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. 2022 Aug 10:20:100190.
doi: 10.1016/j.ahjo.2022.100190. eCollection 2022 Aug.

Higher plasma IL-6 and PTX3 are associated with worse survival in left heart failure with pulmonary hypertension

Sara Helleberg  1   2 , Adam Engel  1   2 , Salaheldin Ahmed  1   2 , Abdulla Ahmed  1   2 , Göran Rådegran  1   2
Affiliations

Higher plasma IL-6 and PTX3 are associated with worse survival in left heart failure with pulmonary hypertension

Sara Helleberg et al. Am Heart J Plus. .

Abstract

Introduction: Left heart failure (LHF) is commonly complicated by pulmonary hypertension (PH), increasing morbidity and mortality. The present study aimed to evaluate the prognostic value of inflammatory proteins in LHF with PH (LHF-PH).

Materials and methods: The levels of 65 plasma proteins, analysed with proximity extension assay, were compared between healthy controls (n = 20), patients with LHF-PH (n = 67) comprising both HFpEF-PH (n = 31) and HFrEF-PH (n = 36), and in a LHF subpopulation before and after heart transplantation (HT, n = 19). Haemodynamic parameters were measured using right heart catheterization.

Results: Plasma levels of Interleukin 6 (IL-6) and Pentraxin related protein PTX3 (PTX3) were elevated in LHF-PH vs. controls (p < 0.001), and these decreased after HT compared to before HT (p < 0.001). Plasma IL-6 and PTX3 correlated to elevated NT-proBNP (r = 0.44, p = 0.0002 and r = 0.4, p = 0.0009, respectively). Additionally, IL-6 correlated with mean pulmonary arterial pressure (r = 0.4, p = 0.0009) and mean right atrial pressure (r = 0.51, p < 0.0001). Higher levels of IL-6 and PTX3 were associated with worse survival rates in patients with LHF-PH (Log rank p < 0.01).

Discussion: In patients with LHF-PH, higher plasma levels of IL-6 and PTX3 were associated with worse survival rates. Future larger studies to validate and investigate the direct clinical applicability of IL-6 and PTX3 as potential prognostic biomarkers are encouraged.

Keywords: Biomarkers; Haemodynamics; Heart transplantation; Inflammation; Interleukin 6; Left heart disease; Pentraxin related protein 3.

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Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Göran Rådegran reports financial support was provided by Janssen Cilag AB. Göran Rådegran reports financial support was provided by Avtal om läkarutbildningen och forskning, ALF. Salaheldin Ahmed reports a relationship with Janssen Cilag AB that includes: speaking and lecture fees. Abdulla Ahmed reports a relationship with Janssen Cilag AB that includes: speaking and lecture fees. Göran Rådegran reports a relationship with Janssen Cilag AB that includes: consulting or advisory, funding grants, and speaking and lecture fees. Göran Rådegran reports a relationship with Actelion Pharmaceuticals Sverige AB that includes: speaking and lecture fees. Göran Rådegran reports a relationship with Bayer health care that includes: speaking and lecture fees. Göran Rådegran reports a relationship with GlaxoSmithKline that includes: speaking and lecture fees. Göran Rådegran reports a relationship with Nordic infucare that includes: speaking and lecture fees. Dr. Rådegran is, and has been primary-, or co-, investigator in; clinical PAH trials for Acceleron, Actelion Pharmaceuticals Sweden AB, Bayer, GlaxoSmithKline, Janssen, Pfizer, and United Therapeutics, and in clinical heart transplantation immunosuppression trials for Novartis. The companies had no role in the data collection, analysis and interpretation and had no right in disapproving of the manuscript.

Figures

Fig. 1
Fig. 1
Protein levels of Interleukin 6 (a), Spearman's correlation analyses with haemodynamic parameters and NT-proBNP (b-d), ROC-curve (e) and Kaplan Meier curve (f). (a) Protein levels of interleukin-6 (IL-6) in controls, patients with left heart failure and pulmonary hypertension (LHF-PH), before heart transplantation (PreHT) and after heart transplant (PostHT). (b-d) Correlation analysis between IL-6 and (b) mean pulmonary arterial pressure (mPAP), (c) mean right atrial pressure (MRAP), and (d) N-terminal pro brain natriuretic peptide (NT-proBNP). (e) ROC-curve of IL-6 to determine threshold for further analysis. (f) Kaplan Meier analysis of patients with LHF-PH (n = 67) dichotomized accordance with attained IL-6 threshold from receiver operating characteristics analysis. During the follow-up period of 48 patients with LHF-PH with higher IL-6 levels exhibited worse survival.
Fig. 2
Fig. 2
Protein levels of PTX3 (a), Spearman's correlation analyses with NT-proBNP (b), ROC-curve (c) and Kaplan Meier (d). (a) Protein levels of Pentraxin related protein PTX3 (PTX3) in controls, patients with left heart failure and pulmonary hypertension (LHF-PH), before heart transplantation (PreHT) and after heart transplant (PostHT). (b) Correlation analysis between PTX3 and N-terminal pro brain natriuretic peptide (NT-proBNP). (c) ROC-curve of PTX3 to determine threshold for further analysis. (d) Kaplan Meier analysis of patients with LHF-PH (n = 67) dichotomized accordance with attained PTX3 threshold from receiver operating characteristics analysis. During the follow-up period of 27 patients with LHF-PH with higher PTX3 levels exhibited worse survival.
Fig. 3
Fig. 3
Study design explained. Statistical significance for boxplots were p < 0.006 and false discovery rate was performed with Q = 0.01 * Proteins included in correlation analysis were IL-6, CXL17, FCRLB, IL2-RA, ALCAM, GRN, CXCL16, PSP-D, IL-1RT1, PGLYRP1, CD93, CCL16, SLAMF7, IL-4RA, IL-17D, PTX3. ** Proteins included in analysis with ROC-curves were IL-6, CXL17, GRN, IL-1RT1, CD93, IL4RA, PTX3. *** Proteins included in Kaplan Meier analysis were IL-6, IL-4RA, PTX3. For a full list of protein abbreviations, please see Section 2.5 “Proteins” in Methods. Abbreviations: Left heart failure with pulmonary hypertension (LHF-PH), heart transplantation (HT), N-terminal pro brain natriuretic peptide (NT-proBNP), Interleukin 6 (IL-6), pentraxin related protein PTX3 (PTX3).
Supplementary Fig. 1
Supplementary Fig. 1
ROC curves (a-e) and Kaplan Meier curves (f) for proteins included in the analysis other than Interleukin 6 and Pentraxin related protein 3. For ROC-and Kaplan Meier curves for IL-6 and PTX3 please see Fig. 1, Fig. 2 respectively.
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