New study shows elevation in enzyme tied to higher cardiovascular risk

Main Category: Cardiovascular / Cardiology
Article Date: 01 Sep 2004 - 11:00 PST


New results from the Rotterdam Study presented at the ESC Congress 2004 validate the growing body of evidence demonstrating a critical link between an enzyme implicated in atherosclerosis - lipoproteinassociated phospholipase A2 (Lp-PLA2) - and both heart disease and stroke.

The results, presented by Albert Hofman, MD, PhD, Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, showed that Lp-PLA2 activity is strongly associated with coronary heart disease and stroke in the general population, regardless of total cholesterol or other markers of inflammation.i

The Rotterdam Study is a population-based, follow-up study of 7,983 subjects ages 55 years and older. Lp-PLA2 activity was determined in a random sample of 1,822 subjects of the Rotterdam Study and in additional coronary heart disease and stroke cases. There were 377 coronary heart disease cases and 110 ischemic stroke cases.ii The results reinforced additional recent findings discussed in the ESC Symposium Inflammation and Atherosclerosis: From Theory to Therapy on Tuesday, August 31 at 4:30 p.m. to 6:30 p.m., CET.

When participants in the Rotterdam study were ranked according to their Lp-PLA2 levels and categorized into four groups of equal size (quartiles) at the beginning of the follow-up period, the risk of coronary heart disease during six years of follow-up in the group with the highest levels of Lp-PLA2 (the highest quartile) was 77% higher than the risk for participants with the lowest levels (lowest quartile).

For stroke, participants with the highest Lp-PLA2 levels were 76% more likely to have a stroke compared to participants with the lowest levels of Lp-PLA2.iii For coronary heart disease as well as stroke, the increased risk of an event during follow-up due to having high levels of Lp-PLA2 remained important even after taking other risk factors into consideration, including age, gender, body mass index, smoking, high blood pressure, total cholesterol, high-density-lipoprotein (HDL, or "good" cholesterol), cholesterol-lowering medications and white cell count, further implicating the independent role of Lp-PLA2 as a novel risk factor for cardiovascular disease.iv

The association between Lp-PLA2 and coronary heart disease was present over the entire range of non-HDL cholesterol levels.v The association between Lp-PLA2 activity and stroke suggests that Lp-PLA2, although carried by low-density-lipoprotein (LDL, or "bad" cholesterol), may convey a different risk.vi

"The Rotterdam Study is consistent with the recent findings of the Atherosclerosis Risk in Communities (ARIC) cohort and adds to the increasing weight of scientific evidence demonstrating that elevated levels of Lp-PLA2 are significantly associated with an increased risk of stroke," vii said Jim Shepherd, MD, Glasgow University, and co-chair of the Symposium.

ARIC stroke findings were reported earlier this year at the 5th Annual Conference on Atherosclerosis, Thrombosis and Vascular Biology (ATVB), held in May 2004. The study found that the risk of stroke for individuals with the highest levels of the Lp-PLA2 enzyme was double that for individuals with the lowest levels.viii

"As more is learned about this important association, it should enable clinicians to more accurately predict cardiovascular risk," added Christie M. Ballantyne, MD, director of the Center for Cardiovascular Disease Prevention at Baylor College of Medicine and the Methodist DeBakey Heart Center, Houston, and a lead investigator of ARIC.

Atherosclerosis, which develops as fatty plaques within arterial walls, underlies both heart attack and stroke. The role of inflammation in atherosclerosis has become well established over the past decade.ix

The growing body of evidence indicates that Lp-PLA2 promotes inflammation in atherosclerotic plaque by acting on oxidized LDL, releasing pro-inflammatory substances.x

"Inflammation clearly plays a role in risk of heart disease and stroke.xi The Rotterdam data reinforce findings of additional recent research into this area, including ARIC and MONItoring of trends and determinants in CArdiovascular disease (MONICA) Men's Study, which showed that elevated Lp-PLA2 is an independent marker for heart disease and appeared to be predictive of future coronary events,"xii said Christopher Cannon, MD, Boston University, co-chair of the Symposium.

The MONICA Men's Study evaluated the relationship between epidemiology and cardiovascular events among apparently health male subjects ages 45-64 from the World Health Organization (WHO) MONICA-Augsburg survey of 1984/85. The results of MONICA Men, presented at ESC Congress 2003, showed that elevated levels of Lp-PLA2 was independently associated with risk for future coronary events in apparently healthy middle-aged men with moderately elevated total cholesterol, independent of C-reactive protein (CRP).xiii

GlaxoSmithKline is actively investigating Lp-PLA2 inhibitors and the role they may play in further reducing the risk of cardiovascular disease. Cardiovascular disease is one of the leading causes of deathxiv and disability around the world.xv Atherosclerosis, which is now recognized to be an inflammatory disease, is the underlying process in the great majority of heart attacks and strokes, and, despite the use of cholesterol-lowering drugs (for example, statins), and other agents, millions of patients remain at risk. diaDexus, Inc., has developed the PLAC™ test for Lp-PLA2.

This test has been cleared by the U.S. Food and Drug Administration (FDA) and is now available in the United States.

The Symposium and Rotterdam Study were funded by unrestricted grants from GlaxoSmithKline.

About GlaxoSmithKline

GlaxoSmithKline - one of the world's leading research-based pharmaceutical and healthcare companies - is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For company information visit www.gsk.com.

About diaDexus

diaDexus, Inc., a privately held biotechnology company, based in San Francisco, CA, is focused on the discovery, development and commercialization of novel, patent-protected diagnostic and therapeutic products with high clinical value. More information about the company and the PLAC Test may be found at www.diaDexus.com and www.plactest.com.

For inquiries regarding the Rotterdam or ARIC* study and other GSK activities, please contact:

GlaxoSmithKline Rick Koenig (610) 270-5546

For inquiries regarding the MONICA Study* or other information on diaDexus, please contact: diaDexus Sharon Tetlow (650) 246-6403

* Lp-PLA2 mass in the MONICA and ARIC Studies was measured using the PLAC™ test by diaDexus.

References

i ESC Conference 2004, abstract no. 1376, Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: The Rotterdam
Study.

ii Ibid.

iii Ibid.

iv Ibid.

v Ibid.

vi Ibid.

vii Ballantyne C et al, Lipoprotein-associated phospholipase A2, high-sensitivity c-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the atherosclerosis risk in communities (ARIC) study. Circulation. 2004;109:837-842.

viii Arterioscler Thromb Vasc Biol, 2004, 24:e51 - e136, abstract no.P441: E-127.

ix Packard CJ et al, Lipoprotein-associated phospholipase A2, as an independent predictor of coronary heart disease. N Engl J Med 2000; 343:1148-55.

x Ibid.

xi Packard, 1148.

xii Koenig et al, Lipoprotein-associated phospholipase A2 adds to risk prediction of incident coronary events by C-reactive protein in apparently healthy middle-aged men with moderately elevated total cholesterol from the general population; 2 (manuscript).

xiii Ibid. xiv World Heart Federation. "Myths and Facts," http://www.worldheart.org/call-to-action mythsfacts.

php.

xv Ibid. "CVD Facts and Risk Factors," http://www.worldheart.org/call-to-action-cvd.php

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