Lipoprotein(a) as an Old and New Causal Risk Factor of Atherosclerotic Cardiovascular Disease

Hayato Tada, Masayuki Takamura, Masa-Aki Kawashiri, Hayato Tada, Masayuki Takamura, Masa-Aki Kawashiri

Abstract

Lipoprotein(a) [Lp(a)], discovered in 1963, has been associated with atherosclerotic cardiovascular disease (ASCVD) independent of other traditional risk factors, including LDL cholesterol. Lp(a) is an apolipoprotein B (apoB)-containing lipoprotein, which contains an LDL-like particle. Unlike LDL, which is a primary therapeutic target to decrease ASCVD, current guidelines recommend measuring Lp(a) for risk assessments because there is no clear evidence demonstrating the clinical benefit of decreasing Lp(a) using classical drugs such as niacin. However, recent Mendelian randomization studies indicate that Lp(a) causally correlates with ASCVD. In addition, novel drugs, including PCSK9 inhibitors, as well as antisense oligonucleotide for apo(a), have exhibited efficacy in decreasing Lp(a) substantially, invigorating a discussion whether Lp(a) could be a novel therapeutic target for further ASCVD risk reduction. This review aims to provide current understanding, and future perspectives, of Lp(a), which is currently considered a mere biomarker but may emerge as a novel therapeutic target in future clinical settings.

Keywords: Aortic valve stenosis; Atherosclerotic cardiovascular disease; LDL; Lipoprotein(a).

Conflict of interest statement

None.

Figures

Fig. 1.
Fig. 1.
The structure of lipoprotein [Lp(a)] Lp(a) is composed of an LDL-like particle, including apolipoprotein B-100 (apoB-100) and apolipoprotein(a) [apo(a)], which has kringle IV (KIV) and KV. Apo(a) contains 10 subtypes of KIV repeats, containing one copy each of KIV1, multiple copies of KIV2 (yellow colored), and one copy of KIV3-10, KV.
Fig. 2.
Fig. 2.
The distribution of the lipoprotein [Lp(a)] frequency The X-axis represents the serum Lp(a) level, while the Y-axis represents the frequency.
Fig. 3.
Fig. 3.
The evidence for lipoprotein [Lp(a)] as an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) A, A meta-analysis of epidemiological studies, adjusted for usual levels of systolic blood pressure, smoking status, history of diabetes, body mass index, and total cholesterol. The X-axis represents the serum Lp(a) level, while the Y-axis represents the risk ratio for non-fatal MI and coronary death. B, the correlation between genetically predicted Lp(a) and CHD risk. The X-axis represents the serum Lp(a) level, while the Y-axis represents the odds ratio for the CHD risk. The blue solid line represents the best-fitting fractional polynomial to model the dose-dependent relationship; the dotted lines show the 95% confidence intervals for the relationship.
Fig. 4.
Fig. 4.
Lipoprotein [Lp(a)] and progression of aortic valve stenosis, as well as the incidence of aortic valve replacement A, both arrows indicate the predicted progression of preexisting mild-to-moderate calcific aortic valve stenosis (CAVS) on echocardiography in meters/second/year in the ASTRONOMER trial. The gray arrow shows the progression of aortic valve stenosis among patients whose Lp(a)

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