Causal role for Lipoprotein(a) levels in cardiovascular disease

Lipoprotein(a) (Lp(a)) is a circulating molecule consisting of a low-density lipoprotein (LDL) that is linked to a proteine called apolipoproteine (a). The blood levels are associated with coronary atherosclerosis and myocardial infarction, according to 2 new studies.

In one Dr. Sawabe and colleagues conducted a path analysis on the association of Lp(a) levels with coronary atherosclerosis and MI using 1062 autopsy cases. The complex relationship among genotypes, intermediate phenotypes, and final phenotypes can be analyzed by this approach.

The prevalence of severe coronary stenosis increased linearly from 15.0% at Lp(a) levels below 0.05 g/L to 35.3% at Lp(a) levels of 0.30 g/L or more. Similarly, the prevalence of pathological MI increased from 11.3% below 0.05 g/L to 26.6% for levels of 0.30 g/L and higher.

In multivariate analysis, elevated Lp(a), hypertension, diabetes, and hypercholesterolemia were independent risk factors for severe coronary stenosis, with the greatest risk coming from elevated Lp(a) levels.

The NEJM study looked for more than 2000 gene variants in 7991 subjects with proven coronary disease and in 7946 control subjects and found a very strong association between 3 different mutations and the disease. But the association between the genotype and the risk of coronary disease was abolished after adjustement to the Lp(a) levels. This confirmed that the protein levels alone explained the pathological findings and that there is indeed a causal role for Lp(a) in cardiovascular disease.

These papers suggest that the measurement of serum Lp(a) level is as necessary as those of LDL cholesterol and HDL cholesterol. If the level of Lp(a) is very high, vigorous control of other risk factors is necessary.

Of approved medecines, Niacin is the only agent know to lower effectively Lp(a) levels but no prospective controlled study exists to prove the clinical usefullness. Nevertheless, the findings will refocus research to Lp(a) levels as a potential therapeutic target.

Source :  Heart 2009;95:1997-2002 et New England Journal of Medecine 12/2009.