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Noninvasive prognostic biomarkers for left heart failure as predictors of survival in pulmonary arterial hypertension
Affiliations
- Johns Hopkins University Department of Medicine, Division of Pulmonary and Critical Care Medicine
Affiliations
- Johns Hopkins University Department of Medicine, Division of Pulmonary and Critical Care Medicine
Affiliations
- Johns Hopkins University Department of Medicine, Division of Pulmonary and Critical Care Medicine
Affiliations
- Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Department of Pediatrics, Division of Human Genetics
Affiliations
- Johns Hopkins University Department of Pediatrics, Division of Pediatric Cardiology
Affiliations
- Johns Hopkins University Department of Pediatrics, Division of Pediatric Cardiology
Affiliations
- Johns Hopkins University Department of Medicine, Division of General Internal Medicine
Affiliations
- Johns Hopkins University Department of Pediatrics, Division of Pediatric Cardiology
Affiliations
- Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Department of Pediatrics, Division of Human Genetics
Affiliations
- Vanderbilt University Department of Pediatrics, Division of Allergy, Immunology, and Pulmonary Medicine
Affiliations
- Children’s Hospital Colorado, Department of Pediatric Cardiology
Affiliations
- Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Department of Pediatrics, Division of Human Genetics
Affiliations
- Johns Hopkins University Department of Pediatrics, Division of Pediatric Cardiology
Correspondence
- Corresponding author: Correspondence and requests for reprints should be addressed to Allen D. Everett, M.D. Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, 1800 Orleans St. Room M2303, Baltimore, MD 21287
Correspondence information about the author MD Allen D. EverettAffiliations
- Johns Hopkins University Department of Pediatrics, Division of Pediatric Cardiology
Correspondence
- Corresponding author: Correspondence and requests for reprints should be addressed to Allen D. Everett, M.D. Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, 1800 Orleans St. Room M2303, Baltimore, MD 21287
Article Info
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Abstract
Background
Three biomarkers, soluble suppression of tumorigenicity 2 (ST2), galectin 3 (Gal3), and the N-terminal brain natriuretic peptide prohormone (NT-proBNP) are approved for noninvasive risk assessment in left heart failure, and small observational studies have shown their prognostic utility in heterogeneous pulmonary hypertension cohorts. We examined associations between these biomarkers and disease severity and survival in a large cohort of patients with Group I pulmonary arterial hypertension (PAH). 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 I PAH. Associations between biomarker levels and clinical variables, including survival times, were examined with multivariable regression models. Likelihood ratio tests and Akaike Information Criteria were used to compare survival models.
Results
Higher ST2 and NT-proBNP were associated with higher pulmonary pressures and vascular resistance and lower 6 minute 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<0.001 and 1.84, 95% CI 1.62-2.10, p<0.001 respectively). The addition of ST2 to survival models comprised 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 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.
Abbreviations:
6MWD (six-minute walking distance), AIC (Akaike Information Criteria), CI (cardiac index), Gal3 (galectin 3), mPAP (mean pulmonary arterial pressure), NT-proBNP (N-terminal brain natriuretic peptide pro-hormone), NYHA FC (New York Heart Association Functional Class), PAH (pulmonary arterial hypertension), PVR (pulmonary vascular resistance), RAP (right atrial pressure), REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management), ST2 (soluble suppression of tumorigenicity 2)To access this article, please choose from the options below
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Conflict of interest summary statement:
Authors report no conflicts of interest.
Funding information:
This study was supported by National Institutes of Health/National Heart, Lung, and Blood Institute awards R01HL135114 (A.D.E., J.Y., R.D., D.V., W.C.N., L.J.M., D.D.I and E.D.A.), R24 HL105333 (W.C.N., M.W.P., L.J.M, D.D.I. and E.D.A.), and T32HL007534 (C.E.S.). Serum/Tissue samples provided by PHBI under the Pulmonary Hypertension Breakthrough Initiative (PHBI). Funding for the PHBI is provided under an NHLBI R24 grant, R24HL123767, and by the Cardiovascular Medical Research and Education Fund (CMREF). M.K.N. was supported by The Matthew and Michael Wojciechowski Pulmonary Hypertension Pediatric Proof-of-Concept Grant (Dr. Robyn J. Barst Pediatric PH Research and Mentoring Fund Grant). Johns Hopkins Pulmonary Hypertension program was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute awards P50 HL084946/R01 and HL114910 (P.M.H.). D.I. was supported by the Jayden de Luca Foundation. Portions of this work were presented in the form of an abstract at the American Thoracic Society International Conference in Dallas, TX, May 21, 2019.
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