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Observational Study
. 2025 Jul 31;20(7):e0328734.
doi: 10.1371/journal.pone.0328734. eCollection 2025.

A multi-biomarker approach to risk stratification and detection of early cardiac disease in systemic sclerosis

Justin K Lui  1 , Fatima El-Adili  2   3 , Matthew Cozzolino  4 , Morgan Winburn  4 , Marcin A Trojanowski  3 , Deepa M Gopal  4 , Michael P LaValley  3   5 , Elizabeth S Klings  1 , Andreea M Bujor  2   3
Affiliations
Observational Study

A multi-biomarker approach to risk stratification and detection of early cardiac disease in systemic sclerosis

Justin K Lui et al. PLoS One. .

Abstract

Objective: We sought to investigate the relationship between serum biomarkers of cardiac dysfunction, longitudinal strain on echocardiography, and all-cause mortality in patients with systemic sclerosis.

Methods: This was an observational study using a biorepository of serum samples of patients with systemic sclerosis who underwent echocardiography. We investigated 3 biomarkers: periostin, galectin-3, and N-terminal prohormone brain natriuretic peptide and applied a K-means clustering resulting in 3 patient clusters. We subsequently measured left ventricular and right ventricular free wall longitudinal strain in each cluster. We then determined the association between each cluster and time to all-cause mortality compared to N-terminal prohormone brain natriuretic peptide, alone.

Results: The 125 patients with systemic sclerosis included in the study were divided into 3 clusters based on biomarker levels (Cluster 1: N = 75; Cluster 2: N = 39; Cluster 3: N = 11). Compared to Cluster 1, Cluster 2 had only elevated periostin levels whereas Cluster 3 had elevated levels of all 3 serum biomarkers and was characterized by reduced left ventricular and right ventricular free wall longitudinal strain, regionally and globally. When adjusted for age, sex, systemic sclerosis disease duration, and forced vital capacity, patients in Cluster 3 had a HR of 14.42 (95% CI: 4.82, 43.18) for all-cause mortality compared to those in Cluster 1.

Conclusion: In conclusion, combining N-terminal prohormone brain natriuretic peptide, periostin, and galectin-3 as serum biomarkers enhances risk stratification and sensitivity in detection of cardiac disease in patients with systemic sclerosis. However, before implementation in routine care, further prospective studies must refine biomarker sensitivity, specificity, and accuracy together with optimizing detection strategies and establishing clinical protocols for integration.

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Conflict of interest statement

J. K. L. has received research support from United Therapeutics. E. S. K. has received research support from Novartis, FORMA Therapeutics/Novo Nordisk, and United Therapeutics. She received royalties for 3 topic cards in UpToDate. She is a consultant/advisory board member for Pfizer, Novo Nordisk, and CSL Behring for sickle cell disease related clinical trials (no conflict with the present work).

Figures

Fig 1
Fig 1. Study population.
A K-means clustering was performed yielding 3 clusters based on serum biomarker levels of periostin, galectin-3, and N-terminal prohormone brain natriuretic peptide (NT-proBNP). The means of periostin, galectin-3, and NT-proBNP are presented in each cluster.
Fig 2
Fig 2. Serum biomarker levels of periostin, galectin-3, and N-terminal prohormone brain natriuretic peptide (NT-proBNP) within each cluster.
The mean ± SD level of each serum biomarker is presented. *p < 0.05; **p < 0.001.
Fig 3
Fig 3. Left ventricular (LV) and right ventricular (RV) free wall longitudinal strain distribution in low risk, intermediate risk, and high risk NT-proBNP groups.
Bull’s eye plot (top panel) and histogram (bottom panel) of longitudinal strain at the following cardiac segments: a) RV basal; b) RV mid; c) RV apical; d) LV basal anterior; e) LV basal anteroseptal; f) LV basal inferoseptal; g) LV basal inferior; h) LV basal inferolateral; i) LV basal anterolateral; j) LV mid anterior; k) LV mid anteroseptal; l) LV mid inferoseptal; m) LV mid inferior; n) LV mid inferolateral; o) LV mid anterolateral; p) LV apical anterior; q) LV apical septal; r) LV apical inferior; s) LV apical lateral. LV GLS for the low risk, intermediate risk, and high risk NT-proBNP groups were 17.9 ± 2.5%, 12.4 ± 2.9%, and 15.4 ± 2.4%, respectively. RV free wall GLS for the low risk, intermediate risk, and high risk NT-proBNP groups were 22.8 ± 5.5%, 13.7 ± 3.9%, and 14.3 ± 6.0%, respectively. *p < 0.05.
Fig 4
Fig 4. Left ventricular (LV) and right ventricular (RV) free wall longitudinal strain distribution in each cluster.
Bull’s eye plot (top panel) and histogram (bottom panel) of longitudinal strain at the following cardiac segments: a) RV basal; b) RV mid; c) RV apical; d) LV basal anterior; e) LV basal anteroseptal; f) LV basal inferoseptal; g) LV basal inferior; h) LV basal inferolateral; i) LV basal anterolateral; j) LV mid anterior; k) LV mid anteroseptal; l) LV mid inferoseptal; m) LV mid inferior; n) LV mid inferolateral; o) LV mid anterolateral; p) LV apical anterior; q) LV apical septal; r) LV apical inferior; s) LV apical lateral. LV GLS for Cluster 1, Cluster 2, and Cluster 3 were 17.7 ± 2.6%, 17.7 ± 3.0%, and 14.8 ± 2.6%, respectively. RV free wall GLS for Cluster 1, Cluster 2, and Cluster 3 were 23.3 ± 5.7%, 20.9 ± 5.5%, and 14.9 ± 5.0%, respectively. *p < 0.05.
Fig 5
Fig 5. Kaplan-Meier survival curve by A.) NT-proBNP risk groups and B.) Cluster.
Vertical bars denote censored data.
See this image and copyright information in PMC

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