Lipoprotein(a) – An independent causal risk factor for cardiovascular disease and current therapeutic options
Introduction
Lipoprotein-(a) (Lp(a)) is a complex of a low-density lipoprotein (LDL)-like particle and apolipoprotein-(B-100) covalently bound to apolipoprotein-a [1]. It has been first described by Berg about 50 years ago who found high serum levels of Lp(a) to be inherited and associated with an increased risk for premature cardiovascular disease (CVD) [2], [3]. The physiological function of Lp(a) and its effects on the vasculature remain indefinite to date. It was found that Lp(a) is able to enter the intima of blood vessels in humans and animals [4]. There it may contribute to inflammation of the intima, thrombosis and foam cell formation – processes that are known to be involved in the development of arteriosclerosis [5], [6]. Serum levels of Lp(a) show a widespread variation between individuals and race (<0.1 mg/dL to >250 mg/dL), whereas they are more or less stable within an individual over time [7]. Diet, physical exercise and other environmental influences seem not to alter serum levels of Lp(a) significantly [8]. In fact, they are predominantly determined by the size of the apolipoprotein-a isoforms which are encoded by different variations of the LPA-gene [9]. Utermann ascertained an inverse relationship between the size of apo-a isoform and the corresponding Lp(a) concentration [10]. Furthermore, Erqou found high Lp(a) concentrations and low molecular weight of apolipoprotein-a isoforms associated with a high risk for CVD [11]. More recently, an analysis of a subsample of white participants of the JUPITER study revealed that concomitant elevated Lp(a) levels represent a significant determinant of residual risk for CVD in participants whose LDL levels were very low under potent statin therapy [12].
Section snippets
Lipoprotein(a) as independent, causal risk factor for cardiovascular disease
The Copenhagen Heart Study could show that individuals with Lp(a) levels > 50 mg/dl have an 2- to 3-fold increased risk to suffer from myocardial infarction [13]. Later, the Emerging Risk Factors Collaboration performed a meta-analysis to further investigate the dosing effect of Lp(a) concentration. They investigated patient data of 36 studies to determine the association between Lp(a) concentration with the risk for coronary heart disease (CHD) and stroke [5]. They found that each 3.5-fold
Which patient groups should be screened for Lp(a)?
The European Atherosclerosis Society Consensus Panel recommended that Lp(a) should be measured in patients with intermediate or high risk for CVD or CHD. In particular, they suggest to screen those patients presenting with i) premature CVD, (ii) familial hypercholesterolemia, (iii) a family history of premature CVD and/or elevated Lp(a), (iv) recurrent CVD despite statin treatment, (v) ≥3% 10-year risk of fatal CVD according to the European guidelines [17] and (vi) ≥10% 10-year risk of fatal
Therapeutic options to lower Lp(a)
Since elevated serum levels of Lp(a) are associated with an increased risk for CVD, therapeutic options targeting at lowering Lp(a) are under development. The European Atherosclerosis Society Consensus Panel considers Lp(a) concentrations below the 80th percentile (<50 mg/dl) as desirable [19]. Consequently, Lp(a) reduction would then result in lower risk for CVD expressed by the reduction of cardiovascular events or a deceleration of CVD progression in patients. Since lifestyle in general
Conclusions
Recent clinical as well as Mendelian randomization studies provide evidence for lipoprotein(a) to be an independent, causal risk factor for cardiovascular disease. The European Atherosclerosis Society Consensus Panel defined criteria to identify patients at high risk, who should be screened for elevated Lp(a). Since diet, exercise and lifestyle in general have no effect on Lp(a) regular lipoprotein apheresis is currently the only therapy to reduce Lp(a). Current studies suggest that lowering of
Conflict of interest
TS received honoraria for lectures by Fresenius Medical Care Germany. AR received speakers' honoraria for presentations and advisory board activities by Fresenius Medical Care Germany and Braun. UK received speakers' honoraria for presentations and advisory board activities by Fresenius Medical Care Germany, Amgen and Sanofi. ESTH received speakers' honoraria for presentations and advisory board activities by Fresenius Medical Care Germany, Amgen and Sanofi.
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Ursula Kassner and Thomas Schlabs contributed equally to this manuscript.