Lipoprotein-Associated Phospholipase A 2 and Risk Stratification for Cardiovascular Disease: Not Ready for “Prime Time”

Abstract

See also page 159 Cardiovascular disease (CVD) was the underlying cause or contributing cause of death in 58% of all deaths in the United States in 2003. Since 1900, CVD has been the No. 1 killer in the United States every year except 1918, when the influenza pandemic took more lives. With CVD being responsible for such staggering mortality, the discovery of a novel risk factor for this disease can surely be considered one of the “holy grails” of medicine. Discovering modifiable risk factors is of prime importance because they may hold the possibility of reducing morbidity and mortality. However, identifying factors that add only to risk stratification are also valuable. Treatment decisions for many important disease states, hyperlipidemia being a prime example, are now based more on baseline risk than on levels of physiologic markers. Fueled by the discovery of inflammatory cells in the cap of atherosclerotic plaques, research has focused on whether markers of inflammation can aid in the prediction of CVD. Many novel markers of CVD, both inflammatory and noninflammatory, have been discovered and studied. A partial list includes C-reactive protein (CRP), lipoproteinassociated phospholipase A 2 (Lp-PLA 2 ), homocysteine, Eselectin, plasminogen, interleukin 6, and vitamin B 6 . In the first systematic review of the topic, Garza et al examined the association between Lp-PLA 2 and CVD. Lipoprotein-associated phospholipase A 2 , also known as platelet-activating factor acetylhydrolase, is an enzyme that circulates bound to low-density lipoproteins, highdensity lipoproteins, and very low-density lipoproteins. The role of Lp-PLA 2 is unclear. Both proatherogenic and antiatherogenic mechanisms have been proposed. Lipoprotein-associated phospholipase A 2 leads to formation of lysophosphatidylcholine, a mediator of inflammation that is proatherogenic. On the other hand, Lp-PLA 2 could be protective by reducing inflammation and the propensity for thrombosis in blood through its hydrolysis of platelet-activating factor. Garza et al are to be commended for their rigorous methodology. They describe a clear and focused question and search strategy, conducted duplicate searching and source abstraction, resolved disagreements by consensus, and defined subgroups a priori. They acknowledge that publication bias may be present but made efforts to limit this by contacting experts in the field in a search for possible unpublished data and by including studies published only in abstract form. Follow-up for some studies in the review was as short as 3 to 4 years, although all studies (except those published in abstract form) were rated highly on the Newcastle-Ottawa Scale, a tool used for quality assessment of cohort and case-control studies. Overall, the systematic review is valid and represents the best available evidence on the subject. To our knowledge, it is the first article to provide a pooled estimate of the association between Lp-PLA 2 and the risk of CVD. Garza et al report an unadjusted odds ratio of 1.51 (95% confidence interval [CI], 1.30-1.75) for the association between elevated Lp-PLA 2 and CVD. When adjusted for traditional CVD risk factors and CRP, the odds ratio was 1.60 (95% CI, 1.36-1.89). Moderate heterogeneity was found across the studies (I=67.4%). Despite this, an association between elevated Lp-PLA 2 and CVD appears to exist.