The plan is to examine markers of underlying chronic inflammation and infection as potential risk factors for future myocardial infarction (MI), stroke (CVA), and venous thromboembolism (VTE) in plasma samples collected at baseline from healthy participants in the Physicians' Health Study (PHS). The PHS is a cohort of 12 years duration which included 14,916 men initially free of cardiovascular disease and cancer who provided plasma samples at study entry in 1982. These men were randomly assigned in a factorial design to aspirin or beta-carotene therapy, and have been followed prospectively for the occurrence of vascular disease. Employing a nested case-control design, baseline plasma samples will be assayed for four markers of inflammation (interleukin-6, TNF-alpha, soluble ICAM, soluble VCAM) and four markers of chronic infection (antibody titers directed against Chlamydia pneumoniae, Helicobacter pylori, Herpes simplex virus, and cytomegalovirus). Case subjects will be those study participants who have subsequently developed MI (N=550), CVA (N=400), or VTE (N=200). Control subjects will be selected from those study participants who remained healthy during follow-up and will be matched to the cases by age, smoking status, and follow-up time. Data on usual cardiovascular risk factors, lipid parameters, and hemostatic markers of risk are already available in the PHS and will be used to evaluate the results for potential confounding and effect modification. Since the PHS was a randomized trial of low-dose aspirin for its initial 5 years, this cohort also provides the unique opportunity to investigate whether the use of an agent with anti-inflammatory properties modifies the risk of subsequent thrombosis among those with underlying inflammation. Indeed, this intriguing hypothesis has recently been raised regarding data relating another marker of inflammation, C-reactive protein, to future risks of myocardial infarction and stroke. These analyses will take advantage of an existing blood bank from a well-characterized large cohort with already over 12 years of follow-up and high quality end-point verification. Thus, this study could provides an efficient and cost-effective mechanism to evaluate the posited, but unproven roles of inflammation and infection as risk factors for future cardiovascular disease.
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