Lipoprotein(a) as a cardiovascular risk factor: current status

Abstract

Aims: The aims of the study were, first, to critically evaluate lipoprotein(a) [Lp(a)] as a cardiovascular risk factor and, second, to advise on screening for elevated plasma Lp(a), on desirable levels, and on therapeutic strategies.

Methods and results: The robust and specific association between elevated Lp(a) levels and increased cardiovascular disease (CVD)/coronary heart disease (CHD) risk, together with recent genetic findings, indicates that elevated Lp(a), like elevated LDL-cholesterol, is causally related to premature CVD/CHD. The association is continuous without a threshold or dependence on LDL- or non-HDL-cholesterol levels. Mechanistically, elevated Lp(a) levels may either induce a prothrombotic/anti-fibrinolytic effect as apolipoprotein(a) resembles both plasminogen and plasmin but has no fibrinolytic activity, or may accelerate atherosclerosis because, like LDL, the Lp(a) particle is cholesterol-rich, or both. We advise that Lp(a) be measured once, using an isoform-insensitive assay, in subjects at intermediate or high CVD/CHD risk with premature CVD, familial hypercholesterolaemia, a family history of premature CVD and/or elevated Lp(a), recurrent CVD despite statin treatment, ≥3% 10-year risk of fatal CVD according to European guidelines, and/or ≥10% 10-year risk of fatal + non-fatal CHD according to US guidelines. As a secondary priority after LDL-cholesterol reduction, we recommend a desirable level for Lp(a) <80th percentile (less than ∼50 mg/dL). Treatment should primarily be niacin 1-3 g/day, as a meta-analysis of randomized, controlled intervention trials demonstrates reduced CVD by niacin treatment. In extreme cases, LDL-apheresis is efficacious in removing Lp(a).

Conclusion: We recommend screening for elevated Lp(a) in those at intermediate or high CVD/CHD risk, a desirable level <50 mg/dL as a function of global cardiovascular risk, and use of niacin for Lp(a) and CVD/CHD risk reduction.

Figure 1

Lipoprotein(a) consists of an LDL-like particle to which apolipoprotein(a) is covalently linked. The LDL-like moiety is composed of a central core of cholesteryl esters (CE) and triglycerides (TG) surrounded by phospholipids (PL), free cholesterol (FC), and a single molecule of apolipoprotein B (apoB). Apolipoprotein(a) contains 10 different types of plasminogen kringle 4-like repeats as well as regions homologous to the kringle 5 and protease (P) regions of plasminogen. The kringle 4 type 2 domain (4₂) is present in multiply repeated copies from 2 to >40 that differ in number between apolipoprotein(a) isoforms. Apolipoprotein(a) is linked to apolipoprotein B100 by a single disulfide bond involving an unpaired cysteine residue in kringle 4 type 9. Modified from Koschinsky and Marcovina.

Figure 2

Typical distributions of lipoprotein(a) levels in the general population. These graphs are based on non-fasting fresh serum samples from ∼3000 men and 3000 women from the Copenhagen General Population Study collected from 2003 through 2004. Green colour indicates levels below the 80th percentile, whereas red colour indicates levels above the 80th percentile.

Figure 3

Risk ratios of coronary heart disease, ischaemic stroke and non-vascular death by quantiles of usual lipoprotein(a) levels. CI, confidence interval. Sizes of data markers are proportional to the inverse of the variance of the risk ratios. (A) Adjustment for age and sex only. (B) Further adjustment for systolic blood pressure, smoking status, history of diabetes, body mass index, and total cholesterol. MI, myocardial infarction. Modified from The Emerging Risk Factors Collaboration.

Figure 4

Risk ratios for various vascular and non-vascular endpoints per 3.5-fold (i.e. 1 SD) higher than usual lipoprotein(a) levels adjusted for cardiovascular risk factors. MI, myocardial infarction. ^aSubtotals do not add to the total number of coronary heart disease outcomes because some studies did not subdivide outcomes into coronary death and non-fatal MI. RR, relative risk; CI, confidence interval. Modified from The Emerging Risk Factors Collaboration.

Figure 5

Risk of myocardial infarction by levels of lipoprotein(a) in the general population. Hazard ratios (HRs) are adjusted for cardiovascular risk factors (multivariable) or for these factors as well as kringle IV type 2 (KIV-2) genotype. P-values are test for trend of hazard ratios where lipoprotein(a) groups with increasing levels were coded 1, 2, 3, 4, and 5. Values are from the 1991–94 examination of the Copenhagen City Heart Study with up to 16 years of follow-up (n= 7524). CI, confidence interval. Modified from Kamstrup et al.

Figure 6

Mean lipoprotein(a) levels in the Copenhagen City Heart Study as a function of quartiles of apolipoprotein(a) KIV-2 repeats. P-value is for the Cuzick non-parametric test for trend of mean lipoprotein(a) levels. Participants in the 1991–94 or 2001–03 examination were included (n= 9867). KIV-2, kringle IV type 2. Error bars indicate 95% confidence intervals. Modified from Kamstrup et al.

Figure 7

Risk of myocardial infarction by quartiles of apolipoprotein(a) KIV-2 repeats in the Copenhagen City Heart Study (CCHS), the Copenhagen General Population Study (CGPS), and the Copenhagen Ischemic Heart Disease Study (CIHDS). P-values are test for trend of risk estimates [hazard ratios (HRs) or odds ratios (ORs)] where kringle IV type 2 (KIV-2) groups with decreasing numbers of KIV-2 repeats were coded 1, 2, 3, and 4. CI, confidence interval (shown as error bars). Modified from Kamstrup et al.