A104-22 Investigating The Association Of Proprotein Convertase Subtilisin-kexin Type 9 With Clinical Outcomes And Characteristics In The Acute Respiratory Distress Syndrome

Rationale

Proprotein Convertase Subtilisin-Kexin type 9 (PCSK9) is a key regulator of lipid metabolism. A pro-inflammatory role for PCSK9 has been hypothesised through reduced bacterial phospholipid clearance. Elevated plasma PCSK9 in Acute Respiratory Distress Syndrome (ARDS) patients has been reported in a single cohort. Whether it is increased in the pulmonary compartment or associated with ‘hypo’ and ‘hyperinflammatory’ ARDS subphenotypes is unknown. This work aimed to confirm that plasma PCSK9 is elevated in ARDS, test whether it is increased in the alveolar compartment of ARDS patients and explore its association with clinical outcomes and inflammatory subphenotypes.

Methods

PCSK9 concentration was measured by enzyme-linked immunosorbent assay (ELISA) in baseline plasma from 487 ARDS patients from the HARP2 clinical trial, and healthy volunteer plasma (N = 32). Baseline bronchoalveolar lavage (BAL) fluid was taken from ARDS patients recruited to the HARP1 and KARE trials (N = 18), and healthy volunteers (HV BAL, ARENA trial, N = 6). BAL fluid was taken from healthy volunteers who had inhaled bacterial lipopolysaccharide as an experimental human challenge model of ARDS at 4hrs (LPS BAL, ARENA and KGF trials, N = 17). BAL fluid was also measured via ELISA for PCSK9 concentration.

Results

PCSK9 concentration was significantly elevated in ARDS patient plasma compared with healthy volunteers (Figure 1A, median 474.1 vs 267.9ng/mL, p < 0.0001). Plasma PCSK9 levels were significantly elevated in those with the ‘hyper’ compared with the ‘hypoinflammatory’ ARDS subphenotype (Figure 1B, median 580.8 vs 410.9ng/mL, p < 0.0001). Higher plasma PCSK9 in ARDS patients was associated with fewer ventilator free days on Poisson regression (p < 0.0001) and was significantly higher in non-survivors than survivors (median 550.8 vs 464.3ng/mL, p = 0.0172). PCSK9 concentration in ARDS patient and LPS BAL fluid was significantly higher than in healthy volunteers (Figure 1C, median 2.59ng/mL vs 1.67ng/mL vs 0.65ng/mL, p < 0.0001). PCSK9 levels in ARDS patient BAL fluid were significantly associated with higher baseline monocyte chemoattractant protein-1 (N = 25, p = 0.0274), interleukin-6 (N = 25, p = 0.002), total cell count (N = 16, p = 0.0321), and extravascular lung water measurements (N = 22, p = 0.0211) upon linear regression.

Conclusions

PCSK9 is elevated in the plasma and alveolar space of patients with ARDS. Plasma PCSK9 is associated with the hyperinflammatory ARDS subphenotype and with worse clinical outcomes, including longer duration of ventilation and higher mortality. BAL fluid PCSK9 levels are associated with pro-inflammatory cytokine concentration. Further work is required to investigate the mechanistic role of PCSK9 in ARDS pathogenesis.

This abstract is funded by: Department for the Economy Northern Ireland Ph.D. studentship awarded to EC, and an Association of Physicians of GB and Ireland Young Investigator’s award to JS