Marker Signals High Heart Disease Risk in Some Women

BOSTON, Sept. 19 -- Women with high serum levels of lipoprotein(a) are at increased risk for cardiovascular disease, especially if they also have high levels of LDL, investigators here reported.

But lipoprotein(a) is unlikely to be a useful marker for cardiovascular risk in the population at large, because only extremely high levels signal peril, according to Jacqueline Suk Danik, M.D., M.P.H., of Brigham and Women's Hospital and Children's Hospital, and colleagues.

"While the threshold effects seen do not support generalized screening, our data do indicate that lipoprotein(a) may have clinical importance for selected high-risk women," they reported in the Sept. 20 issue of the Journal of the American Medical Association.

Lipoprotein(a) is composed of a single copy of apolipoprotein B-100 linked to an apolipoprotein(a) component. It is structurally similar to plasminogen, and could be a contributor to thrombotic events by inhibiting fibrinolysis, the investigators noted.

"Epidemiological studies of lipoprotein(a) have shown disparate results, leading to controversy about the clinical utility of routinely measuring lipoprotein(a)," they wrote. "Although many studies have shown positive associations, others have shown weak or no associations. Part of this controversy has been due to the poor agreement between lipoprotein(a) levels obtained by different lipoprotein(a) assays in clinical studies."

The authors took advantage of a new lipoprotein(a) assay to evaluate the role of baseline lipoprotein(a) and its possible association with later cardiovascular risk among 27,791 women enrolled in the Women's Health Study, which looked at aspirin and vitamin E for prevention of cancer and heart disease.

They also looked for interactions between lipoprotein(a) levels and LDL, and compared levels of the protein among women with and without a family history of heart disease.

The assay they used measures lipoprotein(a) levels in blood samples independent of apolipoprotein(a) isoform size. The main study outcome was the calculated hazard ratio for a first major cardiovascular event: non-fatal MI, non-fatal cerebrovascular event, coronary revascularization, or cardiovascular death.

There were 899 incident cardiovascular events during the 10 years of follow-up. The authors found that after adjusting for age, smoking, blood pressure, body mass index, total cholesterol, HDL, diabetes, hormone use, C-reactive protein, and randomization treatment groups, women in the highest fifth of lipoprotein(a), (> 44.0 mg/dL) were 1.47 times more likely to develop cardiovascular events than women in the lowest quintile (< 3.4 mg/dL. 95% confidence interval , 1.21-1.79, P for trend <0.001).

Nearly all the association was due to a threshold effect of lipoprotein(a) among women with the highest levels, they found.

Again after adjusting for the previously mentioned variables, the hazard ratios associated with lipoprotein(a) levels above the 90th percentile was 1.66 (95% CI, 1.38-1.99), and in women with levels above the 95th and at the 99th percentile, the risk was nearly two-fold, with hazard ratios of 1.87 (95% CI, 1.50-2.34) and 1.99 (95% CI, 1.32-3.00), respectively. There was almost no risk gradient at lower levels, the investigators noted.

They also found that the association between cardiovascular risk and lipoprotein was significantly elevated among women with LDL levels above the median. In these women. the adjusted hazard ratio associated with lipoprotein(a) levels above the 90th percentile was 1.81 (95% CI, 1.48-2.23). For women with LDL above the 95th percentile the hazard ratio was 1.93 (95% CI, 1.51-2.48), and among those with LDL at the 99th percentile, the hazard ratio was 1.93 (95% CI, 1.21- 3.05). The P value for the interaction of lipoprotein(a) with LDL was 0.001.

Women with high levels of lipoprotein(a) had elevated cardiovascular risk regardless of family history of premature heart disease, the authors found.

"While of pathophysiological interest, we do not believe our data support generalized screening of lipoprotein(a) in the population as a whole because only extremely high levels were associated with cardiovascular risk," Dr. Suk Danik and colleagues wrote.

The only lipid-lowering strategy that appears to reduce lipoprotein(a) levels is high-dose nicotinic acid, which is poorly tolerated and requires close patient monitoring, and there is no evidence to suggest that lowering the levels of the protein would also lower cardiovascular risk, they noted.

"However, aggressive lowering of LDL-C levels has been shown to be important in modifying the excess cardiovascular risk associated with elevated lipoprotein(a) levels, suggesting that when lipoprotein(a) levels are elevated, the primary objective should be to treat elevated LDL-C aggressively either with a statin or with niacin," they wrote.

For this reason, they recommended that determination of lipoprotein(a) levels be reserved for high-risk subsets of the population, such as people who have a premature MI in the absence of other risk factors, or those with special risk factors such as familial hypercholesteremia.