The objective of Project 2 is to ascertain how chronic environmental stress in combination with unfavorablegenotypes via 2 new mechanistic pathways (hypothalamic-pituitary-adrenocortical [HPA] axis and oxidativestress) affects BP reactivity to acute stress and development of preclinical cardiovascular disease (CVD).The Project will study a cohort of 300 African Americans and 307 European Americans (mean age will be25.5 yrs) who have been evaluated 14 times over a 17-year period. The continued follow-up of this cohortwill allow us to examine the cumulative effects of environmental stress, genotypes and their interaction onthe time course of the development of preclinical measures of CVD over a period of 22 years. Subjects willhave hemodynamic measures and indices of HPA axis and oxidative stress assessed prior to andimmediately following three acute laboratory challenges, as well as in the naturalistic field setting. Subjectswill also have measures of preclinical CVD evaluated. Two key genes in each of the HPA and oxidativestress pathways will be assessed by a gene-wide approach with all variants within a candidate geneconsidered jointly. In context of the recent evidence suggesting that activation of HPA axis and oxidativestress play an important role in obesity related EH, we hypothesize that obesity will exacerbate theactivation of these two pathways which are elevated by chronic environmental stress.
Specific aims ofProject 2 are to test the hypotheses that individuals from chronically stressful environments and/or withunfavorable genotypes will exhibit greater increases over time in HPA axis and oxidative stress response toacute stressors and chronic stress (i.e., natural environment assessment) and measures of preclinical CVD.Possible moderating influences of obesity will also be examined. We will also test the hypotheses thatindividuals with higher levels (when originally measured) and/or greater increases over time in HPA andoxidative stress responses to acute stress will exhibit higher levels of BP reactivity and measures ofpreclinical CVD.The long term objective of Project 2 is to improve the understanding of the way stress contributes to thedevelopment of EH. Findings will contribute to development of behavioral pharmacogenetic therapies whichwill include lifestyle interventions and pharmaceutical therapies in which the role of stress is taken intoaccount. These efforts will result in more efficacious and personalized primary and secondary preventionapproaches of EH and its co-morbidities.
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