Introduction
Based on good quality epidemiological evidence, it is well established that lipoprotein(a) (Lp[a]) is an independent cardiovascular risk factor and predictor of major adverse cardiovascular events.1 Although research evaluating the pathophysiological mechanisms of Lp(a) is still in its early phases, recent studies have helped to shed light on the mechanistic role of Lp(a) in cardiovascular disease. Lipoprotein apheresis (LA) is currently the most effective approved treatment available for raised Lp(a), with minimal effect conferred by conventional lipid-lowering agents. A growing body of evidence suggests that aggressively lowering raised Lp(a) may improve cardiovascular and clinical outcomes, although more prospective randomised-controlled research is required to objectively assess this and understand the mechanisms of benefit.1
Mechanisms of pathogenicity
Lp(a) promotes the progression of cardiovascular disease through numerous pleiotropic effects that extend beyond its direct atherogenic effect, including its pro-inflammatory impact, as well as its antifibrinolytic and prothrombotic properties.
Role of Lp(a) in promoting atherogenicity
After Lp(a) is transferred from plasma into the arterial intima, it may be more avidly retained than low-density lipoprotein (LDL), as it binds to the extracellular matrix via apolipoprotein(a) (Apo[a]) as well as its apolipoprotein B (ApoB) component,2 thereby directly promoting atherosclerosis by contributing cholesterol to the expanding atherosclerotic plaque.
A recent cross-sectional cohort study in patients with acute coronary syndromes (ACS), demonstrated that raised Lp(a) levels are associated with an increased atherosclerotic burden and predispose patients to features of high-risk coronary atherosclerosis.3 Specifically, upon optical coherence tomography (OCT), patients with higher Lp(a) levels (>300 mg/L), compared with patients with lower Lp(a) levels (<300 mg/L), exhibited a higher prevalence of lipidic plaque at the site of the culprit stenosis (67% vs. 27%; p=0.02), a wider lipid arc (135 ± 114 vs. 59 ± 111; p=0.03) and a higher prevalence of thin cap fibroatheroma (TCFA) (38% vs. 10%; p=0.04).3
The pro-inflammatory role of Lp(a)
In vitro, Lp(a) binds to several extracellular matrix proteins including fibrin4 and defensins, a family of amino acid peptides that are released by neutrophils during inflammation and severe infection.5 It is likely that defensins, like lipoprotein lipase, provide a bridge between Lp(a) and the extracellular matrix.5 Lp(a) seems to be retained at sites of mechanical injury;4 and fibrin deposition appears to occur preferentially at such sites.
Lp(a) has also been shown to bind pro-inflammatory oxidised phospholipids and is a preferential carrier of oxidised phospholipids in human plasma,6 which may represent one of the mechanisms by which raised Lp(a) may lead to cardiovascular risk. Furthermore, numerous previous studies measuring circulating oxidised LDL (OxLDL), have demonstrated its association with atherosclerotic disease. Matsuo et al. found MDA-LDL levels (which is a measurement of OxLDL) might be associated with the presence of TCFAs, as detected by OCT.7 This suggests that circulating MDA-LDL holds promise as a biomarker of plaque vulnerability.7 A prospective study reported that circulating MDA-LDL was significantly related to risk of coronary artery disease (CAD) in multi-variate analysis prior to adjustment for other lipid markers. However, this relationship was lost after adjustment for lipid markers such as high-density lipoprotein (HDL), LDL or triglycerides (TGs).8 Oxidative modification of LDL renders it immunogenic, and auto-antibodies to OxLDL are found in serum and recognise material in atheromatous tissue.9 An observational case–control cohort study showed that the titre of auto-antibodies to MDA-LDL was an independent predictor of the progression of carotid atherosclerosis.9 In addition, in an observational case–control cohort substudy performed in patients participating in the Helsinki Heart Study, elevated levels of antibodies against OxLDL were predictive of myocardial infarction, and the effect was independent of LDL-cholesterol levels.10 Lp(a) also contains lipoprotein-associated phospholipase A2, which may cleave oxidised fatty acids at the sn-2 position in oxidised phospholipids to yield short chain fatty acids and lysolecithin.11
The antifibrinolytic and prothrombotic role of Lp(a)
The Apo(a) component of Lp(a) has close structural similarity with plasminogen, which endows Lp(a) with antifibrinolytic properties via its competitive inhibition of tissue-type plasminogen activator-mediated activation of plasminogen.1 Lp(a) may also enhance coagulation by inhibiting the function of tissue factor pathway inhibitor.12 Lp(a) also promotes the secretion of plasminogen activator inhibitor-1 (PAI-1),13 which may represent another potential mechanism by which Lp(a) promotes thrombosis.
Finally, small isoforms of Apo(a) have been observed to possess elevated potency in inhibiting fibrinolysis and, thereby, promoting thrombosis. Indeed, a recent meta-analysis demonstrated a two-fold increase in the risk of coronary heart disease (CHD) and ischaemic stroke in subjects with small Apo(a) phenotypes.14 Furthermore, prospective findings in the Bruneck study have revealed a significant association specifically between small Apo(a) phenotypes and advanced atherosclerotic disease involving a component of plaque thrombosis.15 These data suggest that the determination of Apo(a) phenotype/genotype may provide clinicians with additional information by which to evaluate Lp(a)/Apo(a)-associated atherothrombotic risk.
The role of genetics in determining the pathogenicity of Lp(a)
The genetic profile of Lp(a) production also plays an important role in the phenotypic characteristics of individuals with raised Lp(a).
Lp(a) levels are co-dominantly inherited, and the LPA gene is located on chromosome 6 (6q26–27).16 The key LPA gene sequence that influences Lp(a) levels and atherogenicity is the number of kringle IV type 2 (KIV-2) repeats.16 This number largely determines the size of Apo(a) and levels of Lp(a). Smaller numbers of KIV-2 repeats (i.e. <22) are associated with higher levels of Lp(a) and potentially more atherogenic Apo(a).16 It has been postulated that small Apo(a) Lp(a) may be associated with higher Lp(a) levels because the smaller molecules are more readily synthesised in the liver and less readily degraded by cellular organelles.16
Clarke et al. used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2,100 candidate genes to test for associations in 3,145 case subjects with coronary disease and 3,352 control subjects.17 Three chromosomal regions (6q26–27, 9p21 and 1p13) were strongly associated with the risk of coronary disease. The LPA gene locus on 6q26–27 encoding Lp(a) lipoprotein had the strongest association.17 They identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI] 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95%CI 1.48 to 2.49).17 Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of KIV-2 repeats), and a small Lp(a) lipoprotein size. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95%CI 1.38 to 1.66) for one variant and 2.57 (95%CI 1.80 to 3.67) for two or more variants.17 These SNPs account for 36% of the variation in the Lp(a) lipoprotein level. One in six people carry a variant LPA allele and, thus, have a risk of coronary disease that is increased by a factor of 1.5.17
Lp(a) as a therapeutic target: understanding the mechanisms of benefit
Although we are gaining more insight into the multi-faceted pathophysiology of Lp(a), less is understood about the mechanistic benefit of reducing raised Lp(a). Currently, lipoprotein apheresis (LA) is the most effective available treatment for elevated Lp(a), with minimal effect conferred by conventional lipid-lowering agents. Longitudinal observational cohort studies have demonstrated patients who commenced LA because of elevated Lp(a) and progressive cardiovascular disease showed a reduction in major adverse coronary events.18 An interesting and clinically relevant question that remains unanswered with limited scientific data, is whether the multi-factorial pathogenic effects of Lp(a) can be reversed by lowering raised Lp(a)?
A quantitative angiographic study demonstrated some coronary atherosclerosis regression in patients with CAD with raised Lp(a), after 18 months of weekly Lp(a)-specific apheresis, compared with statin therapy alone;19 suggesting that apheresis can slow down or potentially reverse the atherogenic effect of raised Lp(a).
A prospective, single-blind, sham-controlled crossover trial was completed in 20 patients with refractory angina and elevated Lp(a) ≥50 mg/dL, randomised to three months of weekly LA or sham procedures followed by crossover.20 This demonstrated that LA resulted in significant improvements in quantitative myocardial perfusion (figure 1),20 carotid atheroma burden, exercise capacity, quality of life and symptoms including angina, with no significant change observed in the sham-treatment arm.20 This study indicates that LA improves microvascular function and, thereby, myocardial perfusion, which in turn leads to improvement in symptoms, quality of life and exercise capacity. As part of the same study, the effect of LA on markers of thrombosis and fibrinolysis were assessed to examine whether apheresis could help reverse the prothrombotic properties of raised Lp(a).21 Apheresis prolonged occlusion time, as assessed by the Global Thrombosis Test, reflecting reduced platelet reactivity and reduced lysis time, reflecting enhanced fibrinolysis, without corresponding changes with sham.21 Apheresis, but not sham, reduced von Willebrand factor as well as fibrinogen.21 As a further substudy of this trial, it was also demonstrated that LA significantly lowers levels of OxLDL and anti-OxLDL antibodies, representing potentially important mechanisms by which LA yields symptomatic and prognostic benefits in this patient cohort.22
Discussion
To summarise, elevated Lp(a) is believed to promote atherosclerosis via Lp(a)-derived cholesterol entrapment in the intima, inflammatory cell recruitment and/or via the binding of pro-inflammatory-oxidised phospholipids, such as OxLDL. In addition, elevated Lp(a) is felt to be prothrombotic via the inhibition of fibrinolysis with enhancement of clot stabilisation, as well as via enhanced coagulation via the inhibition of tissue factor pathway inhibitor.1 The cardiovascular manifestations associated with raised Lp(a), which is co-dominantly inherited, are also mediated by its genotypic profile; with a lower number of KIV-2 repeats correlating with higher and potentially more atherogenic Lp(a) and the rs10455872 and rs3798220 variants conferring higher cardiovascular risk. This suggests that, in future, genetic profiling of patients with raised Lp(a) may help in terms of cardiovascular risk stratification, although further prospective evidence is required to support this theory.
A large gap in the current evidence base is whether the multi-factorial pathogenic effects of Lp(a) can be reversed by lowering raised Lp(a). So far, only a handful of small studies have attempted to address this question, with very few being randomised, limiting the generalisability of the results. Furthermore, mechanistic studies to date have mainly been limited to studies assessing the impact of LA, which casts some doubt on the specific role that Lp(a) lowering plays in the treatment effect. LA removes ApoB-containing lipoproteins from whole blood, which lowers Lp(a), but also lowers LDL. While the treatment efficacy of apheresis remains clear, it leaves open to interpretation whether the effect is mediated by Lp(a) reduction, LDL reduction, or both. An additional limitation is that apheresis removes numerous factors from blood other than lipoproteins, including fibrinogen, coagulation factors, thrombogenic factors, complement factors, inflammatory factors and adhesion molecules,23 which may mediate reduced coagulation and improvements in endothelial function or atherogenesis. Further large-scale, prospective, randomised-controlled trials to address this issue ideally need to utilise Lp(a)-specific therapy to establish the role that lowering Lp(a) plays in reducing cardiovascular disease, and shed light on the mechanisms of benefit, by assessing whether the multi-factorial pathogenic effects of Lp(a) can be reversed with therapy.
Key messages
- Lipoprotein(a) (Lp[a]) promotes the progression of cardiovascular disease through numerous pleiotropic effects that extend beyond its direct atherogenic effect, including its pro-inflammatory impact, as well as its antifibrinolytic and prothrombotic properties
- The cardiovascular manifestations of raised Lp(a) are mediated by its genotypic profile; suggesting that, in future, genetic profiling of patients with raised Lp(a) may help in terms of cardiovascular risk stratification
- In future, randomised-controlled trials are needed, ideally utilising Lp(a)-specific therapy, to establish the role that lowering Lp(a) plays in reducing cardiovascular disease and shed mechanistic light on whether the multi-factorial pathogenic effects of Lp(a) can be reversed with therapy
Conflicts of interest
None declared.
Funding
None.
Tina Z Khan
Consultant Cardiologist
Department of Cardiology, Harefield Hospital, Royal Brompton & Harefield NHS Foundation Trust Hospital, Part of Guy’s and St Thomas’, Hill End Road, Harefield, UB9 6JH
Articles in this supplement
Lipoprotein(a): a historical perspective
Lipoprotein(a): marker and target in calcific aortic valve disease
How to measure lipoprotein(a) and in whom
Current management of the patient with high lipoprotein(a)
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