An epidemiologic reassessment of lipoprotein(a) and atherothrombotic risk

Lipoprotein (a) [Lp(a)] is a unique lipoprotein particle, which appears to play a critical role in both atherogenesis and fibrinolysis. On the basis o f extensive laboratory research, as well as several retrospective case-control studies that demonstrate a positive association between Lp(a) and vascular risk, Lp(a) has often been considered an important atherothrombotic risk factor. However, a controversial series of nine prospective studies evaluating plasma Lp(a) and risk of future myocardial infarction, coronary heart disease, and stroke has provided inconsistent evidence of association. Although some of these studies have been criticized for potential methodologic limitations, the results of four well-designed, large-scale prospective analyses deriving from the Physicians' Health Study, the Lipid Research Clinics Coronary Primary Prevention Trial, the British United Provident Association Study, and the Göttingen Risk Incidence and Prevalence Study still provide apparently conflicting data. What emerges from an epidemiologic overview of these studies is that routine clinical assessment of Lp(a) is likely to have low positive predictive value in terms of screening for atherothrombotic disease, and that any true increase in risk associated with plasma Lp(a) concentration probably is of small absolute magnitude. At the same time, the available epidemiologic data must not be construed to exclude a critical role for Lp(a) in either atherogenesis or fibrinolysis, particularly given the strength of basic science data regarding this unique lipoprotein. Future studies evaluating isoforms and genetic determinants of Lp(a) will therefore be required to address the Lp(a) hypothesis fully.