Phospholipase A2:
Emerging marker of heart attack risk . . .
or drug company scam?
In an effort to better understand why
some people continue to have heart attacks despite favorable cholesterol
values, the world of phospholipids is being explored as a source of
risk. Drug companies have pursued it as a marker to justify intensified
need for statin drugs.
Are phospholipids the miracle marker some claim,
or is it just a ploy for expanding the statin market for drug
manufacturers?
.
Lipoprotein phopholipase A2, it even sounds exotic. Why
has it been making the news recently? Is it an exciting new development
that justifies this much attention?
Scientific basis
The basic concept of phopholipase A2 is based on solid experimental
observations. Phospholipase A2 is one member of an entire family of
molecules that react with phospholipids, compounds that have a
phosphorus group attached to a lipid backbone. It is more properly
called lipoprotein-associated phospholipase A2, or PLA2, since it
usually “rides” on a lipoprotein particle, particularly LDL cholesterol
particles. (We’ll call it PLA2, for short.)
PLA2 is secreted by inflammatory cells (monocytes and macrophages, T
cells, mast cells) and acts as an enzyme that seizes phospholipids and
generates the molecules, lysophosphatidylcholine and oxidized fatty
acids, both of which have inflammation-increasing properties. PLA2 also
helps generate factors (like lysophosphatidic acid) that trigger
platelet activation, leading to blood clot formation (Spector AA 2003).
Greater levels of PLA2 would therefore be expected to increase
inflammatory activity, and perhaps increase unstable atherosclerotic
plaque behavior that results in heart attack. However, PLA2 also reacts
with platelet-activating factor and others that might also reduce
inflammation, and doubt therefore remains over whether PLA2 is good or
bad in humans.
PLA2 is associated primarily with LDL, and its enzyme activity increases
when residing on the dreaded small, dense LDL. Among the most avid of
PLA2 carriers is lipoprotein(a), with 7-fold greater PLA2 content
compared to LDL particles (Blencowe C et al 1995). PLA2 has also been
found to be concentrated specifically in inflammatory macrophages cells
in plaque and in atherosclerotic plaques that are rupture-prone
(“vulnerable”) or have ruptured (Kolodgie FD et al 2006). Interestingly,
PLA2 was nearly absent in early plaques.
What’s the human experience?
The momentum for PLA2 really took off
with the release of the West of Scotland Coronary Prevention Study
reported in 2000, in which 580 participants with established coronary
disease (heart attacks, major procedures) were shown to have higher PLA2
levels than people without heart disease (Packard CJ et al 2000).
Participants with the highest levels of PLA2 had twice the likelihood of
heart attack and other cardiovascular events as those with the lowest
levels. Interestingly, measures of C-reactive protein (CRP), another
measure of hidden inflammatory responses, performed nearly as well in
predicting events. In addition, it was observed that the higher the LDL
cholesterol, the higher PLA2 tended to be.
Similarly, in the ARIC Trial, PLA2 and CRP levels were higher in the 608
participants with heart disease than the 740 people without (Ballantyne
CM et al 2004). Interestingly, in this trial, CRP outperformed PLA2 in
predicting heart disease (risk of 2.53 vs. 1.78), though they appeared
to do so independently of each other.
A recently reported experience in 2700 participants showed a 56%
increased likelihood of heart attack in people with the highest levels
of PLA2. Interestingly, the subgroup of people with both the highest
PLA2 and CRP had nearly a three-fold increase in heart attack risk (Mallat
Z et al 2007).
The report from the Women’s Health Study suggests that, while the above
studies principally of men suggest an association, women may not be as
susceptible (Blake GJ et al 2001). The women experiencing heart attack
and other events had modestly higher PLA2 levels compared to women
without such events, but the association dissolved once LDL cholesterol
was factored in. In other words, PLA2 offered no predictive advantage
over that provided by LDL cholesterol (which, in the Track Your Plaque
program, we know is limited to begin with). CRP, however, did prove to
be predictive at the highest levels.
Not all studies agree that PLA2 adds to risk independent of other
factors. A Swedish compilation of experiences in 2700 individuals showed
that, while PLA2 was higher in people with heart attack, it provided no
additional information when LDL cholesterol was known (Oldgren J et al
2007).
PLA2, heart scans, and other curiosities
Higher CT heart scan scores appear to be associated with increased PLA2,
according to the Rotterdam Coronary Calcification Study. 520
participants had both PLA2 and EBT heart scans; the highest levels of
PLA2 heightened the likelihood of a heart scan score >1000 by 60%.
However, once LDL cholesterol was taken into account, the association
lost all its power (Kardys I et al 2007).
There’s some other interesting aspects to the PLA2 story, including:
- Women experience an increase in PLA2 through the menopause, along with increasing tendency to show small LDL. This might, at least in part, explain the heightened risk for heart disease women experience through this period (Muzzio ML et al 2007).
- Higher PLA2 levels are associated with greater degrees of coronary endothelial dysfunction, i.e., abnormal constriction, a harbinger of coronary plaque, according to a Mayo Clinic study (Yang EH et al 2006).
- People with metabolic syndrome have higher levels of PLA2. A
University of Texas study showed that PLA2 levels in people with
metabolic syndrome averaged levels of 268 ng/ml, compared to 127 ng/ml
in those without (Noto H et al 2006.)
Therapeutic trials
Statin drugs
reduce PLA2, though to varying degrees. Pravastatin (Pravachol®) has
been shown to reduce PLA2 7—20%, simvastatin (Zocor®) 9%, atorvastatin (Lipitor®)
the most at 26% (Schaefer EJ et al 2005).
The DIACOR (Diabetes and Combined Lipid Therapy Regimen) Study of 300
people with diabetes and combinations of low HDL, high LDL, and high
triglycerides examined use of simvastatin (Zocor®) and fenofibrate (Tricor®).
A 17% reduction was seen with either treatment alone, with no additional
PLA2-reducing effect of the combination (Muhlestein JB et al 2006).
Beyond statin drugs, niacin has been shown to reduce PLA2 in a small
trial, with a 20% reduction using 1000 mg per day niacin (Kuvin JT et al
2006).
Drugs that have no lipid (cholesterol) effects, such as blood pressure
medications, seem to exert no reducing effect on PLA2 (Tambaki AP et al
2004).
Zig-zagging to the truth
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