Measurements of lipids levels are frequently used to assess the risk of future coronary heart disease or stroke, commonly termed cardiovascular disease (CVD). Plasma levels of total cholesterol, triglycerides and high density lipoprotein cholesterol (HDL-C) are frequently measured. These numbers are then used to calculate low density lipoprotein cholesterol (LDL-C), which has been found to be strongly correlated with the risk of CVD. Recently measurements of atherogenic lipoprotein particles, such as LDL-P, apolipoprotein B and lipoprotein(a) have been found to be very useful to assess risk.
Lipoprotein(a) or Lp(a) is a risk factor for CVD. However, the lack of clinical trial data have resulted in Lp(a) being largely ignored by clinical guidelines assessing the prevention of CVD. In 2010, the European Atherosclerosis Society (EAS) consensus panel recommended screening for elevated Lp(a), in people at moderate to high risk of cardiovascular disease. Desirable Lp(a) levels < 50 mg/dL were considered a treatment priority, after therapeutic management of LDL-C. According to a statement from the EAS, ‘‘The evidence clearly supports Lp(a) as a priority for reducing cardiovascular risk, beyond that associated with LDL-C. Clinicians should consider screening statin-treated patients with recurrent heart disease, in addition to those considered at moderate to high risk of heart disease”.
What is Lp(a)?
Lipoproteins are the particles that transport cholesterol and triglycerides in the blood stream. Lipoproteins are composed of proteins (apolipoproteins), phospholipids, triglycerides and cholesterol. The lipoproteins vary in the major lipoprotein present, and the relative contents of the different lipid components. Lp(a) is a lipoprotein rich in cholesterol. It differs from LDL as it contains an additional protein, apolipoprotein (a). Similar to LDL, an Lp(a) particle also contains one molecule of apolipoprotein B.
What are normal plasma levels of Lp(a)?
It as assumed that Lp(a) is produced by liver cells. The pathways for the clearance of this substance are not clearly understood. Plasma levels of Lp(a) rise shortly after birth and the levels appear to become consistent within a few months. In adults, plasma levels of Lp(a) vary widely, ranging from 0.2 – 250 mg/dL. The levels are similar in men and women. Studies indicate that about one in five individuals have plasma levels above 50 mg/dL (80th percentile), and about one in four individuals have plasma levels above 32 mg/dL (75th percentile). Lp(a) levels less than 30 mg/dL are considered normal.
The EAS Consensus panel recommends that Lp(a) should be measured in high risk individuals such as those with premature CVD, familial hypercholesterolemia, family history of premature CVD and/or elevated Lp(a), and individuals with recurrent CVD despite statin therapy.
Lp(a) and risk for heart disease
A number of epidemiological evidence indicates that Lp(a) is associated with the risk of CVD. The Copenhagen City Heart Study found that individuals with plasma Lp(a) levels above 50 mg/L had 2 to 3 – fold increase risk for heart attack (myocardial infarction). A series of meta-analyses has provided evidence of a link between Lp(a) and CVD. Furthermore, studies on patients with familial hypercholesterolemia have provided additional evidence. Studies have indicated that the association is without a threshold, and does not depend on high levels of LDL or non-HDL cholesterol, or the presence of other cardiovascular risk factors. However, some authors have suggested that the risk of elevated Lp(a)is small, if LDL-cholesterol is not elevated.
How is Lp(a) involved in atherosclerosis and heart disease?
Lp(a) and LDL penetrate the inner layer of the arterial wall and accumulate together at sites for atherosclerotic plaque formation. Evidence suggests that Lp(a) may be more strongly retained in the arterial wall than LDL. Furthermore, Lp(a) transports oxidized phospholipids whose plasma levels are strongly correlated with the severity of coronary artery disease. Interestingly, these Lp(a) associated oxidized phospholipids possess pro-inflammatory activity. This might be one of the links between lipids and inflammation in atherosclerosis. There is also some experimental data suggesting that Lp(a) may promote clot formation in arteries burdened by atherosclerotic plaque. This may be one of the mechanisms behind the involvement of Lp(a) in heart attack and stroke.
How can Lp(a) be modulated?
Lp(a) is mainly genetically determined and therefore refractory to lifestyle intervention. Dietary changes, exercise and weight loss have not been shown to lower Lp (a). The data on the effects of statins on Lp(a) are conflicting and the same is true for fibrates. Oestrogen replacement therapy in women has been shown to lower Lp(a), although by less than 10 percent. Other agents that have been reported to slightly lower Lp(a) are aspirin, l-carnitine, ascorbic acid/L-lysine, angiotensin converting enzyme inhibitors, calcium antagonists, androgens and anti-oestrogens.
Fat consumption has not been shown to raise Lp(a). One study documented a lowering of plasma Lp(a) levels in individuals placed on diets rich in saturated fat (a palm oil enriched diet). In keeping with this, other investigators have reported an increase in Lp(a) levels in individuals after they reduced their saturated fat intake. Monounsaturated fats also seem to reduce Lp(a) levels, as shown by a study that reported a significant decrease in Lp(a) levels in individuals whose diets were supplemented with almonds.
Consistent with treatment guidelines, reduction of elevated Lp(a) levels should be a secondary treatment priority, after maximal lowering of LDL-C. Niacin lowers Lp(a) by approximately 30 percent. Therefore, the EAS Consensus Panel has recommended niacin as the primary treatment for lowering elevated Lp(a) levels. However, these recommendations may have to be reevaluated in light of the results from the recent AIM-HIGH and HPS2-THRIVE trials. These trials did not show any clinical benefits of adding niacin to statin therapy. Evidence indicates that the new PCSK9 inhibitors that are now being tested in clinicla trials may significantly lower Lp(a).