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Houston, TX - The novel inflammatory marker lipoprotein-associated phospholipase A2 (Lp-PLA2) and high-sensitivity C-reactive protein (hs-CRP) were higher in middle-aged men and women who subsequently developed CHD events than in those patients who remained free of CHD, according to an epidemiological Atherosclerosis Risk in the Communities (ARIC) substudy.1
Moreover, investigators found that in individuals with LDL-C <130 mg/dL, Lp-PLA2 and CRP were both significantly and independently associated with CHD, suggesting Lp-PLA2 and CRP may be complementary in identifying individuals at high CHD risk who have low LDL-C.
"The major issue is that a fair number of MIs occur in people with LDL cholesterol levels that are normal," Dr Christie M Ballantyne (Baylor College of Medicine, Houston, TX) told heartwire. "When you look at the guidelines, what we're really talking about is treating patients with LDL cholesterol levels higher than 130 or, depending on the risk status for primary prevention, treating patients with LDL levels above 160. In terms of CHD risk, we need more information in patients who fall below that cutoff."
The results, first presented at the 2003 American College of Cardiology Scientific Sessions and reported by heartwire, are published in the February 24, 2004 issue of Circulation.
ARIC substudy
ARIC was a case-control trial that followed more than 12000 healthy, middle-aged Americans for six years. Ballantyne's group looked at 608 patients who developed CHD and compared them with 741 age-matched controls.
Dividing the patients in the study by tertiles of Lp-PLA2, the investigators found that patients with LDL levels below the study median of 130 mg/dL were nearly twice as likely to have CHD if they were in the second or third tertile of Lp-PLA2 than if they were in the lowest tertile.
CHD hazard ratios by Lp-PLA2 tertiles|
Outcome |
Second tertile Lp-PLA2 (310-422 g/L) (95% CI) |
Third tertile Lp-PLA2 (>422 g/L) (95% CI) |
|
LDL-C<130 mg/dL (without CRP adjustment) | 1.83 (1.11-3.00) | 1.99 (1.17-3.38) |
|
LDL-C<130 mg/dL (with CRP adjustment) | 1.83 (1.10-3.05) | 2.08 (1.20-3.62) |
In individuals with LDL-C <130 mg/dL, high hs-CRP was associated with increased CHD risk. Ballantyne commented to heartwire that the results confirm those seen by Ridker et al in the Nurses' Health Study, where investigators found CRP was a significant predictor of risk for cardiovascular events in healthy women regardless of their LDL cholesterol. The results also support the concept for the upcoming JUPITER study, a trial that will look at treating high-CRP/low-LDL patients with rosuvastatin, he said.
Finally, the investigators also found that those patients with low LDL-C and high Lp-PLA2 and CRP levels were at the greatest risk of a CHD event.
"The two markers do not correlate with each other and together provided an even better way of identifying patients with low LDL levels who would be at an increased risk for CHD," said Ballantyne.
Association of Lp-PLA2 and hs-CRP with incident CHD|
Outcome |
Low-medium Lp-PLA2 (<422 g/L) |
High Lp-PLA2 (>422 g/L) |
|
High hs-CRP (>3.0 mg/L) | 1.14 | 2.95 |
|
Low-medium hs-CRP (<3.0 mg /L) | 1.00 | 0.99 |
Ballantyne said the findings have the potential to alter practice, moving patients from a low-risk classification to higher risk of CHD. "We do know that if you can identify high-risk patients they seem to respond to interventions," he said.
Ballantyne also noted that GlaxoSmithKline has developed an Lp-PLA2 inhibitor that will enter phase 3 clinical trials soon.
In 2003, the FDA granted market clearance to diaDexus Inc for an Lp-PLA2 test for CHD. The test, called PLACTM, is marketed as a way to identify patients at risk who do not have elevated LDL levels.
