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

Eur Heart J. 2020 Jun 21;41(24):2262-2271. doi: 10.1093/eurheartj/ehaa171.


Aims: Elevated lipoprotein(a) [Lp(a)] is strongly associated with an increased cardiovascular disease (CVD) risk. We previously reported that pro-inflammatory activation of circulating monocytes is a potential mechanism by which Lp(a) mediates CVD. Since potent Lp(a)-lowering therapies are emerging, it is of interest whether patients with elevated Lp(a) experience beneficial anti-inflammatory effects following large reductions in Lp(a).

Methods and results: Using transcriptome analysis, we show that circulating monocytes of healthy individuals with elevated Lp(a), as well as CVD patients with increased Lp(a) levels, both have a pro-inflammatory gene expression profile. The effect of Lp(a)-lowering on gene expression and function of monocytes was addressed in two local sub-studies, including 14 CVD patients with elevated Lp(a) who received apolipoprotein(a) [apo(a)] antisense (AKCEA-APO(a)-LRx) (NCT03070782), as well as 18 patients with elevated Lp(a) who received proprotein convertase subtilisin/kexin type 9 antibody (PCSK9ab) treatment (NCT02729025). AKCEA-APO(a)-LRx lowered Lp(a) by 47% and reduced the pro-inflammatory gene expression in monocytes of CVD patients with elevated Lp(a), which coincided with a functional reduction in transendothelial migration capacity of monocytes ex vivo (-17%, P < 0.001). In contrast, PCSK9ab treatment lowered Lp(a) by 16% and did not alter transcriptome nor functional properties of monocytes, despite an additional reduction of 65% in low-density lipoprotein cholesterol (LDL-C).

Conclusion: Potent Lp(a)-lowering following AKCEA-APO(a)-LRx, but not modest Lp(a)-lowering combined with LDL-C reduction following PCSK9ab treatment, reduced the pro-inflammatory state of circulating monocytes in patients with elevated Lp(a). These ex vivo data support a beneficial effect of large Lp(a) reductions in patients with elevated Lp(a).

Keywords: Apo(a)-antisense; Inflammation; Lipoprotein(a); Monocytes; PCSK9ab; Transcriptomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoprotein(a) / genetics
  • Humans
  • Lipoprotein(a)*
  • Monocytes*
  • Oligonucleotides
  • Proprotein Convertase 9 / genetics


  • AKCEA-APO(a)-LRx
  • Lipoprotein(a)
  • Oligonucleotides
  • Apoprotein(a)
  • Proprotein Convertase 9

Associated data

  • ClinicalTrials.gov/NCT03070782
  • ClinicalTrials.gov/NCT02729025