Image by Gerd Altmann from Pixabay

Historically, cholesterol esters (total cholesterol, LDL, HDL, and triglycerides) have been considered the gold standard for cardiovascular screening, and suppressed for cardiovascular prevention. I’ve been pretty thoroughly convinced that these are not the cause of cardiovascular disease at all. At best, they might correlate with overall risk as part of the metabolic syndrome picture, as one marker among many. Even this isn’t true for everyone, though; sometimes high cholesterol esters are simply genetic, and have no bearing on heart disease risk at all. 

If that’s the case, what should we be testing instead, to evaluate heart disease risk? One is certainly lipoprotein(a), though strategies to lower it have been somewhat elusive, and delivered mixed results at best. Another is hsCRP, though that’s just a sensitive measure of inflammation and isn’t necessarily cardiovascular-specific. (Labs will sometimes call it cardiac CRP, but this is a misnomer). Another is oxidized LDL—more on this below. 

But one very promising marker is Lp-PLA2. 

Lipoprotein-associated Phospholipase A(2) (Lp-PLA2)

Lipoprotein-associated Phospholipase A(2), or Lp-PLA2, has one other name in the literature (which I mention to avoid confusion for those who might follow the study links: it’s platelet-activating factor acetylhydrolase). It’s an enzyme bound to lipoproteins, which are the proteins that are attached to lipids, like cholesterol.

Enzymes are like molecular scissors—their job is to break down their target substance. The target substance for Lp-PLA2 is the phospholipids (the outer portion) of cholesterol esters, and primarily LDL. Even though LDL itself doesn’t appear to cause heart disease, LDL can become problematic once it’s oxidized, leading to vascular damage, which can initiate clot formation. This is when Lp-PLA2 gets activated: it specifically dismantles these oxidized phospholipids.

So is high Lp-PLA2 good or bad, since it’s breaking down a bad thing? Well… there are studies on both sides. Personally, I wonder if this isn’t more of a correlation than a causation issue. 

Lp-PLA2’s Role In Heart Disease

When Lp-PLA2 breaks down the phospholipids of cholesterol esters, the results are called lysoPCs, which in petri dish studies are shown to be inflammatory. 

We generally think of inflammation as bad—and it certainly can be, though it isn’t always. My suspicion is that this process is perhaps analogous to the first phase of liver detoxification: initially, a substance is rendered more toxic than it was before, but it’s also prepped for Phase 2, which allows easy elimination from the body. The toxic intermediate is only a problem if the liver is overwhelmed with too many things to detoxify at once, and/or if there’s a mismatch between the speeds of Phase 1 and Phase 2, such that there’s a bottleneck and the toxic intermediates can’t get out fast enough. 

Likewise, studies seem to show that lysoPCs, while inflammatory (and bad) in high doses, can actually serve a positive benefit in lower doses, sending feedback mechanisms by which the body can respond to a problem. (This is another example of hormesis, in which the dose makes the poison.)

Many studies do seem quite clear that high Lp-PLA2 is correlated with increased cardiovascular risk, and the higher it is, the worse the risk becomes. 

You might think, if you believe that cholesterol esters like LDL cause heart disease, that the two simply move together: the higher the LDL, the higher the Lp-PLA2, and the higher the heart disease risk. But, this review shows that this isn’t true: high Lp-PLA2 is apparently an independent risk factor for heart disease, separate from all other known or speculated triggers. That said, individuals who have both metabolic syndrome and high Lp-PLA2 are potentially at the highest risk of all, compared to those with only one or the other. 

And yet, there’s another side to the story. 

Is High Lp-PLA2 A Feedback Response to High Oxidized LDL?

While all the various cholesterol esters (LDL, HDL, and even Lp(a)) carry some Lp-PLA2, the bulk of it is associated with LDL. Then again (and this is just my speculation): is it mostly LDL, or is it mostly Lp(a), since the two are identical except for an apolipoprotein a on top of the latter? (How hard are these researchers looking for apo(a) to exclude that possibility?)

The reason this might be relevant is because, as mentioned above with lysoPCs, not all Lp-PLA2 appears to be “bad”—it seems to depend upon which cholesterol ester it’s associated with. The Lp-PLA2 on HDL seems to be protective against cardiovascular disease. Also, it seems that most oxidized phospholipids associate with Lp(a), and thus, are degraded by the Lp-PLA2 on Lp(a). 

We already knew that high Lp(a) is much more associated with cardiovascular disease than LDL and total cholesterol ever was. Since oxidized phospholipids themselves can initiate damage to the blood vessel lining, leading to clotting, I wonder if (independent of genetics), Lp(a) increases as oxidized LDL increases, in response to the problem—if this is yet another feedback mechanism. We do know that the two levels are correlated, for whatever reason. 

The Upshot

There are a couple of potential takeaways here. The first is that it does appear that high Lp-PLA2 levels are a clear independent marker for heart disease. It’s worth checking for that reason, in conjunction with Lp(a). Treating the cause of high Lp-PLA2 may be a more effective way to lower Lp(a) too, if there really is a causal relationship between them (which is unknown at this point, but it makes sense to me). 

The second takeaway is that high Lp-PLA2 may also be a surrogate marker for oxidation of all various cholesterol esters, including but not limited to oxLDL. If this is the case, it suggests that the best way to lower it might be via antioxidants. These, too, have a hormetic function in the body, so more antioxidants isn’t always better—but measuring Lp-PLA2 may be a way to track whether or not antioxidant support is having a measurable impact on heart disease risk.