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Back To Vidyya New England Journal of Medicine Study Finds Potential New Risk Factor for Heart Attack

Enzyme That Travels With LDL (Low-Density Lipoprotein) Will Be A Novel Drug Target

According to a report in the current issue of The New England Journal of Medicine, an enzyme that courses through the blood in tandem with LDL (low-density lipoprotein), the carrier molecule containing "bad cholesterol," appears to play its own direct role in heart attacks.(1)

The study reported in the Journal, which was led by investigators at Glasgow University, indicates that the enzyme, called Lp-PLA2 (lipoprotein-associated phospholipase A2), may serve as a significant new marker, independent of LDL, to predict the risk of heart attack. The study thus also suggests the potential importance of Lp-PLA2 as a novel target for therapy to prevent heart attack, therapy that would be based on a rationale different from reducing cholesterol.

"Lp-PLA2 emerges from this study as a new focus for efforts to better identify and manage patients at risk of heart attack, still a leading killer in industrialized societies despite the benefit of cholesterol-lowering therapy," said Dr. Chris Packard, professor of pathological biochemistry at Glasgow and the first author on the report. "Not everyone who suffers a heart attack is found to have above-normal cholesterol levels. So it is important that we examine other potential factors like Lp-PLA2 if we are to continue to reduce the toll of heart disease."

Also contributing to the study in the Journal were scientists at SmithKline Beecham (SB) and diaDexus, Inc.

Lp-PLA2 and bad cholesterol

The cascade of cellular and biochemical events in which Lp-PLA2 participates is long and complex. Lp-PLA2 in the bloodstream is usually bound to LDL, though blood levels of Lp-PLA2 may vary among individuals with equivalent LDL levels.

Once Lp-PLA2 has entered the walls of certain arteries, including the coronary arteries which nourish the heart, its association with LDL continues, sometimes with pathological results. As LDL undergoes a change called oxidation, Lp-PLA2 breaks down the fats in LDL, producing substances that attract inflammatory cells.(2) These cells go on to engulf LDL and so contribute to the formation of atherosclerotic plaques, the thickenings in the arterial wall which grow with the accumulation of cells, fats, and other materials. Growth and rupture of these plaques can lead to blood clotting, blockage of the coronary arteries, heart attack, and death.

Study design and results

Given the inferred role of Lp-PLA2 in atherosclerosis, the study reported in the Journal asked whether a prospective epidemiological investigation would demonstrate that blood levels of the enzyme do in fact correlate with heart attacks and other adverse events related to atherosclerosis. The finding relied upon blood samples collected during the West of Scotland Coronary Prevention Study, an earlier, landmark investigation in the cardiovascular field.(3)

The Lp-PLA2 study examined the cases of 580 men who had suffered adverse coronary events, specifically, either heart attacks, often fatal heart attacks, or procedures performed to prevent heart attacks, namely, angioplasty or coronary-artery-bypass surgery. These cases were compared with those of 1,160 other men who had not suffered adverse events. The comparison was controlled for age and smoking status. All the men had above-normal cholesterol levels.

Examining five ranges of Lp-PLA2 levels, the study found a strong correlation between Lp-PLA2 and adverse events.(4) The risk of an adverse event was about two times greater in the highest range than in the lowest range.(5) Under the most rigorous statistical analysis done in the study, Lp-PLA2 was shown to be a strong risk factor independent of LDL and other markers of inflammation. The risk associated with Lp-PLA2 was observed whether the men studied went on to take pravastatin, a member of the "statins" class of cholesterol-lowering drugs, or placebo - further evidence that lowering Lp-PLA2 levels may offer benefit independently of lowering cholesterol.

"As we continue to study the pathology underlying heart attack, we are confirming the widely known risk factors but discovering new ones as well," Dr. Packard said. "The principal finding of this study is the potential importance of Lp-PLA2. Although our finding must be confirmed in other populations, it points toward a promising new avenue of research aimed at lowering the toll of cardiovascular disease."

Continuing research

Other research concentrating on Lp-PLA2 is under way. SB scientists postulated a role for Lp-PLA2 in atherosclerosis in the early 1990s. Use of a gene-sequence database then enabled the SB team to clone the gene encoding production of Lp-PLA2 for further study. Laboratory studies have since demonstrated that Lp-PLA2 generates inflammatory substances,(2) and that inhibition of Lp-PLA2 reduces atherosclerosis in an animal model.(6) Currently, drug candidates are being progressed toward initial safety trials in human subjects. The assay used in the study was developed by diaDexus.

(1) Packard CJ, O'Reilly DSJ, Caslake MJ, et al. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. N Eng J Med 2000; 343:1148-55.

(2) Macphee CH, Moores KE, Boyd HF et al. Lipoprotein-associated phospholipase A2, platelet activating factor acetylhydrolase, generates two bioactive products during the oxidation of low density lipoprotein. Use of a novel inhibitor. Biochem J 1999; 338:479-87. (The bioactive, inflammatory products are free oxidized fatty acid and lysophosphatidylcholine [lysolecithin].)

(3) Shepherd J, Cobbe SM, Ford I et al, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolaemia. N Engl J Med 1995; 333:1301-7.

(4) In a univariate analysis, p<0.001; in a multivariate analysis, p=0.005.

(5) The quintile ranges were as follows, in mg/l: <1.80, 1.81-2.07, 2.08-2.36, 2.37-2.72, >2.72.

(6) G.M. Benson, D. Grimsditch, K. Milliner, K. Moores, H. Boyd, D. Tew, D. Hickey, R. Ife, K. Suckling, C. Macphee, Anti-atherosclerotic effect of SB-244323, a lipoprotein associated phospholipase A2 inhibitor, in WHHL rabbits. XIIth International Symposium on Atherosclerosis, Stockholm, Sweden, June 25-29, 2000.


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