Boston, MA - The utility of Lp(a) in predicting the future risk of heart disease is markedly attenuated among women taking hormone therapy, a new study suggests [1].

The study, published online July 1, 2008 in the Journal of the American College of Cardiology, was conducted by a team led by Dr Jacqueline Suk Danik (Brigham and Women's Hospital, Boston, MA).

They note that Lp(a) is a lipoprotein different from LDL cholesterol because it contains an apoA component, and it has been shown to be associated with an increased incidence of cardiovascular disease. To explore whether this relationship is modified in women who use hormone therapy, they analyzed data from the Women's Health Study, which followed 27 736 apparently healthy women aged 45 years or older, for up to 13 years. They assessed the effect of low-dose aspirin and vitamin E in the primary prevention of heart disease and cancer in this cohort. Of these women, 12 075 indicated the active use of hormone therapy at study initiation.

For the purpose of the current study, the researchers assessed the risk of a first major cardiovascular event (MI, cerebrovascular event, coronary revascularization, or cardiovascular death) over a 10-year period, on the basis of Lp(a) levels and hormone use. Results showed that Lp(a) values were lower among women taking hormones than among women not taking hormones.

High levels of Lp(a) showed a strong relationship with future cardiovascular risk in women not taking hormones, but there was no association between Lp(a) and cardiovascular risk in women taking hormones.

Danik et al said they believe there are at least two explanations for the effect modification seen: it could be attributable to the biologic interaction between plasma Lp(a) levels and concurrent hormone use; or it could be that hormone use is a surrogate variable for a healthy lifestyle, which is not fully captured by the covariates adjusted for, that ameliorates the deleterious relationships between lipid biomarkers and heart disease.

Concerning a possible direct biologic effect, they note that recent data show that estrogen might induce increased uptake of Lp(a) by the LDL receptor; that estrogen might cause a reduction of Lp(a) production by the liver, where Lp(a) production is likely modulated; and that certain cholesterol metabolites might interact directly with hormones in the vasculature.

In an accompanying editorial [2], Drs Lars Berglund and Erdembileg Anuurad (University of California, Davis) explain that Lp(a) has many features in common with LDL but, unlike LDL, its distribution is very skewed, with plasma levels ranging from <0.1 mg/dL to >300 mg/dL; a minority of people have levels >30 mg/dL, which are commonly associated with cardiovascular risk. These factors, along with the difficulty standardizing its measurement, represent challenges in firmly associating Lp(a) with disease, they say.

The editorialists note that Danik et al's results show a nonlinear association between Lp(a) and cardiovascular risk. The fact that increased risk is evident only at the highest Lp(a) quintile suggests that there is a threshold effect in the role of Lp(a) as a risk factor. Further, the interaction observed between Lp(a) and LDL levels indicates that Lp(a) might have more pronounced risk-factor properties in a high-risk environment, they add.

They point out that currently there are no guidelines recommending intervention based on high Lp(a) levels. Although findings from the current study and other studies suggest that Lp(a)-lowering therapy might be beneficial, at least in some subgroups of patients with high Lp(a) levels, details are lacking about how to define such subgroups according to Lp(a) levels, apoA size, and the presence of other risk factors.

They say the current findings "are encouraging because they provide evidence that high Lp(a) levels in a high-risk setting might be appropriate to consider an intensified intervention. However, further studies are needed to firmly assess any possible therapeutic benefits of a reduction of Lp(a) levels."