Philadelphia, PA - A new study in dialysis patients suggests that both low-molecular-weight (LMW) apolipoprotein(a) (ApoA) size and high levels of lipoprotein(a) [Lp(a)] predict the development of atherosclerotic cardiovascular disease (ASCVD), although the association between CVD and the small ApoA isoforms was the strongest relationship of the two.[1]

The report was published as an express article online on March 30, 2005 and will appear in the June 2005 issue of the Journal of the American Society of Nephrology. Lead author on the paper is Dr J Craig Longenecker (Johns Hopkins University, Baltimore, MD), currently associated with Kuwait University in Safat.

"Whether lowering Lp(a) levels is feasible or ultimately reduces ASCVD risk, elevated Lp(a) levels or the presence of LMW ApoA phenotype may be clinically useful in risk stratification and identification of dialysis patients who warrant more aggressive ASCVD prevention efforts," Longenecker et al conclude.

Lp(a) is composed of an LDL particle covalently bonded to ApoA, a glycoprotein with a highly variable number of Kringle-IV (K-IV) units, Longenecker et al write. Lp(a) levels, which are generally increased in dialysis patients, are inversely related to ApoA isoform size, they point out.

Many previous studies in the general population have found that high Lp(a) levels and small ApoA size are associated with atherosclerotic cardiovascular disease, the authors write. The few studies of Lp(a) in patients with end-stage renal disease (ESRD) have yielded conflicting results, and the only prospective study to evaluate both Lp(a) and ApoA size reported that small ApoA, but not Lp(a) level, was associated with increased CVD risk in these patients.

The Choices for Health Outcomes in Caring for ESRD (CHOICE) study is a prospective study of outcomes among 1041 incident dialysis patients. A previous report from these investigators using the CHOICE data had shown that small ApoA size, but not Lp(a) level, were associated with total mortality.[2] In the current report, Longenecker and colleagues used data from the CHOICE cohort to test the hypothesis that small ApoA size but not Lp(a) level would be associated with prospectively ascertained atherosclerotic CVD.

Over a median follow-up of 27.4 months in 833 of these patients for whom both measures were available, there were 297 ASCVD events, including any of a combined end point of MI, coronary revascularization, cerebrovascular accident, carotid endarterectomy, peripheral revascularization, gangrene, or limb amputation.

In multivariate Cox regression models, both high Lp(a) concentration and LMW ApoA isoforms predicted ASCVD events. In models that included both Lp(a) concentration and ApoA size, only ApoA size remained significantly associated with ASCVD events, they note.

Those patients with both high levels of Lp(a) and small ApoA had more than a 70% increase in ASCVD risk, compared with those who had lower levels of Lp(a) and high-molecular-weight ApoA.

No interactions were seen by age, race, gender, diabetes, or ASCVD, they note.

"If the risk of ASCVD related to Lp(a) is mediated by both ApoA isoform size and the attendant Lp(a) level, then Lp(a)-lowering therapy has potential to prevent ASCVD, particularly among those with LMW ApoA isoforms," the authors conclude. Their finding that high Lp(a) levels are associated with a 40% increase in event rates suggests that successfully lowering Lp(a) may lower risk for dialysis patients, they add.

Lp(a) is difficult to reduce, but treatment strategies include niacin, ascorbic acid with L-lysine, estrogen, aspirin, statins, diet, and apheresis. Since all of these also affect other atherogenic lipids, sorting out a beneficial effect of lowering Lp(a) will require carefully designed randomized trials, they point out.