C-reactive Protein in People With High Lipoprotein A

A Partner in Crime or an Innocent Bystander?

Carl E. Orringer


Eur Heart J. 2023;44(16):1461-1463. 

Graphical Abstract

Results of studies examining C-reactive protein-associated cardiovascular risk in individuals with elevated lipoprotein a levels. Abbreviations: CGPS, Copenhagen General Population Study; MESA, Multi-ethnic Study of Atherosclerosis; ACCELERATE, Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at High Risk of Vascular Outcomes; CHD, coronary heart disease; PCI, percutaneous intervention; MI, myocardial infarction; AVS, aortic valve stenosis; CV, cardiovascular; CRP, C-reactive protein; Lp(a), lipoprotein a.

Lipoprotein(a) [Lp(a)] is an established risk marker for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis (AVS).[1] It is an apolipoprotein B-containing lipoprotein that carries a covalently attached apolipoprotein(a) moiety that interferes with its interaction with the LDL receptor and impairs plasminogen activation. Its role in promoting ASCVD is supported by epidemiological studies, meta-analyses, Mendelian randomization studies, and genome-wide association studies.[2,3] In addition to its proatherosclerotic and prothrombotic properties, its accompanying oxidized phospholipid cargo induces a multifaceted proinflammatory response that promotes plaque progression.[4] In a study of adults with advanced stable coronary artery disease, those with higher levels of Lp(a) of 100 mg/dL (range 82–115) as compared with those with levels of 10 mg/dL (range 5–24) showed accelerated progression of low attenuation plaque, a marker of the presence of a necrotic core that predicts future myocardial infarction risk.[5]

A genome-wide association study and several cohort studies validated the association of a single nucleotide polymorphism, LPA rs10455872, with aortic valve calcification and stenosis,[6–9] and the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial showed that high levels of Lp(a) and oxidized phospholipids in individuals with mild to moderate AVS are associated with both aortic stenosis progression and the need for aortic valve replacement.[10] The pathophysiological link between Lp(a) and AVS is based on the hypothesis that Lp(a) delivers oxidized phospholipids to the valve leaflets and, catalysed by the enzyme autotaxin, produces lysophosphatidic acid, which promotes calcification.[11]

An elevated circulating level of C-reactive protein (CRP) is a marker of vascular inflammation and is recognized by the 2019 ESC/EAS Dyslipidaemia Guidelines as a factor that may improve risk classification. Two studies have attempted to determine the extent to which Lp(a)-related risk is affected by levels of CRP. One was a post-hoc pre-specified subgroup analysis of a placebo-controlled randomized trial [Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE)] examining the effect of therapy with an investigational cholesteryl ester transfer protein inhibitor, evacetrapib, on ASCVD risk in 10 503 high-risk subjects followed for 30 months, from the initiation of treatment until the termination of the trial due to futility. The ASCVD endpoints of that trial were cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. The other was an epidemiological study examining a broad range of ASCVD outcomes including myocardial infarction, fatal and non-fatal coronary heart disease, definite angina, and probable angina if followed by revascularization, resuscitated cardiac arrest, fatal and non-fatal stroke, and other atherosclerotic or cardiovascular disease deaths in 4679 subjects from the Multi-Ethnic Study of Atherosclerosis over a mean follow-up of 13.6 years. Both studies concluded that Lp(a)-associated risk was increased only in those with concomitant elevation of CRP of ≥ 2 mg/L.[12,13]

In this issue of the European Heart Journal, Thomas et al. used data from 68 090 subjects enrolled in the prospective Copenhagen General Population Study (CGPS) with information on both plasma Lp(a) and CRP to examine the relationship between high Lp(a) and CRP and risk for myocardial infarction, ASCVD (including myocardial infarction, coronary heart disease death, ischaemic stroke, and percutaneous intervention), and AVS.[14] Participants were 20–100 years of age and, for this analysis, had a median follow-up of 8.1 years, during which 5104 developed ASCVD, 2432 myocardial infarction, and 1220 AVS. Lp(a) was measured using methodology that was largely independent of apolipoprotein(a) isoform size, and CRP was measured using standardized assays. These data were linked with outcomes derived from the Danish Civil Registration System, which enabled complete follow-up of all subjects.

The authors reported that the multivariable adjusted risk of ASCVD, myocardial infarction, and AVS increased with higher levels of both Lp(a) and CRP. However, when comparing risk of these outcomes in the group with Lp(a) values in the highest decile of Lp(a) (≥69 mg/dL or ≥147 nmol/L) with the group whose Lp(a) values were in the first to 33rd percentile, there was no significant difference in the adjusted risk, regardless of whether CRP was ≥2 mg/L or <2 mg/L. The highest risk group was men 70–79 years of age with Lp(a) in the highest decile and CRP ≥2 mg/L in whom the 10-year absolute risk of ASCVD, myocardial infarction, and AVS was 34, 19, and 10%, respectively, vs. a corresponding risk in women of the same age of 20, 10, and 8%. Multiple sensitivity analyses were performed, with all results being similar to their reported findings. In addition, there was no evidence of significant interaction between Lp(a) and CRP levels on the reported risk of ASCVD, myocardial infarction, or AVS. Based on the above data, the authors concluded that a high level of Lp(a) was the main driver for risk of these outcomes, independent of CRP.[14]

What factors might explain the divergent reported findings on the impact of CRP on Lp(a)-related ASCVD risk in the CGPS vs. the other two studies described above? These differences may be due to differences in the populations studied. The ACCELERATE trial subjects had established ASCVD (acute coronary syndrome within the previous 30–365 days, cerebrovascular atherosclerotic disease, peripheral arterial disease, or type 2 diabetes with coronary artery disease), carried a high baseline ASCVD risk, and were well treated [mean LDL-cholesterol 71.4 mg/dL (1.84 mmol/L)] as compared with the community-dwelling populations whose outcomes were investigated in GGPS and MESA. The number of subjects studied was far greater and the number of ASCVD endpoints achieved in the CGPS was considerably larger than in the other two studies. There were also differences in the racial/ethnic characteristics of the subjects in the three studies. The CGPS enrolled a relatively homogeneous, exclusively Danish cohort; the ACCELERATE trial subjects were 79.2% White, 1.8% Black, 14.5% Asian, and 4.5% 'Other'; and the MESA population was comprised of subjects identified as Caucasian (36.6%), Chinese American (12%), African American (28.7%), and Hispanic (22.7%). Racial/ethnic differences in Lp(a) concentrations and high-sensitivity CRP levels probably account for the higher baseline Lp(a) and CRP levels noted in MESA, a study with higher African American representation. Furthermore, ASCVD endpoints were considerably broader in the MESA study as compared with the CGPS. Thus, in the absence of additional data, the findings reported in each of the three studies should be considered to apply to individuals with baseline characteristics and cardiovascular disease outcomes most consistent with those of each of the studies.

While the independent relationships between Lp(a) and ASCVD and between Lp(a) and AVS are well established, that between CRP and AVS is unclear. The current study is the first to demonstrate epidemiologically that an elevated level of CRP increases that risk in those in the highest decile of Lp(a), but that high Lp(a) increases the risk of ASCVD, myocardial infarction, and AVS regardless of whether CRP is elevated to ≥ 2 mg/dL.[14] While this study identifies an association between these biomarkers and cardiovascular outcomes, it does not, based upon its observational study design, permit conclusions on causation. One cannot determine whether the results would have been different had they included data on these variables in the remaining 40 191 individuals from the CGPS who did not have complete information on Lp(a) and CRP. In addition, the results regarding AVS cannot be generalized to ethnically diverse populations such as those reported in the MESA or the ACCELERATE trial.

The results of this study reinforce the potential value of current investigational Lp(a)-lowering therapies as potential therapeutic agents for both ASCVD and AVS. It has been suggested that the reduction in ASCVD risk from Lp(a)-lowering therapy is more likely to be related to the absolute reduction in Lp(a) concentrations rather than the percentage reduction and that large reductions may be required for meaningful risk reduction.[15] Thus, agents that are associated with very large reductions in Lp(a) will probably be required to demonstrate cardiovascular benefit. Lp(a) HORIZON is a multinational randomized placebo-controlled trial to evaluate the safety and efficacy of subcutaneously administered pelacarsen, an hepatocyte-directed antisense oligonucleotide given once a month in a dose of 80 mg, to reduce cardiovascular events in patients with established cardiovascular disease and a baseline Lp(a) ≥ 70 mg/dL. While this trial does not address the effect of this drug on the incidence or progression of AVS, an additional potential benefit of this drug in patients with AVS relates to its property to reduce oxidized phospholipids on apolipoprotein(a) and apolipoprotein B-100 by 70–88%. The results are anticipated in 2025. Two RNA silencing drugs, olpasiran and SLN360, have been shown to produce a >95% reduction in circulating Lp(a) concentration and, after initial injections at baseline and 3 months, result in persistent Lp(a) lowering when administered every 6 months. While the current approach to patients with elevated Lp(a) levels rests on evidence-based modification of conventional risk factors, the results of outcomes trials for these Lp(a) therapeutics will determine if pharmacological intensive Lp(a) reduction can be safely accomplished and favourably affect cardiovascular outcomes.