Research Article: Circulating angiotensin peptides levels in Acute Respiratory Distress Syndrome correlate with clinical outcomes: A pilot study

Date Published: March 7, 2019

Publisher: Public Library of Science

Author(s): Raju Reddy, Isaac Asante, Siyu Liu, Pranay Parikh, Janice Liebler, Zea Borok, Kathleen Rodgers, Ahmet Baydur, Stan G. Louie, Dulce Elena Casarini.

http://doi.org/10.1371/journal.pone.0213096

Abstract

We propose renin angiotensin system (RAS) peptides are critical in wound reparative processes such as in acute respiratory distress syndrome (ARDS). Their role in predicting clinical outcomes in ARDS has been unexplored; thus, we used a targeted metabolomics approach to investigate them as potential predictors of outcomes.

Thirty-nine ARDS patients were enrolled within 24 hours of ARDS diagnosis. Plasma RAS peptide levels were quantified at study entry and 24, 48 and 72 hours using a liquid chromatography-mass spectrometry based metabolomics assay. RAS peptide concentrations were compared between survivors and non-survivors, and were correlated with clinical and pulmonary measures.

Angiotensin I (Ang-I or A(1–10)) levels were significantly higher in non-survivors at study entry and 72 hours. ARDS survival was associated with lower A(1–10) concentration (OR 0.36, 95% CI 0.18–0.72, p = 0.004) but higher A(1–9) concentration (OR 2.24, 95% CI 1.15–4.39, p = 0.018), a biologically active metabolite of A(1–10) and an agonist of angiotensin II receptor type 2. Survivors had significantly higher median A(1–9)/A(1–10) and A(1–7)/A(1–10) ratios than the non-survivors (p = 0.001). Increased A(1–9)/A(1–10) ratio suggests that angiotensin converting enzyme II (ACE2) activity is higher in patients who survived their ARDS insult while an increase in A(1–7)/A(1–10) ratio suggests that ACE activity is also higher in survivors.

A(1–10) accumulation and reduced A(1–9) concentration in the non-survivor group suggest that ACE2 activities may be reduced in patients succumbing to ARDS. Plasma levels of both A(1–10) and A(1–9) and their ratio may serve as useful biomarkers for prognosis in ARDS patients.

Partial Text

Acute respiratory distress syndrome (ARDS) is characterized by disruption of the alveolar-capillary barrier leading to inflammation causing lung injury [1, 2]. Mortality rates range from 38.5–46.1 percent, with older age and disease severity being key risk factors for increased mortality [2, 3]. Given the high morbidity and mortality associated with ARDS, the development of biomarkers is important to identify patients at greatest risk for poor prognosis and outcome. Biomarkers such as plasma angiopoietin-2, Von-Willebrand factor, intracellular adhesion molecule 1 (ICAM-1), interleukin (IL-6), IL-8, protein C, and plasminogen activator inhibitor 1 (PAI-1) have been associated with clinically relevant outcomes [1–5]. However, these biomarkers may be limited by their specificity to particular disease conditions.

The protocol was approved by the University of Southern California Institutional Review Board to evaluate RAS peptides in patients with a diagnosis of ARDS (HSC-16-00). The Berlin definition of ARDS was used [16]. After the patient or their designee had signed an informed consent, the patient’s history, demographic and clinical information were recorded and blood samples were collected. Data collected included PaO2/FiO2 (P/F) ratios, sequential organ failure assessment (SOFA) score, length of hospital stay, body mass index (BMI), and serum creatinine and plasma lactate concentrations from days 1 through 4 following intensive care unit (ICU) admission. In addition, blood samples were collected at study entry and 24, 48 and 72 hours thereafter to measure RAS peptides.

In this cohort, 19/39 (48.7%) ARDS patients succumbed to their disease similar to other published reports [2, 3]. In univariate analysis, a greater mortality risk was associated with higher SOFA scores, plasma lactate levels and elevated A(1–10) levels at study entry. However, in multivariate analysis, A(1–10) and A(1–9) levels at study entry showed an association with mortality. Specifically, higher A(1–10) levels were associated with increased mortality while higher A(1–9) levels were associated with decreased mortality. Also, higher A(1–9)/A(1–10) and A(1–7)/A(1–10) ratios were observed in the surviving group. A binary regression model using levels of A(1–10) and A(1–9) at study entry could accurately predict outcomes in ARDS with 79.5% confidence.

A(1–10) accumulation and reduced A(1–9) concentration in the non-survivor group suggest that ACE2 activities may be reduced in patients succumbing to ARDS. Plasma levels of both A(1–10) and A(1–9) and their ratio may serve as useful biomarkers for prognosis in ARDS patients.

 

Source:

http://doi.org/10.1371/journal.pone.0213096

 

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