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Biomolecules 2022, 12, 26. https://doi.org/10.3390/biom12010026 www.mdpi.com/journal/biomolecules
Review
Lipoprotein(a)—The Crossroads of Atherosclerosis,
Atherothrombosis and Inflammation
Sabina Ugovšek 1 and Miran Šebeštjen 1,2,3,*
1 Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; ugovsek.sabina@gmail.com
2 Department of Cardiology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
3 Department of Vascular Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
* Correspondence: miran.sebestjen@guest.arnes.si
Abstract: Increased lipoprotein(a) (Lp(a)) levels are an independent predictor of coronary artery
disease (CAD), degenerative aortic stenosis (DAS), and heart failure independent of CAD and DAS.
Lp(a) levels are genetically determinated in an autosomal dominant mode, with great intra- and
inter-ethnic diversity. Most variations in Lp(a) levels arise from genetic variations of the gene that
encodes the apolipoprotein(a) component of Lp(a), the LPA gene. LPA is located on the long arm of
chromosome 6, within region 6q2.6–2.7. Lp(a) levels increase cardiovascular risk through several
unrelated mechanisms. Lp(a) quantitatively carries all of the atherogenic risk of low-density lipo-
protein cholesterol, although it is even more prone to oxidation and penetration through endothelia
to promote the production of foam cells. The thrombogenic properties of Lp(a) result from the ho-
mology between apolipoprotein(a) and plasminogen, which compete for the same binding sites on
endothelial cells to inhibit fibrinolysis and promote intravascular thrombosis. LPA has up to 70%
homology with the human plasminogen gene. Oxidized phospholipids promote differentiation of
pro-inflammatory macrophages that secrete pro-inflammatory cytokines (e. g., interleukin (IL)-1β,
IL-6, IL-8, tumor necrosis factor-α). The aim of this review is to define which of these mechanisms
of Lp(a) is predominant in different groups of patients.
Keywords: lipoprotein(a); atherothrombosis; inflammation; coagulation; fibrinolysis
1. Introduction
Lipoprotein(a) (Lp(a)) is a complex plasma protein that consist of low-density lipo-
protein (LDL) cholesterol and apolipoprotein B-100 (apoB) linked to the plasminogen-like
apolipoprotein(a) (apo(a)) via a disulfide bond. Lp(a) levels are genetically determined by
the LPA gene and they vary among individuals from ≤0.2 to ≥250 mg/dL, although within
a single individual, Lp(a) levels are stable throughout life [1,2]. The LPA gene is located
on chromosome 6q26–q27 and it encodes the highly glycosylated hydrophilic apo(a) [3,4].
Apo(a) shows high amino-acid sequence homology to serine protease plasminogen [3].
Apo(a) contains a protease-like domain and two tri-loop structures known as ‘kringles’
(KIV, KV) [1,3], and the KIV domain has 10 types [3]. The different numbers of KIV type
2 (KIV2) repeat in apo(a) results in Lp(a) isoform size heterogeneity, and more KIV2 re-
peats results in a larger apo(a) isoform. The larger apo(a) isoforms are less efficiently se-
creted from hepatocytes, and consequently there is an inverse correlation between the
apo(a) isoform size and the Lp(a) levels in plasma [1,5]. Patients with a smaller apo(a)
isoform size not only have higher Lp(a) levels, but also have significantly greater risk of
coronary artery disease (CAD) [6]. The number of KIV2 repeats accounts for 69% of the
variation in Lp(a) levels [7]. As well as the different number of KIV2 repeats, the Lp(a)
isoform size and levels are determined by more than 200 single nucleotide polymor-
phisms (SNPs) in the wider LPA region. Among these SNPs, rs10455872 and rs3798220
have the most influence on Lp(a) levels [4], as they explain 36% of the variation in Lp(a)
Citation:
Ugovšek, S.; Šebeštjen, M.
Lipoprotein(a)
—The Crossroads of
Atherosclerosis, Atherothrombosis
and Inflammation.
Biomolecules 2022,
12
, 26. https://doi.org/10.3390/
biom12010026
Academic Editor
s: Roberto Scicali,
Alessandro Mattina
,
Giuseppe Mandraffino
Received:
25 November 2021
Accepted:
23 December 2021
Published:
24 December 2021
Publisher’s Note:
MDPI stays neu-
tral with regard to jurisdictional
claims in published maps and institu-
tional affiliations.
C
opyright: © 2021 by the authors. Li-
censee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and con-
ditions of the Creative Commons At-
tribution (CC BY) license (http
s://cre-
ativecommons.org/licenses/by/4.0/).
Biomolecules 2022, 12, 26 2 of 14
levels [8]. LPA variants are carried by one in six people, who have a 1.5-fold greater risk
of coronary diseases [8]. rs10455872 and rs3798220 polymorphisms are also independent
predictors of cardiovascular events in patients with CAD [8].
Increased Lp(a) levels are also a risk factor for degenerative aortic valve stenosis [9], [10].
Both homozygote and heterozygote carriers of rs10455872 have increased risk of degenerative
aortic valve stenosis, although this risk is not seen for carriers of rs3798220. A trend towards
increased risk has been connected with lower numbers of KIV2 repeats [10].
Elevated levels of Lp(a) can occur in patients with otherwise normal lipid levels [4].
Dietary and environmental factors have minimal contributions to Lp(a) plasma levels [1].
A quarter of the general population has Lp(a) plasma levels >20 mg/dL, which have been
associated with a 2-fold increased risk of developing cardiovascular disease. Although
there is no conclusive evidence for specific Lp(a) cut-off points based on age, sex, and race,
the European guidelines consider those with ≥50 mg/dL Lp(a) to be at high risk [11]. Lp(a)
levels >180 mg/dL are correlated with risk of cardiovascular events similar to that of fa-
milial hypercholesterolemia [1].
According to genetic and epidemiological studies, Lp(a) is considered pro-athero-
sclerotic (Figure 1), pro-inflammatory (Figure 2), pro-thrombotic, and anti-fibrinolytic
(Figure 3) [12].
Figure 1. The role of lipoprotein(a) (Lp(a)) in plaque formation. Ox Lp(a), oxidized Lp(a).
Figure 2. The role of Lp(a) in inflammation. OxPLs, oxidized phospholipids; TNFα, tumor necrosis
factor-α; IL, interleukin; ICAM1, intercellular adhesion molecule-1; VCAM1, vascular cell adhesion
protein-1; NO, nitric oxide.
Biomolecules 2022, 12, 26 3 of 14
Figure 3. The role of Lp(a) in thrombus formation following plaque rupture. TF, tissue factor; TFPI,
tissue factor pathway inhibitor; PAI-1, plasminogen activator inhibitor-1; tPA, tissue plasminogen
activator.
2. Lipoprotein(a) and Atherosclerosis
Lipoprotein(a) can be internalized and accumulated in the intima of arteries and the
aortic valve leaflets. Lp(a) enters the intima at similar rates to LDL cholesterol, although
this does not occur via the lipoprotein receptor for LDL cholesterol, but is dependent on
Lp(a) plasma concentrations, Lp(a) particle size, blood pressure, and arterial wall perme-
ability [13,14]. Lp(a) accumulates all over the intima, whereas LDL cholesterol and other
apoB-containing lipoproteins remain mainly at atherosclerotic lesions. Compared to
LDLs, Lp(a) has a greater affinity for the vascular wall and for proteoglycans and fibron-
ectin on the endothelial cell surface [13]. Furthermore, Lp(a) is more atherogenic than LDL
cholesterol, because it consists of all of the atherogenic components of both LDL choles-
terol and apo(a) [4,15,16].
Various studies have indicated that Lp(a) is taken up by macrophages to produce
foam cells, and thus to promote the development of atherosclerotic lesions [13]. Athero-
sclerosis is an inflammatory disease of the arterial wall, whereby several events result in
the formation of a complex atherosclerotic plaque that is composed of a lipid-rich core
covered with a fibrous cap (Figure 1) [17]. Lp(a) promotes atherosclerotic plaque for-
mation through various mechanisms. Lp(a) induces expression of inflammatory cyto-
kines, including interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α, and increases
expression of adhesion molecules on the surface of the endothelial cells, including vascu-
lar cell adhesion protein-1, intercellular adhesion molecule-1, E-selectin, P-selectin, and
others [3,18,19]. Lp(a) promotes monocyte chemotaxis via stimulation of secretion of mon-
ocyte chemotactic protein and activation of nuclear factor κB [20]. Additionally, Lp(a)
binds and transports more than 70% of circulating oxidized phospholipids, which are in-
volved in plaque vulnerability and destabilization [21].
As indicated, atherosclerotic plaques in patients with elevated Lp(a) levels have a
complex morphology [17]. These plaques are prone to repeated ruptures and healing,
which can lead to severe and rapid progression of atherosclerosis. Coronary atherosclero-
sis in patients with high Lp(a) levels mostly manifests clinically as an acute myocardial
infarction, rather than stable angina [4]. Several large observational studies and meta-
analyses have also reported gradual increased risk of CAD and ischemic stroke with in-
creasing Lp(a) levels, without any threshold value defined [22–25]. This risk is higher in
younger populations than older populations [25]. Indeed, the addition of Lp(a) levels to
traditional risk score charts improve the accuracy of the prediction of susceptibility for
future cardiovascular events. This has been shown by several studies of primary and sec-
ondary prevention [26–28], except for primary prevention in women with low risk of car-
diovasculer events [29].
Biomolecules 2022, 12, 26 4 of 14
Statins are well known to reduce LDL cholesterol levels, but as seen in a meta-analy-
sis of 29,069 patients on statin therapy, they do not provide any significant changes in
Lp(a) levels [30]. Moreover, Lp(a) levels in patients treated with statins are more strongly
associated with cardiovascular disease risk than for those on a placebo. The main expla-
nation for this was that when LDL cholesterol levels are reduced, Lp(a)-attributable risk
becomes an even stronger predictor of residual risk [30]. This observation has been sup-
ported by two interventional studies: ‘Further Cardiovascular Outcomes Research with
PCSK9 Inhibition in Subjects with Elevated Risk’ (FOURIER) and ‘Evaluation of Cardio-
vascular Outcomes After an Acute Coronary Syndrome During Treatment with Aliro-
cumab’ (ODYSSEY Outcomes) [31,32]. Patients on LDL cholesterol-lowering therapies
and with high Lp(a) levels were associated with increased risk for cardiovascular disease
independent of LDL cholesterol levels. Evolocumab therapy in the first of these two trials,
and alirocumab therapy in the second, reduced Lp(a) levels and cardiovascular disease
risk independent of LDL cholesterol lowering [31,32].
Patients with elevated Lp(a) have significantly more recurrent acute myocardial in-
farctions. One of the reasons for this is that Lp(a) specifically accumulates at injured sites,
which results in restenosis after coronary artery revascularisation procedures [4]. A meta-
analysis of 1834 patients reported a positive correlation between high Lp(a) levels and in-
stent restenosis, especially in patients with drug-eluting stents [33]. Lowering Lp(a) levels
with lipoprotein apheresis reduces restenosis rates and helps to prevent recurrent coro-
nary syndromes [34,35].
As well as being a risk factor for coronary atherosclerosis, elevated Lp(a) levels define
the risk of ischemic stroke, peripheral arterial disease, and calcific aortic valve disease.
Calcific aortic valve disease is a multifactor condition and a dynamic process similar to
atherosclerosis. Endothelial cell dysfunction followed by subendothelial accumulation of
lipoproteins and chronic inflammation results in a condition that can vary from mild valve
thickening to severe calcification with stenotic occlusion [36]. Studies have shown that
Lp(a) levels ≥ 30 mg/dL represent a risk factor for calcific aortic valve disease. Lp(a) con-
tributes to this disease at different rates, which depend on ethnicity [9], with the highest
levels of Lp(a) in calcific aortic valve disease seen for Caucasians [9,37,38]. There is also
an association between Lp(a) gene polymorphisms and calcific aortic valve disease [36,38–
40]. Thanassoulis et al. and Ozkan et al. showed strong positive correlations for rs10455872
and rs3798220 polymorphisms with the progression of calcific aortic valve disease [36,40].
Patients with heterozygous familial hyperholesterolemia have significantly higher
Lp(a) levels and hazard ratio for acute myocardial infarction, compared to those without,
as was shown in the prospective population study, ‘Copenhagen General Population
Study,’ and in a cross-sectional analysis of ‘Spanish Familial Hypercholesterolemia Co-
hort Study’ (SAFEHEART) [41,42]. Furthermore, patients with Lp(a) levels ≥50 mg/dL and
LDL-receptor-negative mutations have a higher risk of cardiovascular disease, compared
to patients with less severe mutations [42].
3. Lipoprotein(a) and Inflammation
Inflammation has a vital role in the development and progression of atherosclerosis,
and thus it contributes to increased risk of cardiovascular events [43]. Inflammation pro-
motes endothelial cell activation, dysfunction and loss of endothelial integrity, failure of
endothelial repair, intima lipid deposition, and plaque formation and instability [44].
Despite the evidence that Lp(a) levels are genetically determined, several studies have
shown that chronic inflammation interferes with Lp(a) expression and increases Lp(a) plasma
levels [21]. On the other hand, as for other lipoproteins, Lp(a) is susceptible to oxidative mod-
ifications and formation of pro-inflammatory and pro-atherogenic oxidized phospholipids
(OxPLs) [3]. Lp(a) carries more than 80% OxPLs in its particles, and consequently this in-
creases the inflammatory activity of the arterial wall [21]. Taken together, the evidence shows
a bidirectional link between Lp(a) and inflammation (Figure 2) [44].
Biomolecules 2022, 12, 26 5 of 14
The Lp(a) binding of OxPLs is to lysine residues on isolated fragments of KV of apo(a)
[45]. At low plasma concentrations, Lp(a) has anti-inflammatory effects via its scavenging
of OxPLs and their degradation by Lp(a)-associated phospholipase A2 (Lp-PLA2) [21]. At
high Lp(a) levels, its anti-atherogenic effects are diminished, with decreased Lp-PLA2 low-
ering of oxidative stress, compared to LDL-associated PLA2. The OxPL moieties on apo(a)
compete for the active site and decrease the catalytic efficiency of Lp-PLA2 [46]. Here, the
oxidation–reduction state tends towards oxidation, and Lp(a) releases its oxidative load
into the atheromatous plaque. Consequently, OxPLs induce inflammatory responses by
increasing secretion of inflammatory cytokines and chemokines, and through mediation
of monocyte activation [21]. Removal of apo(a) from Lp(a) particles leads to increased Lp-
PLA2 activity, and thus degradation of OxPLs [46].
Lipoprotein(a) also carries monocyte chemoattractant protein-1 (MCP-1), and it has
been shown that OxPLs are major determinants of MCP-1 binding. It was suggested that
Lp(a)-associated MCP-1 enhances recruitment of monocytes to the vascular wall [47].
Monocyte activation has a pivotal role in atheroma plaque formation, while apo(a) en-
hances the inflammatory and proteolytic potential of monocytes, which release reactive
oxygen species and matrix metalloproteinase-9 (MMP-9). Reactive oxygen species are in-
volved in LDL cholesterol oxidation and formation of foam cells, and MMP-9 contributes
to extracellular matrix degradation and rupture of atherosclerotic plaques. The degree of
stimulation with apo(a) is inversly correlated with the number of KIV2 repeats, which sup-
ports the hypothesis regarding the detrimental effects of small-sized isoforms of apo(a) in
atherosclerosis progression [48].
According to Arai et al. [49], OxPLs are mainly bound to small Lp(a) isoforms. Car-
riers of the rs3798220 variation have significantly higher Lp(a) levels and smaller apo(a)
isoforms, compared to noncarriers. Patients with this variation are associated with greater
levels of proinflammatory OxPLs on apoB particles, and consequently, they might have
increased atherogenic potential [49].
A secondary post-hoc analysis of a double-blind, randomized clinical trial (‘Asses-
ment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib
in Patients at a High Risk for Vascular Outcomes’; ACCELERATE) showed that increased
Lp(a) levels are related to cardiovascular events when high sensitivity C-reactive protein
(CRP) concentrations are ≥2 mg/L, but not when they are <2 mg/L [50]. The inflammatory
marker CRP directly affects endothelial cells, monocytes, macrophages, and smooth mus-
cle cells. It is produced by hepatocytes in response to various inflammatory cytokines.
Among these, IL-6 is most closely associated with inflammation and increased risk of ath-
erosclerosis. As shown by Shufta et al., there is a positive correlation between CRP, IL-6,
and Lp(a) levels [51]. Furthermore, the IL-6 receptor blocker tocilizumab reduced inflam-
matory disease activity and plasma Lp(a) levels in 132 patients with reumatoid arthritis
[52]. Also, in a study of 280 hemodialysis patients and in two studies with 137 and 114
patients with rheumatoid arthritis, CRP levels increased with increasing levels of Lp(a)
[53–55]. However, based on the ‘Copenhagen General Population Study’, Langsted et al.
reported that elevated Lp(a) levels are not causally associated with increased low-grade
inflammation, as measured through CRP, despite a casual association with increased risk
of aortic valve stenosis and acute myocardial infarction [56].
4. Lipoprotein(a) and Atherothrombosis
Coagulation and fibrinolysis have essential roles in atherothrombosis [57]. The rup-
ture of an atherosclerotic plaque results in the activation of platelets and the extrinsic co-
agulation pathway. Lp(a) participates in atherothrombosis through several mechanisms
(Figure 3). As an atherogenic lipoprotein, Lp(a) interferes with platelet aggregation [58],
as it can bind to platelet-activating factor (PAF) acetylhydrolase, which degrades and in-
activates PAF. This mechanism results in reduced platelet aggregation and activation [59].
Lipoprotein(a) has an effect on the coagulation pathway through the promotion of
the expression of tissue factor (TF) [60]. TF is a cell-surface glycoprotein that is
Biomolecules 2022, 12, 26 6 of 14
overexpressed by macrophages and smooth muscle cells within the atherosclerotic
plaque. Tissue damage that results in endothelial denudation exposes TF to the flow of
blood, whereby TF initiates activation of the extrinsic coagulation pathway, which leads
to thrombus formation and intima fibrin deposition [57]. Another prothrombotic effect of
Lp(a) is related to its binding to and inhibition of the activity of the TF pathway inhibitor
(TFPI) [61]. Bilgen et al. and Nisio et al. showed positive correlations between plasma TFPI
and Lp(a) levels [62,63]. Although patients with higher Lp(a) levels had higher TFPI con-
centrations, the TFPI activity was not different between those with high and low Lp(a)
levels. This suggests that the binding of TFPI to Lp(a) partly inhibits TFPI activity [62].
Lipoprotein(a) is believed to promote atherothrombosis due to its homology with
plasminogen [5]. As indicated, one of the component proteins of Lp(a), apo(a), shares
more than 80% of its protein sequence with plasminogen [64]. Lp(a) lacks KI to KIII of
plasminogen, but it contains KIV and KV [60]. Apo(a) KIV10 contains a lysin binding site,
which is most similar to the lysine binding site within plasminogen KIV [65]. Due to this
structural homology, Lp(a) can bind to plasminogen receptors on the surface of platelets
and prevent the interaction between plasminogen and tissue plasminogen activator (tPA).
Therefore, tPA cannot convert plasminogen to plasmin [60].
Plasminogen is the proenzyme precursor of plasmin, and thus it has an important
role in fibrinolysis. Plasminogen is activated to plasmin by tPA or urokinase [66]. The
plasminogen and LPA genes are both on chromosome 6, and a recent study identified nine
SNPs within the plasminogen and LPA gene region that are significantly associated with
plasminogen levels [67]. Among these various SNPs, Wang et al. studied the impact of
rs3798220 and rs10455872 on Lp(a) and plasminogen levels. Although these polymor-
phisms are associated with higher Lp(a) levels, they had no influence on plasminogen
levels and fibrinolytic activity [68]. However, in an in vitro study, Rowland et al. showed
that Caucasian patients carrying the rs3798220 SNP have increased clot lysis times and
reduced clot permeability, compared to noncarriers. On the other hand, among non-Cau-
casians, increased clot permeability and decreased lysis time have been reported [69]. Fur-
thermore, Scipione et al. showed that the isoleucine-to-methionine substitution in apo(a)
protease-like domain of rs3798220 decreased coagulation times and increased fibrin clot
lysis times, compared to wild-type apo(a). Additionally, the fibrin fiber width in plasma
clots was increased, and patients with higher Lp(a) levels had lower clot permeability [70].
Taken together, rs3798220 has antifibrinolytic potential and is associated with increased
Lp(a) levels and cardiovascular risk.
Lipoprotein(a) inhibits the production of tPA, and therefore it promotes a thrombotic
state through the prevention of plasmin-mediated clot lysis [60]. In addition, Lp(a) stim-
ulates the expression and activity of the primary inhibitor of the fibrinolytic system, plas-
minogen activator inhibitor-1 (PAI-1) [60,71]. We have previously shown that patients
with familial hyperholesterolemia who had survived myocardial infarction at a young age
had significanly decreased fibrinolytic activity, as shown by increased PAI-1 antigen and
activity, and increased t-PA antigen, compared to those without myocardial infarction
[72]. Furthermore, these patients had higher Lp(a) levels; however, this difference did not
reach significance, probably due to the small number of patients. Etingin et al. performed
an in vitro study in which they treated human umbilical vein endothelial cells with Lp(a)
and LDL. They showed that Lp(a) levels up to 40 µg/mL increased PAI-1 activity, while
treatment with LDL cholesterol using approximately equimolar concentrations did not
stimulate PAI-1 activity. Lp(a) levels above 40 µg/mL did not show any further increase
in PAI-1 activity. This effect was due to increased mRNA levels of PAI-1 [73]. Shindo et
al. compared coronary atherotomy specimens of patients with acute myocardial infarction
and unstable angina pectoris with those from patients with stable angina pectoris, and
showed that the levels of both Lp(a) and PAI-1 were significantly higher for the former
[74]. PAI-1 activity, but not antigen, was shown to be a predictive factor for future coro-
nary events in patients with or without prior CAD [75]. Some studies have also included
Lp(a) and apoB in the analysis of fibrinolytic parameters, and in all of these, the
Biomolecules 2022, 12, 26 7 of 14
fibrinolytic parameters were correlated with Lp(a) or apoB, which is a component of Lp(a)
(Table 1) [76–78].
Fibrin represents the structural framework for fibrin clots. The structure, stability,
and fibrinolytic potential of fibrin clots depend on differences in the fibrin fiber diameter
and pore size within the fibrin network, and on negatively charged substances. Dense
clots are associated with a reduced fibrin fiber diameter, smaller pores, and increased fi-
brin stiffness [79]. The rate of fibrin clot lysis is predominantly a function of pore size.
Fibrin clots with smaller pores increase clot lysis times and are correlated with greater
cardiovascular risk. Elevated Lp(a) levels are correlated with reduced fibrin clot permea-
bility and impaired fibrinolysis [61]. Lp(a) competes with plasminogen and tPA for bind-
ing sites on fibrin, and consequently, it impairs fibrinolysis [1,60,64]. These antifibrinolytic
effects are more profound for smaller-sized isoforms of Lp(a), because these have a higher
affinity for their binding to fibrin [80]. The predictive value of high Lp(a) levels as a risk
factor therefore depends on the concentration of Lp(a) particles containing small isoforms
of Lp(a) [81]. Other reports have opposed the mechanism whereby Lp(a) directly com-
petes with plasminogen for binding to fibrin, and have indicated that apo(a) forms a qua-
ternary complex with plasminogen, tPA, and fibrin [82,83]. In addition, the negatively
charged apo(a) might affect the Lp(a)-induced alteration of fibrin clot structure, and thus
contribute to reduced fibrin degradation [61].
5. Prognostic Value of Lipoprotein(a) in Combination with Thrombotic and Inflam-
mation Parameters
The prospective studies that have included analysis of Lp(a) and at least one marker
of inflammation and/or coagulation/fibrinolysis as predictors for future coronary events
are presented in Table 1. In primary prevention studies, which have included >40,000 pa-
tients (mostly male), Lp(a) was shown to independently predict the first cardiovascular
event [84–86]. In the first study, by Langsted et al. [84], only Lp(a) and CRP were examined
as markers of inflammation. In the next two studies, by Cremer et al. [85] and Seed et al.
[86], only Lp(a) and fibrinogen were examined as markers of impairment of the coagula-
tion fibrinolytic system. Indeed, none of the studies indicated in Table 1 have examined
Lp(a) plus at least one parameter of inflammation and one of coagulation/fibrinolysis.
For patients with stable coronary disease, their D-dimer and fibrinogen levels
increased with the quartiles of CRP, while no such relation was seen for Lp(a) [87]. In a
survey of 1172 apparently healthy men, CRP levels correlated with several fibrinolytic
parameters (i.e., fibrinogen, t-PA antigen, D-dimer, homocysteine), and also with Lp(a)
[88]. Here, we can conclude that fibrinolytic and inflammatory parameters are
interconnected in patients with stable CAD and in apparently healthy men.
As the rupture of a pre-existing atherosclerotic plaque is responsible for the majority
of acute coronary events, the number of such events in secondary prevention studies is
much higher. In these studies, where no coronary interventions were performed due to
stenosis < 50%, Lp(a) alone, and even more so in combination with fibrinogen, was an
independent predictor of major adverse cardiovascular events after 37 months [89]. This
was expected, because in these patients, both progression of atherosclerosis and rupture
of plaques can lead to future cardiovascular events. In patients with only percutaneous
transluminal coronary angioplasty and no stent implantation due to CAD, t-PA was
shown to be a superior predictor of major adverse cardiovascular events after 13 years,
compared to Lp(a) [90]. This is not surprising, as the endothelium in percutaneous trans-
luminal coronary angioplasty with no stent implantation is highly disrupted, and future
coronary events are mostly due to intracoronary thrombosis. Similarly, in patients six
months after percutaneous transluminal coronary angioplasty, neither Lp(a) nor PAI-1
were predictors of restenosis [91]. The reason here might be the short time of observation.
In studies where patients were mostly treated with drug-eluting stents, Lp(a) and CRP
were independent predictors of future cardiovascular events [92,93]. At first sight, this
might be a surprise, but it can be noted that all these patients had dual antiplatelet therapy
Biomolecules 2022, 12, 26 8 of 14
that prevented early in-stent thrombosis, for which coagulation and fibrinolysis are re-
sponsible. Furthermore, sirolimus- and everolimus-eluting stents are less prone to early
in-stent thrombosis. In contrast, for patients treated with bare metal stents, homocysteine
levels were linked to the fibrinolytic parameters, especially with t-PA and PAI-1 [94,95].
These patients were also treated with dual antiplatelet therapy, although bare metal stents
were much more thrombogenic than drug-eluting stents [96]. On the other hand, there
were no effects on cardiovascular mortality [97]. Finally, plasma levels of t-PA and Lp(a)
were independently associated with the subsequent development of a first myocardial
infarction in a prospective case-control study [98].
Table 1. Overview of prospective studies that have examined Lp(a) and at least one inflammatory
and/or fibrinolytic parameter.
Study
Parameter In-
cluded
Study Population (n)
Primary Endpoint
Independent Pre-
dictor
Ref.
(n)
Age (Years)
Characteristics
Langsted et
al. (2014)
Lp(a), CRP
34,829
-
General population
Ischemic heart dis-
ease
Lp(a), independent
of CRP levels
[84]
Cremer et
al. (1997)
Lp(a), fibrinogen
5790
40
–60
Male, without previ-
ous CAD
MI
after 10 years
Lp(a)
[85]
Seed et al.
(2001)
Lp(a), fibrinogen
2616
51
–61
Male, without previ-
ous CAD
CAD after 6 years
Lp(a)
[86]
Zhang et al.
(2020)
Lp(a), fibrinogen
8417
-
Stable CAD, no stent
implantation
MACE after 37
months
Lp(a), fibrinogen;
combination of
both superior
[89]
Niessner et
al. (2003)
Lp(a), tPA
141
-
CAD after PTCA, no
stent implantation
MACE after 13
years
t
-PA [90]
Alaigh et al.
(1998)
Lp(a), PAI
-1
163
-
CAD after PTCA, no
stent implantation
Restenosis after 6
months
None
[91]
Kardys et al.
(2012)
Lp(a), CRP, IL
-10
161
-
CAD after sirolimus-
eluting stent implan-
tation
MACE after 1, 6
years
1 year: Lp(a); 6
years: CRP
[92]
Zairis et al.
(2002)
Lp(a), CRP
483
-
ACS after PCI, vari-
ous stent implanta-
tions
MACE after 3 years
Lp(a), CRP
[93]
Marcucci et
al. (2006)
Lp(a) PAI-1, ho-
mocysteine
520
-
ACS, bar metal stent
implantation
MACE after 24
months
PAI-1, homocyste-
ine
[95]
Thogersen
et al. (2003)
Lp(a), PAI
-1, t-
PA, leptin
62, plus
124
con-
trols
Sex and age
matched
-
First myocardial in-
farction
Lp(a), t
-PA [98]
Pineda et al.
(2010)
Lp(a), CRP, PAI-
1, t
-PA, fibrino-
gen, D
-dimer,
homocysteine
142; 56;
10
-
MI before 45 years;
treated with fibrinoly-
sis; PCI
MACE after 36
months
Homocysteine
[99]
Moss et al.
(1999)
Lp(a), PAI-1, fi-
brinogen, D
-di-
mer
1045
-
Post-MI (2 months),
treated with thrombo-
lysis or PCI
Coronary death or
nonfatal MI after
26 months
D
-dimer [76]
ACS, acute coronary syndrome; CAD, coronary artery disease; CRP, C-reactive protein; MACE, ma-
jor adverse coronary event; MI, myocardial infarction; PCI, percutaneous coronary intervention;
PTCA, percutaneous transluminal coronary angioplasty.
Biomolecules 2022, 12, 26 9 of 14
6. Conclusions
Lipoprotein(a) has been shown to be an independent predictor for future cardiovas-
cular events in primary and secondary prevention. This has been confirmed in epidemio-
logical and Mendelian randomized trials, and in the last two years, also in randomized
placebo-controlled double-blind trials with PCSK9 inhibitors. Although these drugs were
primarly designed to target LDL cholesterol, they also decrease Lp(a) by 20% to 40%
[100,101]. Similar findings were observed with inclisiran, a small interfering RNA
(siRNA). Inclisiran was developed to target LDL and apoB, but in the phase 2 study enti-
tled Trial to Evaluate the Effect of ALN–PCSSC Treatment on Low Density Lipoprotein
Cholesterol (ORION-1), it also reduced Lp(a) levels by 25.6% [102,103]. Oplasiran, another
siRNA targeting Lp(a), significantly reduced Lp(a) levels in the phase 1 trial [104]. More-
over, these effects persisted for more than six months [104]. Furthermore, promising
Lp(a)-lowering effects have been observed with antisense oligonucleotide AKCEA–
APO(a)–LRX. This drug has shown a dose-dependent reduction in Lp(a) levels up to 80%
among patients with established cardiovascular disease and Lp(a) levels above 60 mg/dL
in a phase 2 trial [105]. Whether viral-mediated gene therapy RGX–501 for homozygous
familial hypercholesterolemia also has influence on reducing Lp(a) levels is currently be-
ing investigated in clinical trial NCT02651675 [106]. Although all the aforementioned ther-
apeutics have shown lipid-related effects, only PCSK9 inhibitors were found to be associ-
ated with decreased cardiovascular events [31,32]. As for their effects on inflammation
and coagulation, the current evidence is scarce.
The atherogenic propensity of Lp(a) arises as a consequence of its structure. Its LDL-
like particle, which is the main part of Lp(a), has similar effects to those of LDL cholesterol,
and it is even more atherogenic because of its higher sensitivity to oxidation. On the other
hand, apo(a) has a very similar structure to plasminogen, and because of this, it interferes
with the coagulation and fibrinolytic system. Apo(a) thus increases coagulation and de-
creases fibrinolysis. The third component of apolipoprotein(a), the OxPLs, is responsible
for its proinflammatory effects.
In the majority of prospective studies that have included patients after acute coronary
syndrome who have undergone bare metal or drug-eluting stent implantation or percu-
taneous transluminal coronary angioplasty with no stent implantation, the fibrinolytic pa-
rameters appear to be more powerful predictors of future cardiovascular events. On the
other hand, in patients with no clinically known cardiovascular disease, Lp(a) was a better
predictor of future cardiovascular events. These appear to make sense, as in the first group
of patients, they already had atherosclerotic plaques prone to rupture, while in the second
group of patients, the formation of such plaques was not complete. It is known that for
the rupture of vulnerable plaques, disruption of the coagulation fibrinolytic equlibrium is
responsible for thrombus formation and a consequent acute coronary event. The for-
mation of such plaques is not only dependent on Lp(a) levels; rather, it is more likely
dependent on the presence of higher Lp(a) levels regardless of the LDL cholesterol levels.
The question of whether only a decrease in Lp(a) results in decreased cardiovascular
events will be answered by the study ‘Assessing the Impact of Lipoprotein(a) Lowering with
TQJ230 on Major Cardiovascular Events in Patients with Cardiovascular Disease’ (HORIZON;
NCT04023552), which will end in 2024. However, to answer which of these three pathophys-
iological mechanisms are affected by Lp(a) lowering, further studies will be needed.
Author Contributions: Conceptualization, S.U. and M.Š.; writing—original draft preparation, S.U.
and M.Š.; writing—review and editing, S.U. and M.Š.; visualization, S.U. and M.Š.; supervision, M.Š.
All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Biomolecules 2022, 12, 26 10 of 14
Acknowledgments: Figures were created using Mind the Graph (https://mindthegraph.com/, ac-
cessed date: 08/nov/2021). The authors acknowledge Chris Berrie for scientific English editing of the
manuscript.
Conflicts of Interest: The authors declare that they have no conflicts of interest.
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