PCSK9 is associated with mortality in patients with septic shock: data from the ALBIOS study

Abstract

Background Pro‐protein convertase subtilisin/kexin 9 (PCSK9) is a proenzyme primarily known to regulate low‐density lipoprotein receptor re‐uptake on hepatocytes. Whether PCSK9 can concurrently trigger inflammation or not remains unclear. Here, we investigated the potential association between circulating levels of PCSK9 and mortality in patients with severe sepsis or septic shock. Methods Plasma PCSK9 levels at days 1, 2 and 7 were measured in 958 patients with severe sepsis or septic shock previously enrolled in the Albumin Italian Outcome Sepsis (ALBIOS) trial. Correlations between levels of PCSK9 and pentraxin 3 (PTX3), a biomarker of disease severity, were evaluated with ranked Spearman’s coefficients. Cox proportional hazards models were used to assess the association of PCSK9 levels at day 1 with 28‐ and 90‐day mortality. Results Median plasma PCSK9 levels were 278 [182–452] ng mL−1 on day 1. PCSK9 correlated positively with PTX3 at the three time‐points, and patients with septic shock within the first quartile of PCSK9 showed higher levels of PTX3. Similar mortality rates were observed in patients with severe sepsis across PCSK9 quartiles. Patients with septic shock with lower PCSK9 levels on day 1 (within the first quartile) showed the highest 28‐ and 90‐day mortality rate as compared to other quartiles. Conclusion In our sub‐analysis of the ALBIOS trial, we found that patients with septic shock presenting with lower plasma PCSK9 levels experienced higher mortality rate. Further studies are warranted to better evaluate the pathophysiological role of PCSK9 in sepsis.

PCSK9: A Potential Therapeutic Target for Sepsis

“…Similarly, PCSK9 LOF variants were associated with an increased clearance of pathogen lipids, a decreased 1-year mortality, and recurrent infection in septic survivors [ 22 ]. Recently, the subanalysis of the Albumin Italian Outcome Sepsis (ALBIOS) study showed that patients with septic shock presenting with lower plasma PCSK9 levels experienced a higher 28- and 90-day mortality rate [ 23 ]. On the other hand, it is known that increased arterial stiffness is associated with clinical outcomes in patients with early sepsis.…”

Proprotein convertase subtilisin/kexin type 9 regulates the production of acute‐phase reactants from the liver

“…Both experimental and clinical data about the harmful/beneficial effects of PCSK9 in sepsis are contradictory 14,17‐21,36 . To study the significance of the pcsk9 gene in a systemic S pneumoniae infection of adult zebrafish, 23 we inoculated bacteria (4 700 000 CFU; SD 990 000 CFU) into the abdominal cavity of fish from both pcsk9 mutation carrying lines; pcsk9 tpu‐13 and pcsk9 tpu‐2,+15 .…”

“…The dual role of PCSK9 in regulating hepatocytic lipoprotein uptake 3,4 and the inflammatory response 13,14 has made this proprotein convertase an attractive candidate for studying sepsis. Although some data indicate that normal PCSK9 levels are associated with a better prognosis, 20,21 and that this effect could be age dependent, 19 other studies support the idea that blocking PCSK9 activity could improve the outcome of treatment in septic patients 14,15,17 . In fact, the PCSK9 inhibiting antibodies alirocumab (Praluent, Sanofi‐Regeneron) and evolocumab (Repatha, Amgen) are being tested in clinical trials to treat septic patients (NCT03634293 and NCT03869073 respectively).…”

The role of resistin and myeloperoxidase in severe sepsis and septic shock: Results from the ALBIOS trial

“…Circulating biomarkers might help understand the underlying inflammatory mechanisms in patients with severe sepsis and septic shock and select the most appropriate monitoring strategies and treatments 1 . A wealth of biomarkers have been investigated, 2‐6 and some of them, such as C‐reactive protein (CRP) and procalcitonin, are routinely used in clinical practice 7,8 …”