A New Marker for Heart Disease

Most people know that high levels of cholesterol and high blood pressure pose an added risk for heart attack and stroke. Mounting evidence suggests chronic inflammation also increases the risk of both these diseases and possibly to Alzheimer's and cancer as well. A recent study in the British Medical Journal Lancet* provides a strong link between the levels in the blood of a protein that contributes to inflammation and the risk of heart attack and stroke.

The protein is called, Lp-PLA2, an abbreviation that stands for Lipoprotein-associated phospholipase A2.

Lp-PLA2 is produced by inflammatory cells in plaques that build up in arteries. These plaques can clog arteries. Heart attacks and strokes occur when these plaques rupture. The Lp-PLA2 protein acts on fats in the plaque and blood to create substances that cause inflammation. Lp-PLA2 rides though the bloodstream attached to the exact type of cholesterol  known to be a predictor of risk for cardiovascular diseases.

The current study, performed by a group in Cambridge England, gathered data from thirty-two independent studies that measured the association between the level of Lp-PLA2 and disease. Data was collected from over 79,000 people, about half with no history of vascular disease. Others in the study had a previous history of heart disease or stroke. The participants included both men and women from Europe and the United States. The average age at the beginning of the study was about 65. People were followed on average for seven years.

The results are clear. The higher the level of Lp-PLA2, the greater the risk of heart attack and stroke. The risk increases steeply with increasing levels of the protein in both men and women, both in those with a previous history of heart disease and stroke and those without.

High blood pressure and high cholesterol levels, both known to be predictors of heart disease and stroke, were also measured. The study shows that high levels of Lp-PLA2 pose just as great a risk as does either high blood pressure or high cholesterol levels. The level of Lp-Pla2 is a clear predictor of vascular disease, at least in the population studied.

This work confirms and extends a series of earlier studies (referenced in the Lancet article) that link the inflammatory protein Lp-Pla2 to heart disease.

GlaxoSmithKline is developing a drug that inhibits the function of this protein. The drug is called darapladip and is currently being tested in two clinical trials on 27,000 people worldwide. The results should be available in two to four years. If successful, this drug may offer an entirely new way to prevent heart attacks, stroke and other vascular diseases.

Genomics contributed early on to this progress.

In 1993, Human Genome Sciences formed an alliance with Smith Klein Beecham to search for new drug targets. I was the Chief Executive Officer of Human Genome Sciences at the time. Scientists at Smith Klein Beecham suspected that Lp-PLA2 played a role in vascular disease, but were only able to isolate minute amounts of the protein -- too little for definitive studies.  They knew that if they could isolate the gene that specified the protein, they could make unlimited amounts to test their ideas. Despite years of trying, they were unsuccessful.

The situation changed dramatically as soon as we began to share data. Amongst the many genes we had already isolated and characterized was the one for the Lp-PLA-2 protein. That discovery, 17 years ago, was one of the first successes of the new genomic methods and the beginning of the work that has culminated in our new understanding of vascular disease described in Lancet. With luck, it will also mark the beginning of a new era in genomic medicine and the discovery of drugs that prevent and treat the major diseases of humankind.

*The Lancet: The Lp-PLA2 Studies Collaboration;  Volume 375, Issue 9725, pages 1536-1544.