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

Lotte C A Stiekema; Koen H M Prange; Renate M Hoogeveen; Simone L Verweij; Jeffrey Kroon; Johan G Schnitzler; Kim E Dzobo; Arjen J Cupido; Sotirios Tsimikas; Erik S G Stroes; Menno P J de Winther; Mahnoush Bahjat

doi:10.1093/eurheartj/ehaa171

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.

Authors

Affiliations

¹ Department of Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
² Department of Medical Biochemistry, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
³ Ionis Pharmaceuticals, 2855 Gazelle Ct, Carlsbad, CA 92008, USA.
⁴ Sulpizio Cardiovascular Center, Vascular Medicine Program, University of California San Diego, 9434 Medical Center Dr, La Jolla, CA 92037, USA.
⁵ Institute for Cardiovascular Prevention, IPEK, LMU, Pettenkoferstrasse 9, Munich 80336, Germany.

Abstract

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

Substances

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

Associated data

ClinicalTrials.gov/NCT03070782
ClinicalTrials.gov/NCT02729025