Lipoprotein(a) (Lp[a]) has been identified as an independent, causal risk factor for
cardiovascular disease (CVD).1, 2 Lp(a) has a structure similar to low‐density lipoprotein
(LDL) in its lipid core composition in addition to a molecule of apolipoprotein B100
(apoB), but also contains a unique glycoprotein—apo(a), with strong structural homology
with plasminogen.2 Apo(a) contains anything from 3, to more than 50 identically repeated
plasminogen‐like kringle IV domains, which gives rise to the heterogeneity in isoform
size reported in the population.3 There is a general inverse correlation between the
size of the apo(a) isoform and the Lp(a) plasma concentration.2, 3 The variation in
the concentration of Lp(a) is primarily controlled by the level of synthesis rather
than catabolism, with as much as 90% of the variation being genetically determined
based on variation in the gene encoding apo(a) (LPA) located on chromosome 6q26‐27.3,
4
The mechanism and sites of Lp(a) catabolism still remain obscure.2, 3 Uptake via the
LDL receptor (LDLR) may not be a major pathway of Lp(a) metabolism (however, the studies
in familial hypercholesterolemia patients with null LDLR allele confirmed the important
role of the receptor), and very low‐density lipoprotein receptor, LDL receptor‐related
protein 1, megalin/gp33018, scavenger receptor class B type 1, and plasminogen receptors
might also play an important role.3 The catabolism pathway of Lp(a) is therefore mainly
sustained by the liver, spleen, and kidney.3, 4 Lp(a) concentrations are also dependent
on the rate of hepatic apo(a) and apoB100 secretion, what might also be the mechanism
(together with the metabolism with LDLR) responsible for the Lp(a) reducing effect
of proprotein convertase subtilisin/kexin type 9 inhibitors.3, 5
Aside from its role as a recognized independent CVD biomarker, the physiological function
of Lp(a) still is not completely understood.1, 2, 3, 4, 6 Because of its structural
similarity to plasminogen and tissue plasminogen activator, it competes with plasminogen
for its binding site, leading to reduced fibrinolysis, and as a result of the stimulation
of secretion of plasminogen activator inhibitor‐1, Lp(a) leads to thrombogenesis.1,
2, 3 Lp(a) also carries cholesterol and binds atherogenic proinflammatory oxidized
phospholipids, which attract inflammatory cells to vessel walls and leads to smooth
muscle cell proliferation. In consequence, Lp(a) strongly contributes to the process
of atherogenesis.1, 2, 3, 4
Despite the recognition of the role of Lp(a) as an independent risk factor of CVD
events, irrespective of other coexisting risk factors, physician knowledge regarding
Lp(a) is limited. Consequently, Lp(a) is measured infrequently. One of the reasons
for this is associated with the lack of clear recommendation associated with the Lp(a)
cut‐off values, another relates to the cost and difficulties associated with diagnostic
methods, and a third reason is the lack of recommendations on management and therapy
of patients with high levels of this biomarker.2, 6 The first guideline relating to
the management of high levels of Lp(a) was the Consensus Paper of European Society
of Atherosclerosis (EAS; 2010).2 The authors recommended the measurement of Lp(a)
once in all subjects at intermediate or high risk of CVD/CHD who present with premature
CVD and/or familial hypercholesterolemia, a family history of premature CVD and/or
elevated Lp(a), recurrent CVD despite statin treatment, ≥3% 10‐year risk of fatal
CVD, and ≥10% 10‐year risk of fatal and/or nonfatal CHD.2 They suggested repeat measurement
only if treatment for high Lp(a) levels is initiated, in order to evaluate the therapeutic
response. For reduction of plasma Lp(a) as a secondary priority after reduction in
low‐density lipoprotein cholesterol (LDL‐C), the experts recommended a desirable level
below 50 mg/dL.2 Almost at the same time (2011) the experts from the National Lipid
Association presented a comprehensive study on the utility of the selected biomarkers
in CVD risk stratification.6 The authors suggested that initial Lp(a) measurement
before the therapy might be considered in selected patients with intermediate risk
(5–20% 10‐year CHD event risk) or CHD or a CHD equivalent. They also suggested measurement
would be reasonable for many patients with a family history of premature CHD or in
patients with established CHD with a history of recurrent events despite appropriate
therapy.6 Having access to the Lp(a) measurements of patients already on treatment
may be useful when considering on‐treatment management decisions in selected patients
with CHD (or a CHD risk equivalent), premature family history, or a history of recurrent
coronary events.6 Both of these recommendations started the discussion on Lp(a), which
has become even louder within the context of trials of cholesteryl ester transfer
protein and proprotein convertase subtilisin/kexin type 9 inhibitors, which are very
effective at lowering Lp(a) concentrations.5 This discussion is increasingly important
as we see more and more patents with complex dyslipidemias, including elevated Lp(a),
as well as individuals with isolated Lp(a) elevations, who are at high and very high
cardiovascular risk, and we need to consider suitable management for these patients.2,
6
Interestingly, in addition to the role of high Lp(a) levels in various vascular diseases,
low concentrations also seem to be important in vascular medicine.7 Some authors have
suggested the existence of a J‐curved phenomenon for Lp(a) concentration with a slight
increase of cardiovascular and cerebrovascular outcomes in the group of patients with
very low levels and a larger increase in the group of patients with significantly
increased Lp(a) levels.7 Available studies have also suggested that decreased values
of Lp(a) have been associated with carotid atherosclerosis and have been proposed
as markers of cerebral hemorrhage risk.8 There are several hypotheses relating to
this phenomenon: one associated with the induction of angionecrosis and impaired nutritional
metabolism within the vessels, another with the impaired metabolism of scavenging
oxidized lipids.8 On the other hand, elevated Lp(a) has been confirmed as a causal
factor for CVD including myocardial infarction, and aortic stenosis.1, 2, 3, 4, 6
Some studies have also suggested its important role in patients with abdominal aortic
aneurysm (AAA).9 In the recent Lipid and Blood Pressure Meta‐analysis Collaboration
Group meta‐analysis, Kotani et al9 aimed to evaluate the association between circulating
Lp(a) levels and the presence of AAA. Meta‐analysis of 9 studies showed that patients
with AAA were found to have a significantly higher level of Lp(a) compared to the
controls (standard mean deviation: 0.87, 95% CI: 0.41–1.33, P<0.001), which might
suggest the causality of high Lp(a) with the presence of AAA.9
Taking the abovementioned into account, the study by Afshar et al10 in this issue
of the Journal of the American Heart Association (JAHA) is of special interest and
importance. The authors verified the current recommendations for Lp(a) and suggested
that treatment should focus on the control of other risk factors first, including
lowering LDL‐C, and assumed that identifying interactions between Lp(a) and other
risk factors could identify individuals at increased risk for Lp(a)‐mediated disease.10
They included 939 participants at median age of 49 (range 18–55) from the GENdEr and
Sex determInantS of cardiovascular disease: From bench to beyond‐Premature Acute Coronary
Syndrome (GENESIS‐PRAXY) study.10 The study population included individuals who developed
symptoms consistent with acute cardiac ischemia within the first 24 hours of hospital
admission. These individuals were considered to have an acute coronary syndrome (ACS),
which included unstable or intermediate coronary syndromes and/or acute myocardial
infarction. The authors showed a higher prevalence of elevated Lp(a) levels (>50 mg/dL)
in study participants as compared to the general population from the Copenhagen General
Population Study (31% versus 20%; P=1.643e‐10). Lp(a) was strongly associated with
LDL‐C (adjusted β 0.17; P=2.072e‐5), and individuals with high Lp(a) were more likely
to have LDL‐C >2.5 mmol/L, indicating a synergistic interaction (adjusted odds ratio
1.51; 95% CI 1.08–2.09; P=0.015). The interaction with high Lp(a) was stronger at
increasing LDL‐C levels (LDL‐C >3.5, adjusted odds ratio 1.87; LDL‐C >4.5, adjusted
odds ratio 2.72), and became attenuated at LDL‐C ≤3.5 mmol/L (OR 1.16; P=0.447). No
other risk factors investigated, such as age, sex, smoking, hypertension, diabetes,
familial hypercholesterolemia, and body mass index were associated with high Lp(a).10
The authors confirmed that in relatively young ACS patients (<55 years), high Lp(a)
was strongly associated with high LDL‐C levels, and Lp(a) confers greater risk for
premature ACS when LDL‐C is elevated. Therefore, especially in individuals with high
Lp(a) (>50 mg/dL) and concomitant elevations in LDL‐C >3.5 mmol/L, intensive LDL‐C
lowering may be warranted to reduce the risk of premature ACS.10 Obviously this study
needs to be confirmed in larger well‐designed controlled trials; however, even based
on these results, we can say that Lp(a) might be an important predictor of premature
ACS in young patients with cardiovascular risk.10 This study clearly confirms that
elevated Lp(a) might often be present in relatively young individuals without any
other important risk factors. Thus, it is always extremely important to ask patients
about family history of CHD. The authors also demonstrated that Lp(a) appears to be
strongly associated with LDL‐C in young ACS cases, confirming the physiological link
between Lp(a) and LDL/LDLR, and emphasizing the potential importance of LDL‐C in these
patients.10 Finally, taking into account that previous studies have confirmed that
Lp(a) and LDL‐C are not associated in the general population, the authors’ finding
that Lp(a) and LDL‐C are strongly associated in young ACS individuals suggest that
Lp(a) excess may promote initiation and early development of atheromatous plaques,
which may be accelerated by the presence of a high level of LDL‐C (especially above
3.5 mmol/L).10
In addition to the discussion about the role of Lp(a) as an important biomarker of
CVD, we are faced with the very great challenge of treating patients with high Lp(a)
levels. Currently, the appropriate management of high Lp(a) is not known and there
are limited therapeutic options to lower Lp(a) directly.2, 6 Niacin reduces Lp(a)
levels by up to 30% to 40% in a dose‐dependent manner and in addition exerts other
potential beneficial effects by reducing LDL‐C, total cholesterol, triglycerides,
and remnant cholesterol and by raising high‐density lipoprotein cholesterol (HDL‐C);
however, the available trials did not show any cardiovascular benefit with niacin
administration as an agent to reduce residual risk of increasing high‐density lipoprotein
cholesterol. Therefore, niacin is not commonly available in many European countries.2,
6, 11 New agents, such as cholesteryl ester transfer protein and proprotein convertase
subtilisin/kexin type 9 inhibitors, are also very effective; however, they are not
still available. In the case of cholesteryl ester transfer protein inhibitors, the
studies with torcetrapib, dalcetrapib, and evacetrapib were terminated prematurely
and we await the results of the Determining the Efficacy and Tolerability of CETP
INhibition with AnacEtrapib (DEFINE) trial with anacetrapib, which seems to be the
most potent agent, both increasing high‐density lipoprotein cholesterol by even 140%,
and significantly reducing LDL‐C and Lp(a).12, 13 Proprotein convertase subtilisin/kexin
type 9 inhibitors have been approved by the US Food and Drug Administration and the
European Medicines Agency, but due to the lack of reimbursement in most countries
as well as the high cost of the therapy they are also still not commonly available.5,
14 Therefore, according to the current recommendations and expert opinions, statins
should be considered as a first‐line therapy in case of high level of Lp(a), despite
their limited efficacy, because such therapy is aimed to reduce overall cardiovascular
risk.2, 5, 6 There are also other drugs as well as nutraceuticals/functional foods
that may be effective in Lp(a) lowering. Within the Lipid and Blood Pressure Meta‐analysis
Collaboration Group, Kotani et al15 investigated the effects of tibolone treatment
on circulating Lp(a) levels in postmenopausal women through systematic review and
meta‐analysis of available randomized controlled trials. Meta‐analysis of 12 trials
suggested a significant reduction of Lp(a) levels following tibolone treatment (weighted
mean difference: −25.28%, 95% CI: −36.50, −14.06; P<0.001), and the effect remained
significant both for the doses <2.5 (−17.00%) and ≥2.5 mg/day (−29.18%), as well as
in the subsets of trials with follow‐up either <24 (−26.79%) or ≥24 months (−23.10%).15
The same group has recently evaluated the effect of l‐carnitine supplementation on
Lp(a) concentrations.16 The meta‐analysis showed a significant reduction of Lp(a)
levels following l‐carnitine supplementation (weighted mean difference: −8.82 mg/dL,
95% CI: −10.09, −7.55, P<0.001), especially when l‐carnitine was administrated orally
(−9.00 mg/dL) but not intravenously (−2.91 mg/dL).16 In another meta‐analysis from
the Lipid and Blood Pressure Meta‐analysis Collaboration Group, Serban et al investigated
the effect of garlic on Lp(a) concentrations; however, they did not show any effect
of garlic supplementation on the reduction of Lp(a) levels.17
In conclusion, the available literature supports the predictive value of Lp(a) on
CVD outcomes—mainly myocardial infarction, and aortic stenosis. Clinical studies and
meta‐analysis also suggest that it might be important to predict the risk of AAA,
and the present study by Afshar et al10 further extends the current knowledge suggesting
that high Lp(a) might be an important biomarker of premature ACS in young individuals
(<55 years), especially with simultaneous high LDL‐C levels. Further studies are still
required to enable an understanding of all of the aspects of Lp(a) (patho)physiology,
its functions, predictive values in different conditions, the “gold standard” method
for its measurement, and whether it is possible to reduce the cost of this method
to enable its widespread use. We also need to determine the cut‐off value for the
risk increase (as some studies suggest that the cardiovascular risk might be increased
even with Lp(a) values over 25–30 mg/dL18), and finally we need to know the most effective
methods of therapy for elevated Lp(a) levels. We know so much yet still have much
to learn …
Disclosures
None.