Elevated inflammatory enzyme, Lp-PLA2, significantly linked to ischemic stroke

New ARIC data confirm enzyme’s potential as a target for independent cardiovascular diagnosis and therapy

High levels of an enzyme – lipoprotein-associated phospholipase A2 (Lp-PLA2) – believed to trigger a cascade of inflammatory events in atherosclerosis can independently predict increased risk of stroke, even after accounting for both traditional and novel cardiovascular risk factors, according to a new analysis by investigators from the ongoing Atherosclerosis Risk in Communities (ARIC) study presented at the American Heart Association’s Scientific Sessions 2004.

Middle-aged participants with the highest levels of Lp-PLA2 had a statistically significant doubling of risk of suffering an ischemic stroke over a period of about six years compared to those with the lowest levels of the enzyme after taking age, gender and race into consideration (p <0.001). Even when traditional cardiovascular risk factors such as systolic blood pressure, smoking status and diabetes, and the novel risk marker of systemic inflammation C-reactive protein (CRP) are accounted for, elevated levels of Lp-PLA2 remained associated with a significantly increased stroke risk of almost twofold. “These ARIC findings illustrate that Lp-PLA2 can be an independent and significant warning — above and beyond standard risk factors — identifying individuals with an increased risk of stroke. Lp-PLA2 may prove to be a useful independent diagnostic measure, and ongoing research is evaluating whether Lp-PLA2 is an important therapeutic target to reduce stroke,” said Christie M. Ballantyne, M.D., 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. GlaxoSmithKline (GSK) is actively investigating Lp-PLA2 inhibitors and the role they may play in further reducing the risk of stroke and coronary heart disease. Lp-PLA2 is an enzyme that helps process a form of low-density lipoprotein, or “bad,” cholesterol (LDL-C) into products within atherosclerotic plaques and produces signals within the plaques that promote inflammation. Several studies have documented the strong association of Lp-PLA2 with coronary heart disease and stroke in the general population, regardless of total cholesterol or other markers of inflammation. CRP is another inflammatory protein involved in atherosclerosis that can independently indicate risk of cardiovascular disease. Atherosclerosis, the underlying cause of heart attacks, strokes and peripheral vascular disease, accounts for 50 percent of all deaths in Western countries. Atherosclerosis involves inflammation within the walls of blood vessels, which likely begins in the presence of LDL-C and then involves certain white blood cells and the formation of fatty plaques within the arteries. Despite the use of cholesterol-lowering drugs, such as statins, and other agents, millions of patients remain at risk. Heart disease and stroke kill some 17 million people each year, almost a third of all deaths globally, the World Health Organization (WHO) reports. By 2020, heart disease and stroke will become the leading cause of both death and disability worldwide, accounting for more than 20 million deaths annually, WHO predicts. About the ARIC Stroke Analysis

ARIC participants who had a stroke during a six-year period had, on average, greater plasma levels of Lp-PLA2 at baseline compared to those who did not subsequently experience a stroke [443 micrograms per liter (mg/L) vs. 374 mg/L], when adjusted for sex, race and age. However, their respective LDL-C levels did not significantly differ (136.6 vs. 132.0 milligrams/deciliter). When investigators also statistically accounted for participants’ levels of LDL-C and high-density lipoprotein cholesterol (HDL-C) and CRP, in addition to the other risk factors, participants with Lp-PLA2 levels in the highest third (>422 mg/L) had a significantly higher 1.97 hazard ratio for stroke (95% confidence interval 1.16–3.33; p=0.012) over six years compared with participants with Lp-PLA2 levels in the lowest third (<310 mg/L). The effect of having both elevated Lp-PLA2 and elevated CRP levels was synergistic in predicting stroke risk. Patients with the highest levels of Lp-PLA2 (>422 mg/L) and of CRP (>3 mg/L) had more than an 11-fold increased risk of stroke compared to those with the lowest levels of Lp-PLA2 (<310 mg/L) and CRP (<1 mg/L) (p<0.001). The investigators’ findings are based on a comparison of 194 study participants who experienced a stroke with a cohort random sample that included 766 participants who did not experience a stroke in a case-cohort study design. All of the individuals were part of the more than 15,592 apparently healthy U.S. men and women aged 45 to 64 who enrolled in the ongoing prospective study, which has followed the participants for about six years. Investigators examined stored blood samples to determine the relationship among Lp-PLA2, traditional cardiovascular risk factors and CRP. The ARIC investigators used the PLAC test developed by diaDexus, Inc., to measure Lp-PLA2 concentration. The U.S. Food and Drug Administration cleared the test, which is now available in the United States.