1. Controversial Pathophysiologic Contributors to Acute MI and Atherosclerosis Atherothrombotic events occur in individuals without readily apparent risk factors, and other factors may initiate or promote progression of disease Inflammation: –Ischemic lesions are infiltrated with neutrophils –Cytokines, adhesion molecules are critical to early atherosclerosis Chronic Infection: –Evidence of prior exposure to Chlamydia, cytomegalovirus, heliobacter pylori have been detected in human atherosclerotic tissue –Retrospective studies show relationship between infectious exposure and disease –Hypothesis: These organisms may activate vessel associated leukocytes or lead to transformation of vascular smooth muscle cells or endothelial cells Problems with Data: –Confounding and selection bias raises a question as to whether infections cause or disease or if they are acausal bystanders –Example: Both infection and inflammation are more prevalent among smokers –Other confounders associated with both atherosclerotic disease and infections include increasing age; poorer health habits; lower socioeconomic status Atherothrombotic events occur in individuals without readily apparent risk factors, and other factors may initiate or promote progression of disease Inflammation: –Ischemic lesions are infiltrated with neutrophils –Cytokines, adhesion molecules are critical to early atherosclerosis Chronic Infection: –Evidence of prior exposure to Chlamydia, cytomegalovirus, heliobacter pylori have been detected in human atherosclerotic tissue –Retrospective studies show relationship between infectious exposure and disease –Hypothesis: These organisms may activate vessel associated leukocytes or lead to transformation of vascular smooth muscle cells or endothelial cells Problems with Data: –Confounding and selection bias raises a question as to whether infections cause or disease or if they are acausal bystanders –Example: Both infection and inflammation are more prevalent among smokers –Other confounders associated with both atherosclerotic disease and infections include increasing age; poorer health habits; lower socioeconomic status Ridker, Circulation 1998;97:1671-1674

2. Prospective Data Regarding the Role of Inflammation in Atherosclerosis C-reactive protein (CRP) –CRP is a nonspecific marker of systemic inflammation –Physicians Health Study: Men with highest quartile of CRP had a threefold increase in the risk of developing MI (p<0.001) and twice the risk of stroke (p=0.02) compared with men in the lowest quartile –This risk was independent of smoking status, total and HDL cholesterol, triglycerides, lipoprotein a, and fibrinogen. Unclear if CRP has a direct vascular effect or is simply a marker for systemic inflammation CRP is not associated with venous thrombosis, suggesting that this acute phase reactant does not induce a hypercoagulable state Elevated CRP is associated with elevations in soluble intercellular adhesion molecules (s ICAM-1), and these adhesion molecules are critical in the adhesion of circulating leukocytes to the endothelial cell and subsequent endothelial transmigration, further supporting the epidemiologic evidence that cellular mediators are involved in atherogenesis C-reactive protein (CRP) –CRP is a nonspecific marker of systemic inflammation –Physicians Health Study: Men with highest quartile of CRP had a threefold increase in the risk of developing MI (p<0.001) and twice the risk of stroke (p=0.02) compared with men in the lowest quartile –This risk was independent of smoking status, total and HDL cholesterol, triglycerides, lipoprotein a, and fibrinogen. Unclear if CRP has a direct vascular effect or is simply a marker for systemic inflammation CRP is not associated with venous thrombosis, suggesting that this acute phase reactant does not induce a hypercoagulable state Elevated CRP is associated with elevations in soluble intercellular adhesion molecules (s ICAM-1), and these adhesion molecules are critical in the adhesion of circulating leukocytes to the endothelial cell and subsequent endothelial transmigration, further supporting the epidemiologic evidence that cellular mediators are involved in atherogenesis Ridker, Circulation 1998;97:1671-1674