Noninvasive Prognostic Biomarkers for Left-Sided Heart Failure as Predictors of Survival in Pulmonary Arterial Hypertension
Authors: Eric D Austin
Lisa J Martin
D Dunbar Ivy
Allen D Everett
Melanie K Nies
Stephanie Brandal
Catherine E Simpson
Michael W Pauciulo
R Dhananjay Vaidya
William C Nichols
Jun Yang
Rachel L Damico
Paul M Hassoun
Journal: Chest (2020)
Discipline: CLINICAL MEDICINE
Keywords: biomarkers; heart failure; molecular biology; pulmonary hypertension.
Affiliations: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD., Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH., Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD., Division of General Internal Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD., Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University, Nashville, TN., Department of Pediatric Cardiology, Children's Hospital Colorado, Aurora, CO., Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD. Electronic address: .

Abstract:  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 &lt; .001 and 1.84; 95% CI, 1.62-2.10; P &lt; .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. 

Retracted: No

PubPeer comments:
 This is certainly a large biomarker study that makes a significant contribution to the field.. However, a few critical points should be raised 1) It is important to note that the researchers did not use the FDA-approved ELISA for Galactin-3, produced by BG Medicine. It is difficult to understand why - probably costs. The authors developed their own multispotted ELISA on an MSD plattform, but did not even use the FDA-approved Galectin-3 ELISA from BG Medicine to validate their own multispotted customized ELISA that includes Galectin-3. It would have been good to invest this validation upfront, instead of using another commercial ELISA for validation (R D). https: www.globenewswire.com news-release 2015 07 06 749891 10140395 en First-Automated-Test-for-Galectin-3-Now-Available-in-U-S.html de Boer R, Lok D, Jaarsma T, et al. Predictive value of plasma galectin-3 levels in heart failure with reduced and preserve ejection fraction. Annals of Medicine. 2011; 43: 60-68. Out of Simpson et al:  A multiplex ELISA was developed to measure ST2, Gal3, and NT-proBNP simultaneously using robotically spotted capture antibodies on the 96-well plate format (Meso Scale Discovery [MSD], Gaithersburg, MD). Capture antibody-spotted plates were blocked with 5% BSA-PBS complemented with .05% TWEEN (PBS-T) and incubated at room temperature on an orbital shaker (500 rpm) for 60 minutes. Calibrators for NTproBNP (MSD C01XX-1), Galectin-3 (R D 840355), and ST-2 (R D 840760) were produced using commercially provided diluent (MSD R51BB-3). How do the authors explain that other studies clearly found Galectin-3 to be predictive in PAH, ?? e.g. Am Heart J. 2019 Feb;208:91-99. doi: 10.1016 j.ahj.2018.11.001. Unfortunately, the authors ignored to cite and discuss a number of original articles (clinical, translational and basic science) published since 2015 on the relevance and prediction potential of Galecctin-3 in PAH, in solid journals. These can be easily found on PubMed. 2) The findings on the link between ST2 and PAH are not new, but it is good confirm them in such a large biomarker study. 3) Isn t a a better approach to create a combined risk and monitoring score that includes 1-3biomarkers (NTproBNP + X plasma, serum) plus ECHO and clinical variables. ,