurred in 62% of interventions, but rarely resulted in a change in clinical status.

Conclusions: Although important barriers to routine intervention on CTOs in CTEPH remain, the current series suggests a higher success rate than previously reported experiences using CTO revascularization techniques including subintimal tracking and re-entry and Stingray balloon-assisted re-entry. Although the frequency of wire perforation was relatively high, the clinical ramifications of these complications were mild.
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August 2021

A novel approach to perioperative risk assessment for patients with pulmonary hypertension.

ERJ Open Res 2021 Jul 19;7(3). Epub 2021 Jul 19.

Dept of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.

Rationale: Pulmonary hypertension (PH) is associated with significant perioperative morbidity and mortality. We hypothesised that pulmonary arterial hypertension (PAH) composite risk assessment scores could estimate perioperative risk for PH patients when adjusted for inherent procedural risk.

Methods: We identified patients in the Johns Hopkins PH Center Registry that had noncardiac surgery (including endoscopies) between September 2015 and January 2020. We collected information on preoperative patient-level and procedural variables and used logistic regression to evaluate associations with a composite outcome of death within 30 days or serious postoperative complication. We generated composite patient-level risk assessment scores for each subject and used logistic regression to estimate the association with adverse surgical outcomes. We adjusted multivariable models for inherent procedural risk of major cardiovascular events and used these models to generate a numerical PH perioperative risk (PHPR) score.

Results: Among 150 subjects, 19 (12.7%) reached the primary outcome, including 7 deaths (4.7%). Individual patient-level and procedural variables were associated with the primary outcome (all p<0.05). A composite patient-level risk assessment score built on three noninvasive parameters was strongly associated with reduced risk for poor outcomes (OR=0.4, p=0.03). This association was strengthened after adjusting the model for procedural risk. A PHPR score derived from the multivariable model stratified patients into low (0%), intermediate (≤10%), or high (>10%) risk of reaching the primary outcome.

Conclusion: Composite PAH risk assessment scores can predict perioperative risk for PH patients after accounting for inherent procedural risk. Validation of the PHPR score in a multicentre, prospective cohort is warranted.
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http://dx.doi.org/10.1183/23120541.00257-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287131PMC
July 2021

Associations of Angiopoietins With Heart Failure Incidence and Severity.

J Card Fail 2021 Jul 17;27(7):786-795. Epub 2021 Apr 17.

University of Washington, Department of Medicine, Seattle, WA; University of Washington, Department of Epidemiology, Seattle, WA. Electronic address:

Background: Angiopoietin-1 and 2 (Ang1, Ang2) are important mediators of angiogenesis. Angiopoietin levels are perturbed in cardiovascular disease, but it is unclear whether angiopoietin signaling is causative, an adaptive response, or merely epiphenomenon of disease activity.

Methods And Results: In a cohort free of cardiovascular disease at baseline (Multi-Ethnic Study of Atherosclerosis [MESA]), relationships between angiopoietins, cardiac morphology, and subsequent incidence of heart failure or cardiovascular death were evaluated. In cohorts with pulmonary arterial hypertension or left heart disease, associations between angiopoietins, invasive hemodynamics, and adverse clinical outcomes were evaluated. In MESA, Ang2 was associated with a higher incidence of heart failure or cardiovascular death (hazard ratio 1.21 per standard deviation, P < .001). Ang2 was associated with increased right atrial pressure (pulmonary arterial hypertension cohort) and increased wedge pressure and right atrial pressure (left heart disease cohort). Elevated Ang2 was associated with mortality in the pulmonary arterial hypertension cohort.

Conclusions: Ang2 was associated with incident heart failure or death among adults without cardiovascular disease at baseline and with disease severity in individuals with existing heart failure. Our finding that Ang2 is increased before disease onset and that elevations reflect disease severity, suggests Ang2 may contribute to heart failure pathogenesis.
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http://dx.doi.org/10.1016/j.cardfail.2021.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277723PMC
July 2021

A multicenter retrospective study of patients with pulmonary hypertension transitioned from inhaled to oral treprostinil.

Pulm Circ 2021 Jan-Mar;11(1):2045894021998203. Epub 2021 Mar 2.

University of Washington, Seattle, WA, USA.

Oral treprostinil has recently been shown to delay disease progression in patients with pulmonary arterial hypertension in a long-term outcomes study. The potential advantages of an oral formulation have resulted in patients transitioning from inhaled to oral treprostinil. The current study reports a retrospective analysis of patients who transitioned from treatment with inhaled to oral treprostinil. A multicenter retrospective chart review was conducted for 29 patients with pulmonary hypertension that transitioned from inhaled to oral treprostinil. Data were collected from inhaled treprostinil initiation and patients were followed until discontinuation of oral treprostinil or the end of the observation period. Persistence was calculated using Kaplan-Meier estimates. Prior to transition to oral treprostinil, patients had received inhaled treprostinil for a median of 643 (IQR: 322-991) days and 52% of patients were New York Heart Association/World Health Organization Functional Class III. For patients that cross-titrated between formulations, the median time to complete the cross titration was 24 (IQR: 1-57) days. At 16- and 24-weeks post-transition, oral treprostinil persistence was 86 and 76%, respectively. Persistence was 59% at 52 weeks post-transition. Clinical stability for the majority of patients at first follow-up post-transition was suggested based on available New York Heart Association/World Health Organization Functional Classification. Transitions from inhaled to oral treprostinil appeared safe and tolerable in the short-term. Additional prospective studies are needed to fully evaluate the safety and efficacy of transitions from inhaled to oral treprostinil.
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http://dx.doi.org/10.1177/2045894021998203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934059PMC
March 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

An expert panel delphi consensus statement on patient selection and management for transitioning between oral and inhaled treprostinil.

Pulm Pharmacol Ther 2021 02 28;66:101979. Epub 2020 Nov 28.

Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.

Treprostinil, a prostacyclin analogue used in the treatment of pulmonary arterial hypertension (PAH), is available for administration by parenteral, oral, or inhaled routes. Transitioning between routes may be beneficial for appropriate patients; however, there is little published data on transitions between oral and inhaled treprostinil. We used a modified Delphi process to develop expert consensus recommendations on transitions between these formulations. Three questionnaires were used to develop statements about relevant aspects of transition management, which the panelists rated, using a Likert scale, from -5 (strongly disagree) to +5 (strongly agree). Eleven physicians with expertise in PAH treatment modalities, participated in the panel. Of the 492 statements evaluated, consensus was reached on 215 (43.7%). Key consensus recommendations included (1) accurately defining successful transition, as stable or improved PAH with good tolerability and adherence, and (2) patients with stable, low-risk PAH showing insufficient response or tolerability to their existing treprostinil therapy (and due to restrictions in up titration of dosing), as appropriate candidates for transitions between treprostinil formulations. Panelists did not reach consensus for an overall strategy for performing these transitions, mainly because of variability in their practice parameters. Consensus was also achieved on recommendations for adverse event management, including reassurance, administration of oral treprostinil 3 times daily with food, and dosing inhaled treprostinil at intervals ≥3 hours apart. The Delphi process aided in developing expert consensus recommendations that may provide clinically useful guidance for transitioning between treprostinil formulations. However, additional data from centers with high volumes of PAH patients undergoing treprostinil transitions would be optimal for defining more complete and robust strategies to facilitate successful transition.
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http://dx.doi.org/10.1016/j.pupt.2020.101979DOI Listing
February 2021

EmPHasis-10 as a measure of health-related quality of life in pulmonary arterial hypertension: data from PHAR.

Eur Respir J 2021 02 25;57(2). Epub 2021 Feb 25.

Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA

Introduction: While the performance of the emPHasis-10 (e10) score has been evaluated against limited patient characteristics within the United Kingdom, there is an unmet need for exploring the performance of the e10 score among pulmonary arterial hypertension (PAH) patients in the United States.

Methods: Using the Pulmonary Hypertension Association Registry, we evaluated relationships between the e10 score and demographic, functional, haemodynamic and additional clinical characteristics at baseline and over time. Furthermore, we derived a minimally important difference (MID) estimate for the e10 score.

Results: We analysed data from 565 PAH (75% female) adults aged mean±sd 55.6±16.0 years. At baseline, the e10 score had notable correlation with factors expected to impact quality of life in the general population, including age, education level, income, smoking status and body mass index. Clinically important parameters including 6-min walk distance and B-type natriuretic peptide (BNP)/N-terminal proBNP were also significantly associated with e10 score at baseline and over time. We generated a MID estimate for the e10 score of -6.0 points (range -5.0--7.6 points).

Conclusions: The e10 score was associated with demographic and clinical patient characteristics, suggesting that health-related quality of life in PAH is influenced by both social factors and indicators of disease severity. Future studies are needed to demonstrate the impact of the e10 score on clinical decision-making and its potential utility for assessing clinically important interventions.
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http://dx.doi.org/10.1183/13993003.00414-2020DOI Listing
February 2021

Renin-Angiotensin-Aldosterone System Inhibitor Use and Mortality in Pulmonary Hypertension: Insights From the Veterans Affairs Clinical Assessment Reporting and Tracking Database.

Chest 2021 04 5;159(4):1586-1597. Epub 2020 Oct 5.

University of Washington, Seattle, WA.

Background: The renin-angiotensin-aldosterone system (RAAS) contributes to pulmonary hypertension (PH) pathogenesis. Although animal data suggest that RAAS inhibition attenuates PH, it is unknown if RAAS inhibition is beneficial in PH patients.

Research Question: Is RAAS inhibitor use associated with lower mortality in a large cohort of patients with hemodynamically confirmed PH?

Study Design And Methods: We used the Department of Veterans Affairs Clinical Assessment Reporting and Tracking Database to study retrospectively relationships between RAAS inhibitors (angiotensin converting enzyme inhibitors [ACEIs], angiotensin receptor blockers [ARBs], and aldosterone antagonists [AAs]) and mortality in 24,221 patients with hemodynamically confirmed PH. We evaluated relationships in the full and in propensity-matched cohorts. Analyses were adjusted for demographics, socioeconomic status, comorbidities, disease severity, and comedication use in staged models.

Results: ACEI and ARB use was associated with improved survival in unadjusted Kaplan-Meier survival analyses in the full cohort and the propensity-matched cohort. This relationship was insensitive to adjustment, independent of pulmonary artery wedge pressure, and also was observed in a cohort restricted to individuals with precapillary PH. AA use was associated with worse survival in unadjusted Kaplan-Meier survival analyses in the full cohort; however, AA use was associated less robustly with mortality in the propensity-matched cohort and was not associated with worse survival after adjustment for disease severity, indicating that AAs in real-world practice are used preferentially in sicker patients and that the unadjusted association with increased mortality may be an artifice of confounding by indication of severity.

Interpretation: ACEI and ARB use is associated with lower mortality in veterans with PH. AA use is a marker of disease severity in PH. ACEIs and ARBs may represent a novel treatment strategy for diverse PH phenotypes.
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http://dx.doi.org/10.1016/j.chest.2020.09.258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173779PMC
April 2021

Accuracy of Doppler blood pressure measurement in HeartMate 3 ventricular assist device patients.

ESC Heart Fail 2020 Oct 1. Epub 2020 Oct 1.

Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, 98195, USA.

Aims: Optimal blood pressure (BP) control is imperative to reduce complications, especially strokes, in continuous flow ventricular assist device (VAD) patients. Doppler BP has been shown to be an accurate and reliable non-invasive BP measurement method in HeartMate II and HVAD patients. We examined whether Doppler BP is also accurate in patients with the HeartMate 3 VAD.

Methods And Results: In a prospective, longitudinal cohort of HeartMate 3 patients, arterial line BP and simultaneously measured Doppler opening pressure were obtained. Correlation and agreement between Doppler opening pressure and arterial line mean arterial pressure (MAP) versus systolic blood pressure (SBP) were analysed, as well as the effect of pulse pressure on the accuracy of Doppler opening pressure. A total of 589 pairs of simultaneous Doppler opening pressure and arterial line pressure readings were obtained in 43 patients. Doppler opening pressure had good correlation with intra-arterial MAP (r = 0.754) and more closely approximated MAP than SBP (mean error 2.0 vs. -8.6 mmHg). Pulse pressure did not have a clinically significant impact on the accuracy of the Doppler BP method. These results in HeartMate 3 patients are very similar to previous results in HeartMate II and HVAD patients.

Conclusions: Doppler BP method should be the default non-invasive BP measurement method in continuous flow VAD patients including patients implanted with the HeartMate 3.
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http://dx.doi.org/10.1002/ehf2.13056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754743PMC
October 2020

A Survey-based Estimate of COVID-19 Incidence and Outcomes among Patients with Pulmonary Arterial Hypertension or Chronic Thromboembolic Pulmonary Hypertension and Impact on the Process of Care.

Ann Am Thorac Soc 2020 12;17(12):1576-1582

Department of Medicine and.

Patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) typically undergo frequent clinical evaluation. The incidence and outcomes of coronavirus disease (COVID-19) and its impact on routine management for patients with pulmonary vascular disease is currently unknown. To assess the cumulative incidence and outcomes of COVID-19 for patients with PAH/CTEPH followed at accredited pulmonary hypertension centers, and to evaluate the pandemic's impact on clinic operations at these centers. A survey was e-mailed to program directors of centers accredited by the Pulmonary Hypertension Association. Descriptive analyses and linear regression were used to analyze results. Seventy-seven center directors were successfully e-mailed a survey, and 58 responded (75%). The cumulative incidence of COVID-19 recognized in individuals with PAH/CTEPH was 2.9 cases per 1,000 patients, similar to the general U.S. population. In patients with PAH/CTEPH for whom COVID-19 was recognized, 30% were hospitalized and 12% died. These outcomes appear worse than the general population. A large impact on clinic operations was observed including fewer clinic visits and substantially increased use of telehealth. A majority of centers curtailed diagnostic testing and a minority limited new starts of medical therapy. Most centers did not use experimental therapies in patients with PAH/CTEPH diagnosed with COVID-19. The cumulative incidence of COVID-19 recognized in patients with PAH/CTEPH appears similar to the broader population, although outcomes may be worse. Although the total number of patients with PAH/CTEPH recognized to have COVID-19 was small, the impact of COVID-19 on broader clinic operations, testing, and treatment was substantial.
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http://dx.doi.org/10.1513/AnnalsATS.202005-521OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706604PMC
December 2020

In reply, endothelin-1 and the Anrep effect.

J Heart Lung Transplant 2020 08 8;39(8):847. Epub 2020 Apr 8.

Department of Medicine, University of Washington, Seattle, Washington. Electronic address:

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http://dx.doi.org/10.1016/j.healun.2020.03.021DOI Listing
August 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

Endothelin-1, cardiac morphology, and heart failure: the MESA angiogenesis study.

J Heart Lung Transplant 2020 01 10;39(1):45-52. Epub 2019 Aug 10.

Department of Medicine, Medical University of South Carolina, Charleston, South Carolina.

Background: Circulating levels of endothelin-1 (ET1) are elevated in heart failure and predict poor prognosis. However, it is not clear whether ET1 elevation is an adaptive response, maladaptive response, or an epiphenomenon of heart failure. In this study, we evaluated the relationships between ET1, cardiac morphology, and incident heart failure or cardiovascular death in participants with no evidence of clinical cardiovascular disease at the time ET1 was measured.

Methods And Results: ET1 was measured in 1,361 participants in the Multi-Ethnic Study of Atherosclerosis Angiogenesis Sub-Study. As suggested by linear regression, participants with lower circulating ET1 levels tended to be older, non-white, more likely to have smoked heavily, and less likely to report intentional exercise. Participants with higher ET1 levels had smaller left ventricular end-diastolic volumes (8.9 ml smaller per log increase in ET1, 95% confidence interval 17.1-0.7, p = 0.03) with an increased left ventricular ejection fraction (2.8% per log increase in ET1, 95% confidence interval 0.5%-5.2%, p = 0.02). As suggested by Cox Proportional Hazards estimates, participants with higher ET1 levels had a lower risk for the composite outcome of heart failure or cardiovascular death in models that were unadjusted or had limited adjustment (p = 0.03 and p = 0.05, respectively). Lower risk for heart failure with higher ET1 levels could not be clearly shown in a model including health behaviors.

Conclusions: These results suggest, but do not confirm, that elevated levels of circulating ET1 are associated with a more favorable cardiac phenotype. The relationship between ET1 and outcomes was not fully independent of one or more covariates.
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http://dx.doi.org/10.1016/j.healun.2019.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942224PMC
January 2020

Impact of the New Pulmonary Hypertension Definition on Heart Transplant Outcomes: Expanding the Hemodynamic Risk Profile.

Chest 2020 01 22;157(1):151-161. Epub 2019 Aug 22.

Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, SC. Electronic address:

Background: At the recent 6th World Symposium on Pulmonary Hypertension (PH), the definition of PH was redefined to include lower pulmonary artery pressures in the setting of elevated pulmonary vascular resistance (PVR). However, the relevance of this change to subjects with PH due to left-heart disease as well as the preoperative assessment of heart transplant (HT) recipients is unknown.

Methods: The United Network for Organ Sharing database was queried to identify adult recipients who underwent primary HT from 1996 to 2015. Recipients were subdivided into those with mean pulmonary artery pressure (mPAP) < 25 mm Hg and ≥ 25 mm Hg. Exploratory univariable analysis was undertaken to identify candidate risk factors associated with 30-day and 1-year survival (conditional on 30-day survival) in recipients with mPAP < 25 mm Hg, and subsequently, parsimonious multivariable Cox proportional hazards models were constructed to assess the independent association with PVR.

Results: Over the study period, 32,465 patients underwent HT, including 12,257 (38%) with mPAP < 25 mm Hg. The median age was 55 years (interquartile range, 47-62) and the median PVR was 1.5 Wood units (WU) (interquartile range, 1-2.2) in recipients with mPAP < 25 mm Hg. After controlling for confounders, PVR was independently associated with increased risk for 30-day mortality (hazard ratio, 1.16; 95% CI, 1.05-1.27; P < .01), but not conditional 1-year mortality (hazard ratio, 1.03; 95% CI, 0.94-1.12; P = .55). PVR ≥ 3 WU was associated with an absolute 1.9% increase in 30-day mortality in those with mPAP < 25 mm Hg, a similar risk to recipients with PVR ≥ 3 WU and mPAP ≥ 25 mm Hg.

Conclusions: Elevated PVR remains associated with a significant increase in the hazard for 30-day mortality after cardiac transplantation, even in the setting of lower pulmonary artery pressures. These data support the validity of the new definition of pulmonary hypertension.
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http://dx.doi.org/10.1016/j.chest.2019.07.028DOI Listing
January 2020

Pulmonary Arterial Elastance and INTERMACS-Defined Right Heart Failure Following Left Ventricular Assist Device.

Circ Heart Fail 2019 08 12;12(8):e005923. Epub 2019 Aug 12.

Division of Cardiology, Department of Medicine (B.T., B.R., M.L.C., A.B.V.B., B.A.H., R.J.T.), Medical University of South Carolina, Charleston.

Background: Acute right heart failure (RHF) after left ventricular assist device implantation remains a major source of morbidity and mortality, yet the definition of RHF and the preimplant variables that predict RHF remain controversial. This study evaluated the ability of (1) INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) RHF classification to predict post-left ventricular assist device survival and (2) preoperative characteristics and hemodynamic parameters to predict severe and severe acute RHF.

Methods And Results: An international, multicenter study at 4 large academic centers was conducted between 2008 and 2016. All subjects with hemodynamics measured by right heart catheterization within 30 days before left ventricular assist device implantation were included. RHF was defined using the INTERMACS definition for RHF. In total, 375 subjects were included (mean age, 57.4±13.2 years, 54% bridge-to-transplant). Mild RHF was most common (34%), followed by moderate RHF (16%), severe RHF (13%), and severe acute RHF (9%). Estimated on-device survival rates at 2 years were 72%, 71%, and 55% in the patients with none, mild-to-moderate, and severe-to-severe acute RHF, respectively (P=0.004). In addition, the independent hazard ratio for mortality was only increased in the patients with severe-to-severe acute RHF (hazard ratio, 3.95; 95% CI, 2.16-7.23; P<0.001). INTERMACS-defined RHF was superior to postimplant inotrope duration alone in the prediction of all-cause mortality. In multivariable analysis, older age, lower INTERMACS classes, and higher pulmonary arterial elastance (ratio of systolic pulmonary artery pressure to stroke volume) before left ventricular assist device, were identified as significant predictors of severe-to-severe acute RHF. Stratifying patients by ratio of systolic pulmonary artery pressure to stroke volume and right atrial pressure significantly improved the discrimination between patients at risk for severe-to-severe acute RHF.

Conclusions: The INTERMACS RHF classification correctly identifies patients at risk for mortality, though this risk is only increased in patients with severe-to-severe acute RHF. Several predictors for RHF were identified, of which ratio of systolic pulmonary artery pressure to stroke volume was the strongest hemodynamic predictor. Coupling ratio of systolic pulmonary artery pressure to stroke volume with right atrial pressure may be most helpful in identifying patients at risk for severe-to-severe acute RHF.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.005923DOI Listing
August 2019

Which Needle in Which Haystack? Multisystem Care for Pulmonary Hypertension Patients.

Ann Am Thorac Soc 2019 08;16(8):979-981

1Department of Medicine, University of Washington, Seattle, Washington.

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http://dx.doi.org/10.1513/AnnalsATS.201905-370EDDOI Listing
August 2019

Accuracy of Doppler blood pressure measurement in continuous-flow left ventricular assist device patients.

ESC Heart Fail 2019 08 17;6(4):793-798. Epub 2019 May 17.

Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, 98195, USA.

Aims: Accurate blood pressure (BP) measurement in continuous-flow ventricular assist device (CF-VAD) patients is imperative to reduce stroke risk. This study assesses the accuracy of the Doppler opening pressure method compared with the gold standard arterial line method in CF-VAD patients.

Methods And Results: In a longitudinal cohort of HeartMate II and HVAD patients, arterial line BP and simultaneously measured Doppler opening pressure were obtained. Overall correlation, agreement between Doppler opening pressure and arterial line mean vs. systolic pressure, and the effect of arterial pulsatility on the accuracy of Doppler opening pressure were analysed. A total of 1933 pairs of Doppler opening pressure and arterial line pressure readings within 1 min of each other were identified in 154 patients (20% women, mean age 55 ± 15, 50% HeartMate II and 50% HVAD). Doppler opening pressure had good correlation with invasive mean arterial pressure (r = 0.742, P < 0.0001) and more closely approximated mean than systolic BP (mean error 2.4 vs. -8.4 mmHg). Arterial pulsatility did not have a clinically significant effect on the accuracy of the Doppler opening pressure method.

Conclusions: Doppler opening pressure should be the standard non-invasive method of BP measurement in CF-VAD patients.
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http://dx.doi.org/10.1002/ehf2.12456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676287PMC
August 2019

The Association of Ambient Air Pollution with Sleep Apnea: The Multi-Ethnic Study of Atherosclerosis.

Ann Am Thorac Soc 2019 03;16(3):363-370

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

Rationale: Air pollution may influence sleep through airway inflammation or autonomic nervous system pathway alterations. Epidemiological studies may provide evidence of relationships between chronic air pollution exposure and sleep apnea.

Objectives: To determine whether ambient-derived pollution exposure is associated with obstructive sleep apnea and objective sleep disruption.

Methods: We analyzed data from a sample of participants in MESA (Multi-Ethnic Study of Atherosclerosis) who participated in both the Sleep and Air studies. Mean annual and 5-year exposure levels to nitrogen dioxide (NO) and particulate matter ≤ 2.5 μm in aerodynamic diameter (PM) were estimated at participants' homes using spatiotemporal models based on cohort-specific monitoring. Participants completed in-home full polysomnography and 7 days of wrist actigraphy. We used multivariate models, adjusted for demographics, comorbidities, socioeconomic factors, and site, to assess whether air pollution was associated with sleep apnea (apnea-hypopnea index ≥ 15) and actigraphy-measured sleep efficiency.

Results: The participants (n = 1,974) were an average age of 68 (±9) years, 46% male, 36% white, 24% Hispanic, 28% black, and 12% Asian; 48% had sleep apnea and 25% had a sleep efficiency of ≤88%. A 10 ppb annual increase in NO exposure was associated with 39% greater adjusted odds of sleep apnea (95% confidence interval [CI], 1.03-1.87). A 5 μg/m greater annual PM exposure was also associated with 60% greater odds of sleep apnea (95% CI, 0.98-2.62). Sleep efficiency was not associated with air pollution levels in fully adjusted models.

Conclusions: Individuals with higher annual NO and PM exposure levels had a greater odds of sleep apnea. These data suggest that in addition to individual risk factors, environmental factors also contribute to the variation of sleep disorders across groups, possibly contributing to health disparities.
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http://dx.doi.org/10.1513/AnnalsATS.201804-248OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394120PMC
March 2019

Pulmonary Hypertension: Good Intentions, But a Questionable Approach.

Ann Am Thorac Soc 2018 06;15(6):664-666

6 Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana; and.

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http://dx.doi.org/10.1513/AnnalsATS.201803-197EDDOI Listing
June 2018

Pulmonary Effective Arterial Elastance as a Measure of Right Ventricular Afterload and Its Prognostic Value in Pulmonary Hypertension Due to Left Heart Disease.

Circ Heart Fail 2018 04;11(4):e004436

Division of Cardiology (E.T., B.W.K., E.K.K., D.A.K., R.J.T.) and Division of Pulmonary and Critical Care Medicine (T.M.K., R.D., S.C.M., P.M.H.), Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD. Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S., H.H.P.). Division of Cardiology, Mayo Clinic, Rochester, MN (B.A.B., W.L.M.). Division of Pulmonary, Critical Care, and Sleep Medicine, University of Washington, Seattle (P.J.L.). Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston (B.A.H., R.J.T.).

Background: Patients with combined post- and precapillary pulmonary hypertension due to left heart disease have a worse prognosis compared with isolated postcapillary. However, it remains unclear whether increased mortality in combined post- and precapillary pulmonary hypertension is simply a result of higher total right ventricular load. Pulmonary effective arterial elastance (Ea) is a measure of total right ventricular afterload, reflecting both resistive and pulsatile components. We aimed to test whether pulmonary Ea discriminates survivors from nonsurvivors in patients with pulmonary hypertension due to left heart disease and if it does so better than other hemodynamic parameters associated with combined post- and precapillary pulmonary hypertension.

Methods And Results: We combined 3 large heart failure patient cohorts (n=1036) from academic hospitals, including patients with pulmonary hypertension due to heart failure with preserved ejection fraction (n=232), reduced ejection fraction (n=335), and a mixed population (n=469). In unadjusted and 2 adjusted models, pulmonary Ea more robustly predicted mortality than pulmonary vascular resistance and the transpulmonary gradient. Along with pulmonary arterial compliance, pulmonary Ea remained predictive of survival in patients with normal pulmonary vascular resistance. The diastolic pulmonary gradient did not predict mortality. In addition, in a subset of patients with echocardiographic data, Ea and pulmonary arterial compliance were better discriminators of right ventricular dysfunction than the other parameters.

Conclusions: Pulmonary Ea and pulmonary arterial compliance more consistently predicted mortality than pulmonary vascular resistance or transpulmonary gradient across a spectrum of left heart disease with pulmonary hypertension, including patients with heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, and pulmonary hypertension with a normal pulmonary vascular resistance.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.117.004436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901761PMC
April 2018

Histamine H Receptor Polymorphisms, Myocardial Transcripts, and Heart Failure (from the Multi-Ethnic Study of Atherosclerosis and Beta-Blocker Effect on Remodeling and Gene Expression Trial).

Am J Cardiol 2018 01 20;121(2):256-261. Epub 2017 Oct 20.

Department of Medicine, University of Colorado, Denver, Colorado.

Myocardial H receptor activation contributes to heart failure (HF) in preclinical models, and H receptor antagonists are associated with decreased HF incidence. This study evaluated whether H histamine receptor (HRH2) single nucleotide polymorphisms (SNPs) are associated with HF incidence and whether myocardial transcript abundance is associated with HF recovery. The association of SNPs in HRH2 with incident HF was characterized using Cox proportional hazards regression among participants in the Multi-Ethnic Study of Atherosclerosis. Differences in myocardial HRH2 transcripts were characterized in participants with dilated cardiomyopathy comparing 6 "super-responders" with 6 nonresponders to β blockade in the Beta-Blocker Effect on Remodeling and Gene Expression Trial. In MESA, no candidate SNP was associated with HF in black, Hispanic, or white participants. The rs2241562 minor allele was present only in Chinese participants and the adjusted HF hazard among those with 1 or more copies of this allele was 3.7, 95% confidence interval 1.0 to 13.4. In BORG, super-responders to β blockade had higher levels of myocardial HRH2 transcript at baseline compared with nonresponders (fragments per kilobase per transcript per million mapped reads: Variant 2, 5.5 ± 1.1 compared with 3.2 ± 0.8 in nonresponders, p = 0.002; Variant 1 + 2, 32.1 ± 7.4 compared with 23.3 ± 4.2 in nonresponders, p = 0.04). In conclusion, the presence of a minor allele at rs2241562 was associated with increased HF incidence in Chinese participants. Differences in myocardial HRH2 transcript abundance were seen in participants with dilated cardiomyopathy who responded to β blockade. These observations support the hypothesis that HRH2 is involved in the pathogenesis of HF.
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http://dx.doi.org/10.1016/j.amjcard.2017.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742297PMC
January 2018

A Tale of Two Hearts: Patients with Decompensated Right Heart Failure in the Intensive Care Unit.

Ann Am Thorac Soc 2017 06;14(6):1025-1030

3 Division of Pulmonary and Critical Care, University of Washington, Seattle, Washington; and.

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http://dx.doi.org/10.1513/AnnalsATS.201612-960CCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566310PMC
June 2017

What's in a side effect? The association between pulmonary vasodilator adverse drug events and clinical outcomes in patients with pulmonary arterial hypertension.

Int J Cardiol 2017 Aug 6;240:386-391. Epub 2017 Apr 6.

Stanford University Medical Center, Division of PCCM, United States. Electronic address:

Background: Adverse drug events (ADEs) with pulmonary vasodilator use in pulmonary arterial hypertension (PAH) are common. ADEs may contribute to worse quality of life; however, their relationship to prognosis is unknown. The objective of this study was to determine whether common ADEs after initiating subcutaneous treprostinil were associated with prognosis in PAH.

Methods: We assembled a retrospective cohort of participants from four clinical trials of treprostinil for PAH, including 908 participants who received subcutaneous treprostinil and 243 who received placebo at the time ADEs were ascertained. The occurrences of four common early ADEs (infusion reactions, headaches, jaw pain, or gastrointestinal side effects) were assessed during the eight weeks after starting the infusion. We used Cox proportional hazards to estimate associations between ADEs and mortality.

Results: No ADEs related to placebo were associated with mortality. In participants who received treprostinil, infusion reactions, headaches, and jaw pain were not associated with mortality. Gastrointestinal side effects occurring during the first eight weeks following treprostinil infusion were associated with a 57% increase in the hazard of mortality (95% CI: 14-118%). This relationship was unchanged after adjusting for demographic differences and differences in baseline PAH severity.

Conclusions: Gastrointestinal ADEs after starting subcutaneous treprostinil were associated with an increased risk for mortality. Increased mortality was not observed with other early ADEs or with gastrointestinal symptoms in participants who were not receiving treprostinil at the time. This hypothesis-generating association suggests ADEs may identify different phenotypes in PAH.
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http://dx.doi.org/10.1016/j.ijcard.2017.04.016DOI Listing
August 2017
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