Low PCSK-9 levels Are Associated with Favorable Neurologic Function after Resuscitation from out of Hospital Cardiac Arrest

Abstract

Endotoxemia after cardiopulmonary resuscitation (CPR) is associated with unfavorable outcome. Proprotein convertase subtilisin/kexin type-9 (PCSK–9) regulates low-density lipoprotein receptors, which mediate the hepatic uptake of endotoxins. We hypothesized that PCSK–9 concentrations are associated with neurological outcome in patients after CPR. Successfully resuscitated out-of-hospital cardiac arrest patients were included prospectively (n = 79). PCSK–9 levels were measured on admission, 12 h and 24 h thereafter, and after rewarming. The primary outcome was favorable neurologic function at day 30, defined by cerebral performance categories (CPC 1–2 = favorable vs. CPC 3–5 = unfavorable). Receiver operating characteristic curve analysis was used to identify the PCSK–9 level cut-off for optimal discrimination between favorable and unfavorable 30-day neurologic function. Logistic regression models were calculated to estimate the effect of PCSK–9 levels on the primary outcome, given as odds ratio (OR) and 95% confidence interval (95%CI). PCSK–9 levels on admission were significantly lower in patients with favorable 30-day neurologic function (median 158 ng/mL, (quartiles: 124–225) vs. 207 ng/mL (174–259); p = 0.019). The optimally discriminating PCSK–9 level cut-off was 165ng/mL. In patients with PCSK–9 levels ≥ 165 ng/mL, the odds of unfavorable neurological outcome were 4.7-fold higher compared to those with PCSK–9 levels < 165 ng/mL. In conclusion, low PCSK–9 levels were associated with favorable neurologic function.

Sex difference in circulating PCSK9 and its clinical implications

“…An extensive investigation of PCSK9 revealed its novel potential functions, including the regulation of neuronal development, apoptosis and differentiation, but the precise role of PCSK9 in brain physiology remained unclear ( Mannarino et al, 2018 ). Moreover, high circulating PCSK9 levels were associated with unfavorable neurological function after resuscitation from out-of-hospital cardiac arrest ( Merrelaar et al, 2020 ). The increase in PCSK9 levels was most likely caused by the inflammatory response and organ dysfunction after cardiopulmonary resuscitation (CPR).…”

Micellar Curcumin: Pharmacokinetics and Effects on Inflammation Markers and PCSK‐9 Concentrations in Healthy Subjects in a Double‐Blind, Randomized, Active‐Controlled, Crossover Trial

“…The washout period was deemed sufficient based on the following assumptions: i) a terminal elimination half-life of micellar curcumin of 4-6 h from earlier studies was estimated, [38,39] ii) the study hypothesized that like other NF𝜅B inhibitors, any anti-inflammatory effects of curcumin were concentration-dependent, and iii) the study previously showed that PCSK9 was quickly regulated, and concentrations could adapt within a few hours to clinical conditions. [66,67] On the morning of the first study day, participants arrived at the Department of Clinical Pharmacology following an overnight fast. After baseline blood sampling, participants received a single dose of 35 mg curcumin (in the form of capsules containing either 43 mg of micellar curcuminoids or native curcuminoids).…”

“…The washout period was deemed sufficient based on the following assumptions: i) a terminal elimination half‐life of micellar curcumin of 4–6 h from earlier studies was estimated, [ 38 , 39 ] ii) the study hypothesized that like other NFκB inhibitors, any anti‐inflammatory effects of curcumin were concentration‐dependent, and iii) the study previously showed that PCSK9 was quickly regulated, and concentrations could adapt within a few hours to clinical conditions. [ 66 , 67 ]…”