Brief Report
Annexin A1 is a Potential Novel Biomarker of Congestion in Acute Heart Failure

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Objectives

This study sought to identify the role of annexin A1 (AnxA1) as a congestion marker in acute heart failure (AHF) and to identify its putative role in predicting clinical outcomes.

Background

AnxA1 is a protein that inhibits inflammation following ischemia–reperfusion injury in cardiorenal tissues. Because AHF is a state of tissue hypoperfusion, we hypothesized that plasma AnxA1 levels are altered in AHF.

Methods

In the Renal Optimization Strategies Evaluation (ROSE) trial, patients hospitalized for AHF with kidney injury were randomized to receive dopamine, nesiritide, or placebo for 72 hours in addition to diuresis. In a subanalysis, plasma AnxA1 levels were measured at baseline and at 72 hours in 275 patients. Participants were divided into 3 tertiles based on their baseline AnxA1 levels.

Results

The prevalence of peripheral edema 2+ increased with increasing AnxA1 levels (P < .007). Cystatin C, blood urea nitrogen, and kidney injury molecule-1 plasma levels were higher among participants in tertile 3 vs tertiles 1 or 2 (P< .05). Patients with a congestion score of 4 had a mean baseline AnxA1 level 8.63 units higher than those with a congestion score of 0 (P = .03). Patients in tertiles 2 and 3 were twice as likely to experience creatinine elevation as patients in tertile 1 (P = .03). Patients in tertiles 2 and 3 were at a higher risk of 60-day all-cause mortality or heart failure hospitalization and 180-day all-cause mortality (P < .05).

Conclusions

Among patients hospitalized for AHF with impaired kidney function, elevated AnxA1 levels are associated with worse congestion, higher risk for further creatinine elevation, and higher rates of 60-day morbidity or all-cause mortality and 180-day all-cause mortality.

Clinical Trial Registration

clinicaltrials.gov Identifier: NCT01132846

Introduction

Annexin A1 (AnxA1) is a 37-kDa phospholipid-binding, calcium-dependent pro-resolving protein that is present intracellularly1 and extracellularly.2 AnxA1 inhibits leukocyte recruitment into inflammation sites and reduces the expression of inflammatory cytokines after ischemia-reperfusion (I-R) injury,3 including renal4 and cardiovascular tissues.5

After renal I-R injury, AnxA1 is upregulated in epithelial cells, ameliorating acute tubular necrosis.4 In the cardiovascular system, I-R injury results in AnxA1 upregulation.5 Like I-R injury, acute heart failure (AHF) is a state of tissue hypoperfusion secondary to increased venous congestion and low cardiac output, both of which result in tissue ischemia. Because AnxA1 is upregulated in hypoxic states, we hypothesized that plasma AnxA1 levels are altered in AHF, and that the levels have potential prognostic significance.

In a subanalysis of the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-AHF) study, we examined the plasma levels of AnxA1 in a cohort of hospitalized patients with AHF, its association with acute kidney injury, congestion signs and symptoms, and its value in predicting the rates of morbidity and mortality.

Section snippets

Study Overview and Design

The ROSE-AHF was a double-bind, placebo-controlled, randomized clinical trial. There were no differences in outcomes among the control and the 2 treatment arms.6

The ROSE-AHF trial6 enrolled patients hospitalized for AHF management (N = 360) with impaired kidney function within 24 hours. AHF involved having at least 1 symptom (dyspnea, orthopnea, or edema) and 1 sign (rales, edema, ascites, or pulmonary vascular congestion on a chest radiograph); impaired kidney function was defined as an

Patient Population

The cohort (n = 275) was stratified into tertiles based on their baseline AnxA1 levels (Table 1). The prevalence of peripheral edema 2+ increased with increasing AnxA1 levels (P = .007). More patients in tertile 2 (24% vs 12%, P = .041) and tertile 3 (23% vs 12%, P = .055) were hospitalized for heart failure in the preceding year compared with patients in tertile 1. The rest of the characteristics were similar across all tertiles.

Baseline AnxA1 and Renal Biomarkers

Cystatin C, blood urea nitrogen, and KIM1 were higher among

Discussion

There is a need for biomarkers that correlate with congestion and overall clinical course among patients hospitalized for AHF. To the best of our knowledge, this is the first study to elucidate the characteristics and potential prognostic value of plasma AnxA1 in AHF.

AHF precipitates pan-tissue congestion8,9 leading to tissue ischemia; ischemia causes AnxA1 upregulation,3, 4, 5 which may explain the correlation between elevated plasma AnxA1 and congestion markers. Further, although AnxA1 is

Conclusions

Among patients hospitalized for AHF with impaired kidney function, elevated AnxA1 levels at baseline and at 72 hours are associated with worse congestion, increased risk for further creatinine elevation, worse 60-day morbidity or mortality, and worse 180-day mortality. Further studies are warranted to further characterize the prognostic value of plasma AnxA1 in AHF.

Funding/Support

Supported by grants from the National Heart, Lung, and Blood Institute (NHLBI): R01HL84155, and R01-HL136440 awarded to H. H. Chen and Heart Failure Network (coordinating center: U10 HL084904; regional clinical centers: U01 HL084861, U10 HL110312, U109 HL110337, U01 HL084889, U01 HL084890, U01 HL084891, U10 HL110342, U10 HL110262, U01 HL084931, U10 HL110297, U10 HL110302, U10 HL110309, U10 HL110336, U10 HL110338). This work is also supported by the National Center for Advancing Translational

Disclosures

Dr Chen reports being a co-Founder of Zumbro Discovery, receiving grants from Scios Inc, and receiving royalties from UpToDate, and that his institution has patents for designer natriuretic peptides. Dr Tang reports consulting for MyoKardia Inc and Sequana Medical. Dr Felker reports research grants from NHLBI, American Heart Association, Amgen, Merck, Cytokinetics, and Roche Diagnostics; he has acted as a consultant to Novartis, Amgen, BMS, Medtronic, Cardionomic, Relypsa, V-Wave, Myokardia,

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