Publications by authors named "Paul M Hassoun"

203 Publications

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

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

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

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

Hit Early and Hit Hard in Pulmonary Arterial Hypertension? Not so Fast!

Am J Respir Crit Care Med 2021 Aug 17. Epub 2021 Aug 17.

Tufts Medical Center, 1867, Boston, Massachusetts, United States.

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http://dx.doi.org/10.1164/rccm.202107-1570EDDOI Listing
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

Time Is of the Essence in PAH Therapy.

Chest 2021 Jul;160(1):25-26

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD. Electronic address:

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http://dx.doi.org/10.1016/j.chest.2021.02.009DOI Listing
July 2021

Basement Membrane Extracellular Matrix Proteins in Pulmonary Vascular and Right Ventricular Remodeling in Pulmonary Hypertension.

Am J Respir Cell Mol Biol 2021 09;65(3):245-258

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland.

The extracellular matrix (ECM), a highly organized network of structural and nonstructural proteins, plays a pivotal role in cellular and tissue homeostasis. Changes in the ECM are critical for normal tissue repair, whereas dysregulation contributes to aberrant tissue remodeling. Pulmonary arterial hypertension is a severe disorder of the pulmonary vasculature characterized by pathologic remodeling of the pulmonary vasculature and right ventricle, increased production and deposition of structural and nonstructural proteins, and altered expression of ECM growth factors and proteases. Furthermore, ECM remodeling plays a significant role in disease progression, as several dynamic changes in its composition, quantity, and organization are documented in both humans and animal models of disease. These ECM changes impact vascular cell biology and affect proliferation of resident cells. Furthermore, ECM components determine the tissue architecture of the pulmonary and myocardial vasculature as well as the myocardium itself and provide mechanical stability crucial for tissue homeostasis. However, little is known about the basement membrane (BM), a specialized, self-assembled conglomerate of ECM proteins, during remodeling. In the vasculature, the BM is in close physical association with the vascular endothelium and smooth muscle cells. While in the myocardium, each cardiomyocyte is enclosed by a BM that serves as the interface between cardiomyocytes and the surrounding interstitial matrix. In this review, we provide a brief overview on the current state of knowledge of the BM and its ECM composition and their impact on pulmonary vascular remodeling and right ventricle dysfunction and failure in pulmonary arterial hypertension.
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http://dx.doi.org/10.1165/rcmb.2021-0091TRDOI Listing
September 2021

Comprehensive echocardiographic evaluation of the right heart in patients with pulmonary vascular diseases: the PVDOMICS experience.

Eur Heart J Cardiovasc Imaging 2021 Jun 7. Epub 2021 Jun 7.

Bluhm Cardiovascular Institute, Northwestern University, 676 N Saint Clair, Chicago Illinois 60611 USA.

Aims: There is a wide spectrum of diseases associated with pulmonary hypertension, pulmonary vascular remodelling, and right ventricular dysfunction. The NIH-sponsored PVDOMICS network seeks to perform comprehensive clinical phenotyping and endophenotyping across these disorders to further evaluate and define pulmonary vascular disease.

Methods And Results: Echocardiography represents the primary non-invasive method to phenotype cardiac anatomy, function, and haemodynamics in these complex patients. However, comprehensive right heart evaluation requires the use of multiple echocardiographic parameters and optimized techniques to ensure optimal image acquisition. The PVDOMICS echo protocol outlines the best practice approach to echo phenotypic assessment of the right heart/pulmonary artery unit.

Conclusion: Novel workflow processes, methods for quality control, data for feasibility of measurements, and reproducibility of right heart parameters derived from this study provide a benchmark frame of reference. Lessons learned from this protocol will serve as a best practice guide for echocardiographic image acquisition and analysis across the spectrum of right heart/pulmonary vascular disease.
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http://dx.doi.org/10.1093/ehjci/jeab065DOI Listing
June 2021

Systemic Sclerosis-Associated Pulmonary Hypertension: Spectrum and Impact.

Diagnostics (Basel) 2021 May 20;11(5). Epub 2021 May 20.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.

Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is a catastrophic complication of one of the most common and devastating autoimmune diseases. Once diagnosed, it becomes the leading cause of mortality among this patient population. Screening modalities and risk assessments have been designed and validated by various organizations and societies in order to identify patients early in their disease course and promptly refer them to expert centers for a hemodynamic assessment and formal diagnosis. Moreover, several large multicenter clinical trials have now included patients with SSc-PAH to assess their response to therapy. Despite an improved understanding of the condition and significant advances in supportive and targeted therapy, outcomes have remained far from optimal. Therefore, rigorous phenotyping and search for novel therapies are desperately needed for this devastating condition.
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http://dx.doi.org/10.3390/diagnostics11050911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161029PMC
May 2021

Assessment of right ventricular reserve utilizing exercise provocation in systemic sclerosis.

Int J Cardiovasc Imaging 2021 Jul 16;37(7):2137-2147. Epub 2021 Apr 16.

Division of Rheumatology, Johns Hopkins University, Baltimore, MD, USA.

Right ventricular (RV) capacity to adapt to increased afterload is the main determinant of outcome in pulmonary hypertension, a common morbidity seen in systemic sclerosis (SSc). We hypothesized that supine bicycle echocardiography (SBE), coupled with RV longitudinal systolic strain (RVLSS), improves detection of limitations in RV reserve in SSc. 56 SSc patients were prospectively studied during SBE with RV functional parameters compared at rest and peak stress. We further dichotomized patients based on resting RV systolic pressure (RVSP) to determine the effects of load on contractile response. Our pooled cohort analysis revealed reduced global RVLSS at rest (-16.2 ± 3.9%) with normal basal contractility (-25.6 ± 7.7%) and relative hypokinesis of the midventricular (-14.1 ± 6.0%) and apical (-8.9 ± 5.1%) segments. With exercise, global RVLSS increased significantly (p = 0.0005), however despite normal basal contractility at rest, there was no further augmentation with exercise. Mid and apical RVLSS increased with exercise suggestive of RV contractile reserve. In patients with resting RVSP < 35 mmHg, global and segmental RVLSS increased with exercise. In patients with resting RVSP ≥ 35 mmHg, global and segmental RVLSS did not increase with exercise and there was evidence of exertional RV dilation. Exercise provocation in conjunction with RVLSS identified differential regional contractile response to exercise in SSc patients. We further demonstrate the effect of increased loading conditions on RV contractile response exercise. These findings suggest subclinical impairments in RV reserve in SSc that may be missed by resting noninvasive 2DE-based assessments alone.
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http://dx.doi.org/10.1007/s10554-021-02237-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292174PMC
July 2021

Inflammatory Mechanisms in the Pathogenesis of Pulmonary Arterial Hypertension: Recent Advances.

Compr Physiol 2021 04 1;11(2):1805-1829. Epub 2021 Apr 1.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

Inflammatory processes are increasingly recognized in the pathogenesis of the vascular remodeling that characterizes pulmonary arterial hypertension (PAH). Chronic inflammation may contribute to disease progression or serve as a biomarker of PAH severity. Furthermore, inflammatory pathways may represent possible therapeutic targets for novel PAH-specific drugs beyond the currently approved therapies targeting the endothelin, nitric oxide/cyclic GMP, and prostacyclin biological pathways. The main focus of this article is to provide recent advances in the understanding of the role of inflammatory pathways in the pathogenesis of PAH from preclinical studies and current clinical data supporting chronic inflammation in PAH patients and to discuss emerging therapeutic implications. © 2021 American Physiological Society. Compr Physiol 11:1805-1829, 2021.
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http://dx.doi.org/10.1002/cphy.c200025DOI Listing
April 2021

Exercise right ventricular ejection fraction predicts right ventricular contractile reserve.

J Heart Lung Transplant 2021 Jun 17;40(6):504-512. Epub 2021 Feb 17.

Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

Background: Right ventricular (RV) contractile reserve shows promise as an indicator of occult RV dysfunction in pulmonary vascular disease. We investigated which measure of RV contractile reserve during exercise best predicts occult RV dysfunction and clinical outcomes.

Methods: We prospectively studied RV contractile reserve in 35 human subjects referred for right heart catheterization for known or suspected pulmonary hypertension. All underwent cardiac magnetic resonance imaging, echocardiography, and supine invasive cardiopulmonary exercise testing with concomitant RV pressure-volume catheterization. Event-free survival was prospectively adjudicated from time of right heart catheterization for a 4-year follow-up period.

Results: RV contractile reserve during exercise, as measured by a positive change in end-systolic elastance (Ees) during exertion, was associated with elevation in pulmonary pressures but preservation of RV volumes. Lack of RV reserve, on the other hand, was tightly coupled with acute RV dilation during exertion (R = 0.76, p< 0.001). RV Ees and dilation changes each predicted resting RV-PA dysfunction. RV ejection fraction during exercise, which captured exertional changes in both RV Ees and RV dilation, proved to be a robust surrogate for RV contractile reserve. Reduced exercise RV ejection fraction best predicted occult RV dysfunction among a variety of resting and exercise RV measures, and was also associated with clinical worsening.

Conclusions: RV ejection fraction during exercise, as an index of RV contractile reserve, allows for excellent identification of occult RV dysfunction, more so than resting measures of RV function, and may predict clinical outcomes as well.
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http://dx.doi.org/10.1016/j.healun.2021.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169559PMC
June 2021

Safety and Efficacy of B-Cell Depletion with Rituximab for the Treatment of Systemic Sclerosis-associated Pulmonary Arterial Hypertension: A Multicenter, Double-Blind, Randomized, Placebo-controlled Trial.

Am J Respir Crit Care Med 2021 07;204(2):209-221

Division of Pulmonary, Allergy, and Critical Care Medicine and.

Systemic sclerosis (SSc)-pulmonary arterial hypertension (PAH) is one of the most prevalent and deadly forms of PAH. B cells may contribute to SSc pathogenesis. We investigated the safety and efficacy of B-cell depletion for SSc-PAH. In an NIH-sponsored, multicenter, double-blinded, randomized, placebo-controlled, proof-of-concept trial, 57 patients with SSc-PAH on stable-dose standard medical therapy received two infusions of 1,000 mg rituximab or placebo administered 2 weeks apart. The primary outcome measure was the change in 6-minute-walk distance (6MWD) at 24 weeks. Secondary endpoints included safety and invasive hemodynamics. We applied a machine learning approach to predict drug responsiveness. We randomized 57 subjects from 2010 to 2018. In the primary analysis, using data through Week 24, the adjusted mean change in 6MWD at 24 weeks favored the treatment arm but did not reach statistical significance (23.6 ± 11.1 m vs. 0.5 ± 9.7 m;  = 0.12). Although a negative study, when data through Week 48 were also considered, the estimated change in 6MWD at Week 24 was 25.5 ± 8.8 m for rituximab and 0.4 ± 7.4 m for placebo ( = 0.03). Rituximab treatment appeared to be safe and well tolerated. Low levels of RF (rheumatoid factor), IL-12, and IL-17 were sensitive and specific as favorable predictors of a rituximab response as measured by an improved 6MWD (receiver operating characteristic area under the curve, 0.88-0.95). B-cell depletion therapy is a potentially effective and safe adjuvant treatment for SSc-PAH. Future studies in these patients can confirm whether the identified biomarkers predict rituximab responsiveness. Clinical trial registered with www.clinicaltrails.gov (NCT01086540).
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http://dx.doi.org/10.1164/rccm.202009-3481OCDOI Listing
July 2021

Effect of riociguat on pulmonary arterial compliance in the PATENT and CHEST studies.

Pulm Circ 2020 Oct-Dec;10(4):2045894020963836. Epub 2020 Nov 20.

Pulmonary, Critical Care and Sleep Division, Tufts University Medical Center, Boston, MA, USA.

Pulmonary arterial compliance is a measure of the pulsatile afterload of the right ventricle. Lower pulmonary arterial compliance is associated with reduced right ventricular function and worse prognosis in pulmonary hypertension. The effect of pulmonary vasodilators on pulmonary arterial compliance has not been evaluated in detail in pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. In this post hoc analysis of patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension in the PATENT and CHEST studies, we evaluated the change in pulmonary arterial compliance with riociguat versus placebo. Association of pulmonary arterial compliance with clinical outcomes was assessed using Kaplan-Meier and Cox proportional hazards analyses. Compared with placebo, riociguat significantly improved pulmonary arterial compliance in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Pulmonary arterial compliance at baseline was associated with survival and clinical worsening-free survival in pulmonary arterial hypertension but only with clinical worsening-free survival in chronic thromboembolic pulmonary hypertension. In patients with pulmonary arterial hypertension, pulmonary arterial compliance at follow-up ≥1.6 mL/mmHg was associated with better outcomes than pulmonary arterial compliance <1.6 mL/mmHg. In patients with chronic thromboembolic pulmonary hypertension, pulmonary arterial compliance at follow-up did not predict outcomes. Cox proportional hazards analyses showed no association between change in pulmonary arterial compliance and outcomes in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. In conclusion, riociguat improved pulmonary arterial compliance in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Pulmonary arterial compliance at baseline or follow-up, rather than change in pulmonary arterial compliance, is of prognostic importance for outcomes.
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http://dx.doi.org/10.1177/2045894020963836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686638PMC
November 2020

Insulin-like growth factor binding protein-2: a new circulating indicator of pulmonary arterial hypertension severity and survival.

BMC Med 2020 10 6;18(1):268. Epub 2020 Oct 6.

Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, 720 Rutland Ave. Ross RM 1143, Baltimore, MD, 21205, USA.

Background: Pulmonary arterial hypertension (PAH) is a fatal disease that results from cardio-pulmonary dysfunction with the pathology largely unknown. Insulin-like growth factor binding protein 2 (IGFBP2) is an important member of the insulin-like growth factor family, with evidence suggesting elevation in PAH patients. We investigated the diagnostic and prognostic value of serum IGFBP2 in PAH to determine if it could discriminate PAH from healthy controls and if it was associated with disease severity and survival.

Methods: Serum IGFBP2 levels, as well as IGF1/2 levels, were measured in two independent PAH cohorts, the Johns Hopkins Pulmonary Hypertension program (JHPH, N = 127), NHLBI PAHBiobank (PAHB, N = 203), and a healthy control cohort (N = 128). The protein levels in lung tissues were determined by western blot. The IGFBP2 mRNA expression levels in pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) were assessed by RNA-seq, secreted protein levels by ELISA. Association of biomarkers with clinical variables was evaluated using adjusted linear or logistic regression and Kaplan-Meier analysis.

Results: In both PAH cohorts, serum IGFBP2 levels were significantly elevated (p < 0.0001) compared to controls and discriminated PAH from controls with an AUC of 0.76 (p < 0.0001). A higher IGFBP2 level was associated with a shorter 6-min walk distance (6MWD) in both cohorts after adjustment for age and sex (coefficient - 50.235 and - 57.336 respectively). Cox multivariable analysis demonstrated that higher serum IGFBP2 was a significant independent predictor of mortality in PAHB cohort only (HR, 3.92; 95% CI, 1.37-11.21). IGF1 levels were significantly increased only in the PAHB cohort; however, neither IGF1 nor IGF2 had equivalent levels of associations with clinical variables compared with IGFBP2. Western blotting shown that IGFBP2 protein was significantly increased in the PAH vs control lung tissues. Finally, IGFBP2 mRNA expression and secreted protein levels were significantly higher in PASMC than in PAEC.

Conclusions: IGFBP2 protein expression was increased in the PAH lung, and secreted by PASMC. Elevated circulating IGFBP2 was associated with PAH severity and mortality and is a potentially valuable prognostic marker in PAH.
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http://dx.doi.org/10.1186/s12916-020-01734-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537100PMC
October 2020

Pulmonary and systemic hemodynamics are associated with myocardial injury in the acute respiratory distress syndrome.

Pulm Circ 2020 Jul-Sep;10(3):2045894020939846. Epub 2020 Jul 23.

Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, USA.

Background: Whether right and left heart hemodynamics are associated with myocardial injury in the acute respiratory distress syndrome (ARDS) is not known.

Methods: We performed a retrospective cohort study of subjects who had right heart catheterization within the ALVEOLI trial and Fluid and Catheter Treatment Trial. Myocardial injury was assessed using a highly sensitive troponin assay (hsTn; Abbot ARCHITECT). Hemodynamic variables included right atrial pressure, pulmonary artery wedge pressure, cardiac index and stroke volume, pulmonary vascular resistance, pulmonary arterial compliance, and pulmonary effective arterial elastance. We performed linear, logistic, and Cox regression to determine the association of hemodynamic variables with myocardial injury and to determine if hemodynamics mediated the association between myocardial injury and death.

Results: Among 252 ARDS patients, median day 0 troponin was 65.4 (13.8-397.8) ng/L. Lower cardiac index (β -0.23 SE 0.10; P < 0.001) and stroke volume (β -0.26 SE 0.005; P < 0.001), higher pulmonary vascular resistance (β 0.22 SE 0.11; P < 0.001), lower pulmonary arterial compliance (β -0.24 SE 0.06; P < 0.001), and higher arterial elastance (β 0.27 SE 0.43; P < 0.001) were associated with greater myocardial injury in univariable and adjusted models. Changes in stroke volume, cardiac index, pulmonary arterial compliance, pulmonary vascular resistance, and arterial elastance were all associated with progressive myocardial injury over three days. hsTn levels were associated with mortality; however, the association was attenuated after adjustment for each of stroke volume, pulmonary vascular resistance, pulmonary arterial compliance, and arterial elastance.

Conclusion: Pulmonary vascular hemodynamics are associated with myocardial injury in ARDS, while filling pressures are not. Pulmonary vascular disease may represent a treatable contributor to myocardial injury in ARDS.
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http://dx.doi.org/10.1177/2045894020939846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378723PMC
July 2020

A comprehensive echocardiographic method for risk stratification in pulmonary arterial hypertension.

Eur Respir J 2020 09 24;56(3). Epub 2020 Sep 24.

University Hospital Giessen und Marburg GmbH, Pulmonary Hypertension Division, Medical Clinic II, Giessen, Germany.

Question Addressed: Echocardiography is not currently considered as providing sufficient prognostic information to serve as an integral part of treatment goals in pulmonary arterial hypertension (PAH). We tested the hypothesis that incorporation of multiple parameters reflecting right heart function would improve the prognostic value of this imaging modality.

Methods And Main Results: We pooled individual patient data from a total of 517 patients (mean age 52±15 years, 64.8% females) included in seven observational studies conducted at five European and United States academic centres. Patients were subdivided into three groups representing progressive degrees of right ventricular dysfunction based on a combination of echocardiographic measurements, as follows. Group 1 (low risk): normal tricuspid annular plane systolic excursion (TAPSE) and nonsignificant tricuspid regurgitation (TR) (n=129); group 2 (intermediate risk): normal TAPSE and significant TR or impaired TAPSE and nondilated inferior vena cava (IVC) (n=256); group 3 (high risk): impaired TAPSE and dilated IVC (n=132). The 5-year cumulative survival rate was 82% in group 1, 63% in group 2 and 43% in group 3. Low-risk patients had better survival rates than intermediate-risk patients (log-rank Chi-squared 12.25; p<0.001) and intermediate-risk patients had better survival rates than high-risk patients (log-rank Chi-squared 26.25; p<0.001). Inclusion of other parameters such as right atrial area and pericardial effusion did not provide added prognostic value.

Answer To The Question: The proposed echocardiographic approach integrating the evaluation of TAPSE, TR grade and IVC is effective in stratifying the risk for all-cause mortality in PAH patients, outperforming the prognostic parameters suggested by current guidelines.
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http://dx.doi.org/10.1183/13993003.00513-2020DOI Listing
September 2020

Multi-Beat Right Ventricular-Arterial Coupling Predicts Clinical Worsening in Pulmonary Arterial Hypertension.

J Am Heart Assoc 2020 05 8;9(10):e016031. Epub 2020 May 8.

Department of Medicine Medical University of South Carolina Charleston SC.

Background Although right ventricular (RV) to pulmonary arterial (RV-PA) coupling is considered the gold standard in assessing RV dysfunction, its ability to predict clinically significant outcomes is poorly understood. We assessed the ability of RV-PA coupling, determined by the ratio of multi-beat (MB) end-systolic elastance (Ees) to effective arterial elastance (Ea), to predict clinical outcomes. Methods and Results Twenty-six subjects with pulmonary arterial hypertension (PAH) underwent same-day cardiac magnetic resonance imaging, right heart catheterization, and RV pressure-volume assessment with MB determination of Ees/Ea. RV ejection fraction (RVEF), stroke volume/end-systolic volume, and single beat-estimated Ees/Ea were also determined. Patients were treated with standard therapies and followed prospectively until they met criteria of clinical worsening (CW), as defined by ≥10% decline in 6-minute walk distance, worsening World Health Organization (WHO) functional class, PAH therapy escalation, RV failure hospitalization, or transplant/death. Subjects were 57±14 years, largely WHO class III (50%) at enrollment, with preserved average RV ejection fraction (RVEF) (47±11%). Mean follow-up was 3.2±1.3 years. Sixteen (62%) subjects met CW criteria. MB Ees/Ea was significantly lower in CW subjects (0.7±0.5 versus 1.3±0.8, =0.02). The optimal MB Ees/Ea cut-point predictive of CW was 0.65, defined by ROC (AUC 0.78, =0.01). MB Ees/Ea below this cut-point was significantly associated with time to CW (hazard ratio 5.1, =0.001). MB Ees/Ea remained predictive of outcomes following multivariate adjustment for timing of PAH diagnosis and PAH diagnosis subtype. Conclusions RV-PA coupling as measured by MB Ees/Ea has prognostic significance in human PAH, even in a cohort with preserved RVEF.
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http://dx.doi.org/10.1161/JAHA.119.016031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660856PMC
May 2020

Novel Mutations and Decreased Expression of the Epigenetic Regulator in Pulmonary Arterial Hypertension.

Circulation 2020 06 20;141(24):1986-2000. Epub 2020 Mar 20.

Department of Medicine (F.P., L.T., J.M., C.L.D., B.S., A.Y.M., S.L.A.), Queen's University, Kingston, Ontario, Canada.

Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations in and 16 other genes; however, these mutations occur in <25% of patients with idiopathic PAH and are rare in PAH associated with connective tissue diseases. Preclinical studies suggest epigenetic dysregulation, including altered DNA methylation, promotes PAH. Somatic mutations of Tet-methylcytosine-dioxygenase-2 (), a key enzyme in DNA demethylation, occur in cardiovascular disease and are associated with clonal hematopoiesis, inflammation, and adverse vascular remodeling. The role of in PAH is unknown.

Methods: To test for a role of , we used a cohort of 2572 cases from the PAH Biobank. Within this cohort, gene-specific rare variant association tests were performed using 1832 unrelated European patients with PAH and 7509 non-Finnish European subjects from the Genome Aggregation Database (gnomAD) as control subjects. In an independent cohort of 140 patients, we quantified expression in peripheral blood mononuclear cells. To assess causality, we investigated hemodynamic and histological evidence of PAH in hematopoietic -knockout mice.

Results: We observed an increased burden of rare, predicted deleterious germline variants in in PAH patients of European ancestry (9/1832) compared with control subjects (6/7509; relative risk=6; =0.00067). Assessing the whole cohort, 0.39% of patients (10/2572) had 12 mutations (75% predicted germline and 25% somatic). These patients had no mutations in other PAH-related genes. Patients with mutations were older (71±7 years versus 48±19 years; <0.0001), were more unresponsive to vasodilator challenge (0/7 versus 140/1055 [13.2%]), had lower pulmonary vascular resistance (5.2±3.1 versus 10.5±7.0 Wood units; =0.02), and had increased inflammation (including elevation of interleukin-1β). Circulating expression did not correlate with age and was decreased in >86% of PAH patients. -knockout mice spontaneously developed PAH, adverse pulmonary vascular remodeling, and inflammation, with elevated levels of cytokines, including interleukin-1β. Long-term therapy with an antibody targeting interleukin-1β blockade resulted in regression of PAH.

Conclusions: PAH is the first human disease related to potential germline mutations. Inherited and acquired abnormalities of occur in 0.39% of PAH cases. Decreased expression is ubiquitous and has potential as a PAH biomarker.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299806PMC
June 2020

Diffusing Capacity Is an Independent Predictor of Outcomes in Pulmonary Hypertension Associated With COPD.

Chest 2020 08 14;158(2):722-734. Epub 2020 Mar 14.

Johns Hopkins University Division of Pulmonary and Critical Care, Baltimore, MD. Electronic address:

Background: Patients with COPD who experience pulmonary hypertension (PH) have worse mortality than those with COPD alone. Predictors of poor outcomes in COPD-PH are not well-described. Diffusing capacity of the lung (Dlco) assesses the integrity of the alveolar-capillary interface and thus may be a useful prognostic tool among those with COPD-PH.

Research Question: Using a single center registry, we sought to evaluate Dlco as a predictor of mortality in a cohort of patients with COPD-PH.

Study Design And Methods: This retrospective cohort study analyzed 71 COPD-PH patients from the Johns Hopkins Pulmonary Hypertension Registry with right-sided heart catheterization (RHC)-proven PH and pulmonary function testing data within one year of diagnostic RHC. Transplant-free survival was calculated from index RHC. Adjusted transplant-free survival was modelled using Cox proportional hazard methods; age, pulmonary vascular resistance, FEV, oxygen use, and N-terminal pro-brain natriuretic peptide were included as covariates.

Results: Overall unadjusted transplant-free 1-, 3-, and 5-year survivals were 87%, 60%, and 51%, respectively. Survival was associated with reduced Dlco across the observed range of pulmonary artery pressures and pulmonary vascular resistance. Severe Dlco impairment was associated with poorer survival (log-rank χ 13.07) (P < .001); adjusting for covariates, for every percent predicted decrease in Dlco, mortality rates increased by 4% (hazard ratio, 1.04; 95% CI, 1.01-1.07).

Interpretation: Among patients with COPD-PH, severe gas transfer impairment is associated with higher mortality, even with adjustment for airflow obstruction and hemodynamics, which suggests that Dlco may be a useful prognostic marker in this population. Future studies are needed to further investigate the association between Dlco and morbidity and to determine the utility of Dlco as a biomarker for disease risk and severity in COPD-PH.
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http://dx.doi.org/10.1016/j.chest.2020.02.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173778PMC
August 2020

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

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

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

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

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

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

Cellular sources of interleukin-6 and associations with clinical phenotypes and outcomes in pulmonary arterial hypertension.

Eur Respir J 2020 04 16;55(4). Epub 2020 Apr 16.

Johns Hopkins University, Department of Pediatrics, Division of Pediatric Cardiology, Baltimore, MD, USA.

The pro-inflammatory cytokine interleukin (IL)-6 has been associated with outcomes in small pulmonary arterial hypertension (PAH) cohorts composed largely of patients with severe idiopathic PAH (IPAH). It is unclear whether IL-6 is a marker of critical illness or a mechanistic biomarker of pulmonary vascular remodelling. We hypothesised that IL-6 is produced by pulmonary vascular cells and sought to explore IL-6 associations with phenotypes and outcomes across diverse subtypes in a large PAH cohort.IL-6 protein and gene expression levels were measured in cultured pulmonary artery smooth muscle cells (PASMCs) and endothelial cells (PAECs) from PAH patients and healthy controls. Serum IL-6 was measured in 2017 well-characterised PAH subjects representing each PAH subgroup. Relationships between IL-6 levels, clinical variables, and mortality were analysed using regression models.Significantly higher IL-6 protein and gene expression levels were produced by PASMCs than by PAECs in PAH (p<0.001), while there was no difference in IL-6 between cell types in controls. Serum IL-6 was highest in PAH related to portal hypertension and connective tissue diseases (CTD-PAH). In multivariable modelling, serum IL-6 was associated with survival in the overall cohort (hazard ratio 1.22, 95% CI 1.08-1.38; p<0.01) and in IPAH, but not in CTD-PAH. IL-6 remained associated with survival in low-risk subgroups of subjects with mild disease.IL-6 is released from PASMCs, and circulating IL-6 is associated with specific clinical phenotypes and outcomes in various PAH subgroups, including subjects with less severe disease. IL-6 is a mechanistic biomarker, and thus a potential therapeutic target, in certain PAH subgroups.
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http://dx.doi.org/10.1183/13993003.01761-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243361PMC
April 2020

Noninvasive Prognostic Biomarkers for Left-Sided Heart Failure as Predictors of Survival in Pulmonary Arterial Hypertension.

Chest 2020 06 25;157(6):1606-1616. Epub 2020 Jan 25.

Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD. Electronic address:

Background: Three biomarkers, soluble suppression of tumorigenicity 2 (ST2), galectin 3 (Gal3), and N-terminal brain natriuretic peptide prohormone (NT-proBNP), are approved for noninvasive risk assessment in left-sided heart failure, and small observational studies have shown their prognostic usefulness in heterogeneous pulmonary hypertension cohorts. We examined associations between these biomarkers and disease severity and survival in a large cohort of patients with pulmonary arterial hypertension (PAH) (ie, group 1 pulmonary hypertension). We hypothesized that additive use of biomarkers in combination would improve the prognostic value of survival models.

Methods: Biomarker measurements and clinical data were obtained from 2,017 adults with group 1 PAH. Associations among biomarker levels and clinical variables, including survival times, were examined with multivariable regression models. Likelihood ratio tests and the Akaike information criterion were used to compare survival models.

Results: Higher ST2 and NT-proBNP were associated with higher pulmonary pressures and vascular resistance and lower 6-min walk distance. Higher ST2 and NT-proBNP levels were associated with increased risk of death (hazard ratios: 2.79; 95% CI, 2.21-3.53; P < .001 and 1.84; 95% CI, 1.62-2.10; P < .001, respectively). The addition of ST2 to survival models composed of other predictors of survival, including NT-proBNP, significantly improved model fit and predictive capacity.

Conclusions: ST2 and NT-proBNP are strong, noninvasive prognostic biomarkers in PAH. Despite its prognostic value in left-sided heart failure, Gal3 was not predictive in PAH. Adding ST2 to survival models significantly improves model predictive capacity. Future studies are needed to develop multimarker assays that improve noninvasive risk stratification in PAH.
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http://dx.doi.org/10.1016/j.chest.2019.12.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268446PMC
June 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

Functional Impact of Human Genetic Variants of /Endostatin on Pulmonary Endothelium.

Am J Respir Cell Mol Biol 2020 04;62(4):524-534

Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.

Pulmonary arterial hypertension (PAH) is an incurable disease characterized by disordered and dysfunctional angiogenesis leading to small-vessel loss and an obliterative vasculopathy. The pathogenesis of PAH is not fully understood, but multiple studies have demonstrated links between elevated angiostatic factors, disease severity, and adverse clinical outcomes. ES (endostatin), one such circulating angiostatic peptide, is the cleavage product of the proteoglycan (collagen α1[XVIII] chain). Elevated serum ES is associated with increased mortality and disease severity in PAH. A nonsynonymous variant of ES (aspartic acid-to-asparagine substitution at amino acid 104; p.D104N) is associated with differences in PAH survival. Although /ES expression is markedly increased in remodeled pulmonary vessels in PAH, the impact of ES on pulmonary endothelial cell (PEC) biology and molecular contributions to PAH severity remain undetermined. In the present study, we characterized the effects of exogenous ES on human PEC biology and signaling. We demonstrated that ES inhibits PEC migration, proliferation, and cell survival, with significant differences between human variants, indicating that they are functional genetic variants. ES promotes proteasome-mediated degradation of the transcriptional repressor ID1, increasing expression and release of TSP-1 (thrombospondin 1). ES inhibits PEC migration via an ID1/TSP-1/CD36-dependent pathway, in contrast to proliferation and apoptosis, which require both CD36 and CD47. Collectively, the data implicate ES as a novel negative regulator of ID1 and an upstream propagator of an angiostatic signal cascade converging on CD36 and CD47, providing insight into the cellular and molecular effects of a functional genetic variant linked to altered outcomes in PAH.
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http://dx.doi.org/10.1165/rcmb.2019-0056OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7110972PMC
April 2020

Early Detection of Pulmonary Vascular Dysfunction in Neonatal Bronchopulmonary Dysplasia.

Authors:
Paul M Hassoun

Am J Respir Crit Care Med 2020 01;201(1):7-9

Department of MedicineJohns Hopkins UniversityBaltimore, Maryland.

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http://dx.doi.org/10.1164/rccm.201910-1993EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938142PMC
January 2020

Serum uric acid as a marker of disease risk, severity, and survival in systemic sclerosis-related pulmonary arterial hypertension.

Pulm Circ 2019 Jul-Sep;9(3):2045894019859477. Epub 2019 Jul 29.

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

The object of this paper is to assess associations between serum uric acid (UA) and pulmonary arterial hypertension (PAH) risk, disease severity, and mortality in a well-characterized cohort of systemic sclerosis (SSc) patients referred for evaluation of possible PAH. Consecutive SSc patients aged >18 years with serum UA drawn within two weeks of a diagnostic right heart catheterization (RHC) were included. Associations between baseline serum UA and PAH at RHC were examined using logistic regression and receiver operating characteristic curves. Relationships between UA levels and metrics of disease severity were assessed using Pearson and Spearman correlation. Associations between UA and survival were assessed using Kaplan-Meier analysis and Cox proportional hazard modeling. A total of 162 SSc patients were included; 82 received a diagnosis of PAH at RHC. Patients found to have PAH had significantly higher UA than those without PAH. Elevated baseline UA was associated with significantly increased odds of PAH diagnosis at RHC (odds ratio [OR] = 4.07, 95% confidence interval [CI] = 2.11-7.87,  < 0.001). Each mg/dL higher UA was associated with a 14% increase in mortality (hazard ratio [HR] = 1.14, 95% CI = 1.02-1.28,  < 0.05). In multivariable models adjusting for potential confounders of the relationship between UA and survival, UA > 6.3 mg/dL remained significantly associated with increased mortality (HR = 1.84, 95% CI = 1.02-3.32,  < 0.05). Among SSc patients with suspected PAH, elevated serum UA is associated with increased risk of SSc-PAH. Among individuals diagnosed with SSc-PAH by RHC, UA is associated with disease severity and survival. These results indicate UA is a useful predictor of PAH risk and prognosis in SSc.
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http://dx.doi.org/10.1177/2045894019859477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664664PMC
July 2019

Myocardial Fibrosis as a Potential Maladaptive Feature of Right Ventricle Remodeling in Pulmonary Hypertension.

Am J Respir Crit Care Med 2019 09;200(6):662-663

Division of Pulmonary and Critical Care Medicine Johns Hopkins UniversityBaltimore, Maryland.

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http://dx.doi.org/10.1164/rccm.201906-1154EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775878PMC
September 2019

SU5416 does not attenuate early RV angiogenesis in the murine chronic hypoxia PH model.

Respir Res 2019 Jun 17;20(1):123. Epub 2019 Jun 17.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, 1830 E. Monument Street, 5th Floor, Baltimore, MD, 21205, USA.

Background: Right ventricular (RV) angiogenesis has been associated with adaptive myocardial remodeling in pulmonary hypertension (PH), though molecular regulators are poorly defined. Endothelial cell VEGFR-2 is considered a "master regulator" of angiogenesis in other models, and the small molecule VEGF receptor tyrosine kinase inhibitor SU5416 is commonly used to generate PH in rodents. We hypothesized that SU5416, through direct effects on cardiac endothelial cell VEGFR-2, would attenuate RV angiogenesis in a murine model of PH.

Methods: C57 BL/6 mice were exposed to chronic hypoxia (CH-PH) to generate PH and stimulate RV angiogenesis. SU5416 (20 mg/kg) or vehicle were administered at the start of the CH exposure, and weekly thereafter. Angiogenesis was measured after one week of CH-PH using a combination of unbiased stereological measurements and flow cytometry-based quantification of myocardial endothelial cell proliferation. In complementary experiments, primary cardiac endothelial cells from C57 BL/6 mice were exposed to recombinant VEGF (50 ng/mL) or grown on Matrigel in the presence of SU5416 (5 μM) or vehicle.

Result: SU5416 directly inhibited VEGF-mediated ERK phosphorylation, cell proliferation, and Kdr transcription, but not Matrigel tube formation in primary murine cardiac endothelial cells in vitro. SU5416 did not inhibit CH-PH induced RV angiogenesis, endothelial cell proliferation, or RV hypertrophy in vivo, despite significantly altering the expression profile of genes involved in angiogenesis.

Conclusions: These findings demonstrate that SU5416 directly inhibited VEGF-induced proliferation of murine cardiac endothelial cells but does not attenuate CH-PH induced RV angiogenesis or myocardial remodeling in vivo.
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http://dx.doi.org/10.1186/s12931-019-1079-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580559PMC
June 2019

Validation of the REVEAL Prognostic Equation and Risk Score Calculator in Incident Systemic Sclerosis-Associated Pulmonary Arterial Hypertension.

Arthritis Rheumatol 2019 10 26;71(10):1691-1700. Epub 2019 Aug 26.

The Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: A prognostic equation and risk score calculator derived from the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) are being used to predict 1-year survival in patients with pulmonary arterial hypertension (PAH), but little is known about the performance of these REVEAL survival prediction tools in systemic sclerosis (SSc)-associated PAH (SSc-PAH).

Methods: Prospectively gathered data from the Johns Hopkins Pulmonary Hypertension Program and Pulmonary Hypertension Assessment and Recognition of Outcome in Scleroderma Registries were used to evaluate the predictive accuracy of the REVEAL models for predicting the probability of 1-year survival in patients with SSc-PAH. Model discrimination was assessed by comparison of the Harrell's C-index, model fit was assessed using multivariable regression techniques, and model calibration was assessed by comparing predicted to observed survival estimates.

Results: The validation cohort consisted of 292 SSc-PAH patients with a 1-year survival rate of 87.4%. The C-index for predictive accuracy of the REVEAL prognostic equation (0.734, 95% confidence interval [95% CI] 0.652-0.816) and for the risk score (0.743, 95% CI 0.663-0.823) demonstrated good discrimination, comparable to that in the model development cohort. The calibration slope was 0.707 (95% CI 0.400-1.014), indicating that the overall model fit was marginal (P = 0.06). The magnitude of risk assigned to low distance on the 6-minute walk test (6MWD) and elevated serum levels of brain natriuretic peptide (BNP) was lower in the validation cohort than was originally seen in the REVEAL derivation cohort. Model calibration was poor, particularly for the highest risk groups.

Conclusion: In predicting 1-year survival in patients newly diagnosed as having SSc-PAH, the REVEAL prognostic equation and risk score provide very good discrimination but poor calibration. REVEAL prediction scores should be interpreted with caution in newly diagnosed SSc-PAH patients, particularly those with higher predicted risk of poor 1-year survival resulting from a low 6MWD or a high BNP serum level.
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http://dx.doi.org/10.1002/art.40918DOI Listing
October 2019
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