由巨噬细胞产生的脂蛋白磷脂酶A2（Lp-PLA2）的主要作用是：催化OX-LDL产生的各种致炎因子，Lp-PLA2水平升高已经被明确为与CRP同样重要的心血管事件独立危险因子。目前由FDA批准的PLAC检测技术现已经用于临床检测Lp-PLA2水平。
Inflammatory Enzymes in Cardiovascular Disease: A Focus on Lp-PLA2
Program
Introduction to Cardiovascular Disease
Atherosclerosis – An Inflammatory Disorder
Markers of Inflammation
Epidemiological Studies linking Lp-PLA2 with CHD
The Role of Lp-PLA2 in Screening and Managing Patients with CHD
Cardiovascular Diseases Many advances, but far from conquered
Cardiovascular diseases are the prime cause of mortality in the United States and around the world
Mortality from CV disease is greater than that of the next 7 causes of death combined
Cost to society: over $130 billion dollars in 2003
Will continue to be an even greater concern due to an:
Explosive increase in obesity, diabetes, hypertension and atherosclerotic vascular disease
Aging population - 40 million Americans will be over 65 in 2010 - with associated disease consequences
Heart Disease & Stroke Statistics – 2004 Update, AHA; NHANES III (1988-1994); ARIC, NHLBI (1987-1994)
The Importance of Coronary Heart Disease
Coronary Heart Disease (CHD) is the leading cause of death in men and women in the United States and much of the western world
Over 500,000 deaths, or more than 1 of every 5 deaths, in the United States in 2000
Incidence: Over 1 million MI cases each year, up to 44% result in death
Prevalence: Over 12 million cases of angina
Broad range of ages
Men and women
All socioeconomic sectors
Major social and economic consequences
Heart Disease and Stroke Statistics – 2004 Update
Unmet Need
In spite of major advances made in the screening, detection, and management of heart disease, a major need exists for more ways to predict CV risk
Approximately 50% of individuals diagnosed with coronary artery disease do not have high blood cholesterol levels
Therefore, other factors must be involved
50% of CHD Occurs in People With Below Average TC
Adapted from Castelli W. Atherosclerosis 1996;124(suppl):S1-S9.
Framingham Heart Study—26-Year Follow-up
150
200
No CHD
Total Cholesterol (mg/dL)
250
300
CHD
Atherosclerotic Plaque Development
Libby P. Atlas of Heart Diseases: Atherosclerosis: Risk Factors and Treatment. Edited by Peter W.F. Wilson. 2003. (with permission)
Role of Inflammatory Cells in Atherosclerosis and Plaque Vulnerability
Adapted from: Libby P. Sci Amer 2001;May:47-55.
Atherosclerosis is a progressive inflammatory disease that develops over many years
Inflammation has been shown to have a direct effect on plaque formation and plaque rupture
Inflammatory markers may help predict cardiovascular risk
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a novel inflammatory marker
Inflammation and CHD Risk
Identifying patients at risk – need better ways to identify patients at risk
Need new markers specific for CHD
Drug therapy – despite adequate therapy, many patients go on to experience CV events
New treatments need to target factors other than LDL
New treatments need to target factors that specifically link to disease mechanism
Limitations of the Current Approach to CHD
Rader D. N Engl J Med 2000;343:1179-1182.
Markers of Inflammation and Myocardial Damage
Lipoprotein-associated phospholipase A2 (Lp-PLA2)
50 kDa, Ca-independent lipase
Produced predominantly by macrophages
Upregulated in atherosclerosis
Plays a role in LDL oxidation
Not responsive to IL-1, IL-6, TNF-?
Specific marker for CHD
Secretory phospholipase A2 (sPLA2)
14 kDa, Ca-dependent lipase
Produced by arterial wall SMC and macrophages
Increased by cytokines IL-1, IL-6, TNF-?
Less specific marker
Lp-PLA2 and sPLA2
Lp-PLA2 and Atherosclerosis
Lp-PLA2 resides mainly on LDL in human plasma
Lp-PLA2 is highly up-regulated in atherosclerotic plaques
Lp-PLA2 is responsible for generating two pro-inflammatory mediators during oxidation of LDL:
Lysophosphatidylcholine (lyso-PC)
Oxidized fatty acid (oxFA)
Lp-PLA2 may be the “missing link” between circulating LDL and plaque formation
Phosphatidylcholine (PC)
Oxidatively-Modified PC
Lysophosphatidylcholine (Lyso-PC)
Oxidized Fatty Acid (oxFA)
Oxidation
Lp-phospholipase A2
The LDL Oxidation Process
+
Tselepis AD, Chapman MJ. Athero Suppl 2002;3:57-68.
Pro-Atherogenic Activities of Lysophosphatidylcholine (Lyso-PC)
Lyso-PC
promotes endothelial cell dysfunction, upregulates adhesion molecules
stimulates macrophage proliferation
is a T-cell and monocyte chemoattractant
upregulates cytokine & CD40 ligand expression
is cytotoxic to smooth muscle cells
Lp-PLA2 and CRP: Independent and Distinct Inflammatory Markers
Biovariability of Lipid and Inflammation Parameters
Data on file; diaDexus, Inc.
Epidemiological Studies
Studies that have shown a relationship between Lp-PLA2 and CHD include three that studied data from:
WOSCOPS - West of Scotland Coronary Prevention Study
ARIC - Atherosclerosis Risk in Communities
West of Scotland Coronary Prevention Study (WOSCOPS)
Original Study Design
Randomized, double-blind, placebo-controlled trial
6595 men, aged 45 to 65
Hypercholesterolemic (range 174-232 mg/dL or 4.5-6.0 mM)
Primary prevention study
Mean follow-up of 5 years
Study Results
Treatment with pravastatin reduced risk of first-ever MI (by 31%) and death (by 22%)
Shepherd J, Cobbe SM, Ford I, et al. N Engl J Med 1995;333:1301-1307.
WOSCOPS: Inflammatory Markers as Predictors of Coronary Events
Case-Control Study Design
580 patients included: had either an MI or death as first event (503), and the remainder had revascularization as a first event (77)
1160 controls matched (2:1) based on age and smoking status
Lp-PLA2, CRP, WBC and fibrinogen measured on plasma samples taken at third screening visit and kept at -70oC
Packard CJ, O‘Reilly DSJ, Caslake MJ, et al. N Engl J Med 2000;343:1148-1155.
WOSCOPS Study Conclusions
A statistically significant association (p = 0.0003) between elevated Lp-PLA2 levels and the risk of a first coronary event was demonstrated by multivariate analysis
Men with Lp-PLA2 in the 5th quintile had double the risk of a coronary event attack compared to men with LpPLA2 levels in the 1st quintile (Relative risk of 1 SD increase = 1.20, 95% CI 1.08-1.34, p=0.0008)
Lp-PLA2 was the strongest predictor / biomarker of an adverse outcome, and was independent of traditional and emerging risk factors, including CRP (Relative risk of 1 SD increase = 1.18, 95% CI 1.05-1.33, p=0.005)
Packard CJ, O‘Reilly DSJ, Caslake MJ, et al. N Engl J Med 2000;343:1148-1155.
ARIC Study (Atherosclerosis Risk in Communities)
Study under NIH sponsorship
Four US communities (MD, MN, MS, NC)
Relevant population (ages 45-64)
African-American / Caucasian
Men / women
16,000 participants
>200 peer-reviewed publications
Tertile
Risk Ratio
Adjusted for demographics, current smoking status, blood pressure, LDL, HDL, diabetes, CRP, and interaction of LDL and Lp-PLA2
ARIC Results: Lp-PLA2 in Entire Cohort
(n=1348; 608 cases)
2.12
*P<0.05
*
*
1.71
Data on file, diaDexus; PLAC Package Insert.
Tertile
Risk Ratio
ARIC Results: Lp-PLA2, CRP, and CHD risk in LDL<130 Population
2.04
1.73
(n=573; 203 cases)
* P<0.05
*