Physicians' Academy for Cardiovascular Education

Pro-inflammatory activation of monocytes by elevated Lp(a) is reversible by potent Lp(a)-lowering

Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a)

Literature - Stiekema LCA, Prange KHM, Hoogeveen RM et al., - Eur Heart J. 2020 doi: 10.1093/eurheartj/ehaa171.

Introduction and methods

An independent and causal relationship between elevated lipoprotein(a) [Lp(a)] levels (>50 mg/dL or ~125 nmol/L) and CVD risk has been suggested by epidemiological and Mendelian randomization studies [1,2]. Healthy individuals with elevated Lp(a) have an activated innate immune system. This is characterized by pro-inflammatory circulating monocytes and coincides with increased white blood cell influx in the arterial wall and increase in arterial wall inflammation [3]. However, mechanistic understanding of monocyte activation in individuals with elevated Lp(a) is missing, as well as whether the inflammatory state can be reversed.

This study assessed the gene expression profile of circulating monocytes in four study groups: healthy subjects with normal Lp(a) (median Lp(a) 7 mg/dL [18 nmol/L], n=13), healthy subjects with elevated Lp(a) (matched for age, sex and BMI, median Lp(a) 87 mg [218 nmol/L], n=12) and CVD patients with elevated Lp(a) from two separate clinical intervention trials: The AKCEA-APO(a)-LRx-trial (n=14) and the ANITSCHKOW study (n=18) [4,5]. In addition, monocyte gene expression and function was assessed before and after treatment with either potent Lp(a) lowering (antisense[AKCEA-APO(a)-LRx]) in the AKCEA-APO(a)-LRx trial or moderate Lp(a) lowering (PCSK9ab [evolocumab, 420 mg once every 4 weeks]) in the ANITSCHKOW trial to evaluate the reversibility of an Lp(a) effect on monocyte activation.

Blood sampling was performed at baseline and after 26 weeks of treatment with AKCEA-APO(a)-LRx or 16 weeks of PCSK9ab treatment. Median Lp(a) at baseline was 82 mg/dL (250 nmol/L) in the AKCEA-APO(a)-LRx-trial. The pooled mean absolute reduction in Lp(a) was 51 (53) mg/dL [128 (132) nmol/L], compared to baseline. The achieved pooled mean percent reduction after a treatment period of 26 weeks was 47(18)%. In ANITSCHKOW study, the median Lp(a) at baseline was 102 mg/dL (255 nmol/L). The mean absolute reduction in Lp(a) was 19 (20) mg/dL [48 (49) nmol/L], compared to baseline. The mean percent reduction was 16 (19)% after 16 weeks of treatment.

Main results


The data from this study imply that elevated Lp(a) contributes to a pro-inflammatory gene expression in both healthy subjects and CVD patients. They also support the hypothesis that pro-inflammatory activation is reversible only by large absolute reductions in Lp(a).


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Find this article online at Eur Heart J.

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