The hypotheses to be tested in this proposal are built on findings from two intriguing, but rather disparate lines of investigation. The first is the recent data suggesting that the excess mortality experienced by people with rheumatoid arthritis (RA) may result from increased rates of coronary heart disease (CHD) among RA patients compared to the general population. The second is the rapidly growing body of evidence indicating that chronic systemic inflammation (such as that which occurs in RA) plays an important role of chronic inflammation in CHD. We propose 3 specific aims to investigate this subject: First, we will use a cohort study to test the hypothesis that the incidence of acute MI (the central manifestation of CHD) is higher in RA subjects compared to controls. Second, we will identify high-risk RA subgroups and, using a novel adaptation of the case-cohort design, investigate interactions between RA and the major CHD risk factors (e.g. smoking, hyperlipidemia, exogenous estrogens). Third, we will conduct studies on archived autopsy heart tissue to test the hypothesis that coronary atherosclerosis is more extensive in RA subjects compared to matched controls. A unique set of circumstances allows us to address each of these aims rigorously and efficiently. We will incorporate and extend our already assembled population-based RA incidence cohort and identify validated definite acute MI outcomes using the cardiovascular surveillance techniques developed through out NIH-funded companion study, """"""""Coronary Disease Morbidity and Mortality in a Population"""""""" (HL59205). Our population-based data resources, with essentially complete enumeration of a geographically defined population, allowed us to design an analytic plan which nearly quadruples the statistical power of our risk factor analyses, compared with typical cohort analyses. Third, the availability of extensive autopsy material (the autopsy rate in this community is four-fold higher than the national rate and all autopsies have been performed at the same center since 1930) provides us with a unique opportunity to assess the pathologic characteristics of atherosclerosis among RA subjects compared to controls. When combined with our experienced multidisciplinary investigative team, these resources lend us a capability, not available elsewhere, to rigorously examine the risks and determinants of coronary heart disease in patients with RA. These results will lay the foundation for a program of research aimed at elucidating the mechanisms for CHD in RA patients and at improving our understanding of the role of inflammation in the pathogenesis of CHD in the general population.
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