It is well-established that lipoprotein(a) (Lp[a]) is a genetically determined causal risk factor for a range of cardiovascular diseases. Large prospective population-based observational studies along with genetic studies have demonstrated the causal association of high Lp(a) levels with increased risk for coronary artery disease and acute coronary events, ischemic stroke, peripheral arterial disease, calcific aortic valve disease, and abdominal aortic aneurysms (Figure 1).[1–4] Lipoprotein(a) is an apolipoprotein-B (apoB) containing lipoprotein that is similar in size and structure to low-density lipoprotein (LDL) particles. However, the defining feature of Lp(a) is that the apoB100 is covalently bound to an apolipoprotein(a) (apo[a]) "tail." The LPA gene encodes for the apo(a) protein and variation at the LPA locus is the strongest (although not the only) genetic determinant of circulating Lp(a) levels. The mechanism underlying the propensity of Lp(a) to initiate or promote the progression of cardiovascular diseases remains poorly understood.
Figure 1.
Lp(a), OxPLs, and Cardiovascular Disease
Lp(a) is the preferred lipoprotein carrier of OxPLs, which have been implicated in mediating several different cardiovascular diseases. apo(a) = apolipoprotein(a); apoB = apolipoprotein B; CAD = coronary artery disease; Lp(a) = lipoprotein(a); MI = myocardial infarction; OxPL = oxidized phospholipid.
One possible culprit is that Lp(a) is the preferred lipoprotein carrier of oxidized phospholipids (OxPLs) (Figure 1). OxPLs are generated when phospholipid molecules containing polyunsaturated fatty acids undergo oxidation, often at sites of tissue oxidative stress, for example, atherosclerotic lesions. OxPLs promote a proinflammatory cascade, including endothelial dysfunction and lipid deposition[5] as well as osteogenic differentiation, which, for example, may be an important component in development of calcific aortic valve disease.[6] The remarkable affinity of OxPLs for Lp(a) has been clearly demonstrated, and under steady state >85% of plasma OxPLs are found in association with Lp(a).[7] In the post percutaneous coronary intervention setting, there are rapid and substantial increases of both Lp(a) and OxPLs by an average of 64% and 36%, respectively.[8] In the immediate time point after the intervention, only ~50% of the OxPLs are localized to Lp(a), with the remaining on the other apoB-containing lipoproteins, however, by 6 hours post percutaneous coronary intervention and consistently thereafter, almost all OxPLs are localized to Lp(a), suggesting transfer of OxPLs from LDL and other apoB-containing lipoproteins to Lp(a).[8]
In this issue of the Journal of the American College of Cardiology, Gilliland et al[9] extend our understanding of the relationship of plasma Lp(a) and OxPLs to prospective acute coronary events, clearly showing that both are strongly associated with incident major adverse cardiovascular event (MACE) outcomes. They used a convenience sample from the CASABLANCA (Catheter Sampled Blood Archive in Cardiovascular Diseases) cohort of 1,098 participants undergoing coronary angiography (93% were White, 71% were male, and 51% had coronary artery disease at baseline). Using preprocedural arterial blood samples, they measured isoform-independent Lp(a), OxPL-apoB, and OxPL-apo(a) levels using robust validated assays. Although the OxPL-apoB measurement detects all OxPLs bound to all apoB-containing lipoproteins, the OxPL-apo(a) assay detects only the OxPLs bound to apo(a). All 3 measures were strongly intercorrelated and all 3 were associated cross-sectionally with angiographic multivessel coronary artery disease. Most importantly, during a median follow-up of 4.2 years, all 3 were strongly associated with incident MACE outcomes. These findings are consistent with prior work asserting the association of Lp(a) with risk for atherosclerotic disease and cardiovascular events,[3] and it expands on prior evidence[10] by demonstrating the association of OxPLs with these outcomes in a statin-treated population with relatively low LDL-cholesterol levels (baseline median: 83.4 mg/dL).
Levels of OxPL-apoB and OxPL-apo(a) both highly correlate with Lp(a) levels, which was confirmed in the present work by Gilliland et al.[9] Prior studies have shown the association of OxPL-apoB with risk for cardiovascular disease, however, in most studies, the association was not independent from Lp(a) levels.[11,12] In the present work, when the authors adjusted for the OxPLs, the association of Lp(a) with MACE outcomes was substantially attenuated, suggesting the importance of OxPL itself to cardiovascular disease. However, the association of OxPLs with the outcomes was not further adjusted for Lp(a) levels, leaving the question of whether OxPLs are independent and causal predictors of risk. Is the risk of OxPLs due in some way to their specific association with Lp(a)? Or, do OxPLs alone contribute directly to the overall cardiovascular pathogenicity attributed to Lp(a)?
It is estimated that >90% of Lp(a) levels are determined by genetic variations at the LPA gene locus,[3] but genome-wide association studies for Lp(a) have identified other loci (eg, APOH, a phospholipid binding protein) that contribute to the genetic variation in plasma Lp(a) levels.[13] The genetic variants associated with Lp(a) levels have been extraordinarily useful instruments for Mendelian randomization leading to the conclusion that Lp(a) is causal for cardiovascular diseases.[3,14] Genetic data for OxPL could be useful in helping to assess the causal role of OxPL for cardiovascular disease; however, a genome-wide association study for OxPL has never been reported. The variant rs10455872 at the LPA gene locus has been shown to be strongly associated with both Lp(a) levels and OxPL levels, as well as with risk for cardiovascular disease,[15,16] but these data are far from compelling with regard to evidence for a direct causal role of OxPLs.
Therapies in development to lower Lp(a) have been shown to reduce OxPL levels. Pelacarsen is an antisense oligonucleotide targeting Lp(a) that is now in phase 3 clinical trials. In the phase 2 study, at a dose of 20 mg per week, equivalent to the dose being tested in the phase 3 trial, pelacarsen at 6 months resulted in a mean 88% reduction in OxPL-apoB and 70% reduction in OxPL-apo(a).[17] Olpasiran, a small interfering RNA that disrupts translation of the apo(a) protein, and thus Lp(a) production, showed >95% placebo-adjusted mean percent reductions in Lp(a) in its phase 1 trial.[18] Data on reductions in OxPL have not yet been published but would be expected to be significant given the magnitude of Lp(a) lowering.
Could targeting OxPLs directly be an approach to reducing cardiovascular diseases associated with Lp(a) independent of Lp(a)-lowering? Notably, there are preclinical data suggesting that neutralizing OxPL activity leads to inhibition or even regression of atherosclerosis. E06 is a murine immunodominant immunoglobulin M antibody isolated from apoE knockout mice that binds to OxPL. Expression of an E06 fragment in transgenic Ldlr−/- mice fed a 1% high-cholesterol diet led to significant reductions in atherosclerotic lesions in the aorta and of aortic valve calcification.[19] Neutralization of OxPLs by E06 has also been shown to reduce myocardial infarct size in Ldlr−/- mice.[20] It is interesting to note that the pneumococcal vaccine generates similar anti-OxPL antibodies and reduces atherosclerosis in mice;[21] it also induces anti-OxPL antibodies in humans,[22] raising the interesting hypothesis that it could have a protective effect in cardiovascular disease.[23]
Lp(a) has emerged as a common, inherited, and potentially modifiable causal contributor to a range of important cardiovascular diseases and conditions. OxPLs are a potential mechanistic contributor to the cardiovascular pathogenicity of Lp(a). As novel Lp(a)-lowering therapies advance in clinical development, it will be interesting to note whether they reduce cardiovascular outcomes in part through lowering OxPL levels. Approaches to neutralizing OxPLs, such as through induction of anti-OxPL antibodies, suggest another avenue for clinical translation to reduce the potency of Lp(a) and OxPLs in causing cardiovascular disease.
J Am Coll Cardiol. 2023;81(18):1793-1796. © 2023 American College of Cardiology Foundation
