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1、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,Cardiova
2、scular 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 conti
3、nue 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 ARIC, NHLBI (1987-1994),The Importance of Coron
4、ary 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
5、 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 m
6、ajor 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 199
7、6;124(suppl):S1-S9.,Framingham Heart Study26-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
8、 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 h
9、elp 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
10、 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,Lip
11、oprotein-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 Pr
12、oduced 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
13、-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),O
14、xidation,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 a
15、nd 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 show
16、n 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 pra
