Elsevier

Clinica Chimica Acta

Volume 445, 20 May 2015, Pages 73-78
Clinica Chimica Acta

Analysis of BAG3 plasma concentrations in patients with acutely decompensated heart failure,☆☆,

https://doi.org/10.1016/j.cca.2015.02.048Get rights and content

Highlights

  • BAG3 is a novel biomarker associated with cardiomyocyte stress and cardiomyopathy.

  • In patients with ADHF, BAG3 is a significant predictor of death at one year.

  • BAG3 is weakly correlated with the natriuretic peptides and sST2.

  • Future studies are needed to explore the prognostic role of BAG3 in ADHF.

Abstract

Background

BCL-2-associated athanogene 3 (BAG3) is a protein implicated in the cardiomyocyte stress response and genesis of cardiomyopathy. Extracellular BAG3 is measurable in patients with heart failure (HF), but the relationship of BAG3 with HF prognosis is unclear.

Methods

BAG3 plasma concentrations were measured in 39 acutely decompensated HF patients; the primary endpoint was death at 1 year. Baseline characteristics were compared by vital status and median BAG3 concentration. Correlation of BAG3 with left ventricular ejection fraction (LVEF) and other biomarkers was performed. Prognostic value was assessed using Cox proportional hazards regression and Kaplan–Meier analysis.

Results

At baseline, median BAG3 was significantly higher in decedents (N = 11) than survivors (N = 28; 1489 ng/mL versus 50 ng/mL; P = 0.04); decedents also had worse renal function and higher median natriuretic peptide (NP) and sST2. BAG3 was not significantly correlated with NPs, mid-regional pro-adrenomedullin, sST2, or eGFR, however. Mortality was increased in patients with supra-median BAG3 (> 336 ng/mL; 42.1% versus 15.0%, P = 0.06). In age and LVEF-adjusted Cox proportional hazards, BAG3 remained a significant mortality predictor (HR = 3.20; 95% CI = 1.34–7.65; P = 0.02); those with supra-median BAG3 had significantly shorter time-to-death (P = 0.04).

Conclusion

The stress response protein BAG3 is measurable in patients with ADHF and may be prognostic for death.

Introduction

As the number of patients with heart failure (HF) continues to grow, techniques to help improve our understanding of its pathophysiology may lead to superior strategies for risk prediction and therapy [1]. In this regard, study of biomarkers in HF has vastly expanded, with several new biomarkers under investigation for their use in diagnosis, prognosis, and management of HF [2], [3]. Notably, most novel biomarkers in HF suffer from a relative lack of cardiovascular specificity, which may reduce their potential value. Accordingly, identification and assessment of biomarkers with greater cardiovascular specificity would be of considerable benefit.

The BCL-2-associated athanogene (BAG) family consists of proteins that are involved in the regulation of heat shock proteins Hsp70 and HSc70 and possess a conserved C-terminus; members of this family differ based on the upstream region of the protein [4]. BAG3 is a member of this family; this protein is natively expressed in high concentrations in cardiac and skeletal muscle cells [5], and it has been implicated in apoptosis, cell adhesion, cytoskeleton remodeling, and autophagy [6]. BAG3 has also been linked to development of dilated cardiomyopathy [7]. Functionally, BAG3 may play a role in maintaining myofibril structural integrity and Z-disc stability by its association with HSc70 and the β1 subunit of F-actin capping protein (CapZβ1) [8].

Recently, an extracellular form of BAG3 was found to be released from stressed cardiomyocytes in patients with chronic HF; furthermore, antibodies directed at BAG3 were also identified in these patients, implying a potential immune response [9]. Another report identified higher BAG3 concentrations in twenty patients with New York Heart Association (NYHA) class IV symptoms when compared to healthy controls or less symptomatic patients with HF, and elevated concentrations of BAG3 were associated with impending death or need for advanced HF therapies [10]. Given these promising results, further study is needed regarding measurement of BAG3 in HF. We therefore conducted a post hoc analysis of the Biomonitoring and Cardiorenal Syndrome in Heart Failure (BIONICS-HF) trial (Clinicaltrials.gov; NCT01570153), examining BAG3 measurement in a subgroup of the enrolled subjects [11].

Section snippets

Study procedures and patient population

All procedures were approved by the Partners Healthcare Institutional Review Board, and informed consent was obtained from all patients. The details of the BIONICS-HF study have been reported previously [11]. In brief, this was originally a two center study involving the Massachusetts General Hospital and Ospedale Sant'Andrea whose focus was on identifying biomonitoring tools to better predict risk for HF complications, including renal failure and death. Patients were enrolled between April and

Results

Thirty-nine subjects were included in this analysis. At one year, twenty-eight patients were alive and eleven had died. Baseline characteristics divided by vital status at 1 year are shown in Table 1. Patients who expired were significantly older, had lower LVEF, and were more likely to have lower blood pressure and body-mass index and significantly higher sST2 and NT-proBNP concentrations. Additionally, those who were deceased also had significantly worse renal function and evidence of renal

Discussion

In this report, we examined BAG3 concentrations in patients with ADHF. Patients who were deceased at 1 year were significantly older, had lower LVEF, worse renal function, and significantly higher concentrations of BAG3, sST2, and NT-proBNP. Patients with BAG3 concentrations above the median value of 336 ng/mL had a trend towards a more deleterious risk profile, including older age, more impaired renal function, and higher concentrations of several important prognostic biomarkers. Despite these

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    Funding sources: Dr. Gandhi is supported by the Dennis and Marilyn Barry Fellowship in Cardiology, Dr. Gaggin is supported in part by the Clark Fund for Cardiac Research Innovation, and Dr. Januzzi is supported in part by the Roman W. DeSanctis Clinical Scholar Endowment and the Hutter Family Professorship.

    ☆☆

    Disclosures: Dr. Januzzi has received grant support from Thermo-Fisher, Singulex, and Siemens, and has received consulting income from Roche Diagnostics, Critical Diagnostics, and Sphingotec. Dr. Turco has received grant support from BIOUNIVERSA s.r.l. Dr. Gaggin has received consulting income from Roche Diagnostics, American Regent and Critical Diagnostics.

    Clinical Trial Registration: Clinicaltrials.gov; NCT01570153.

    1

    Contributed equally.

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