ASPIRIN AND RECURRENT CARDIOVASCULAR DISEASE EVENTS IN HIGH RISK SIBSHIPS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Currently, low dose aspirin (ASA) therapy is considered cost effective and efficacious for the secondary prevention of cardiovascular disease (CVD) including 1) acute coronary artery disease (CAD) syndromes like myocardial infarction (MI), 2.) acute thrombotic strokes (CVA), and 3.) peripheral vascular disease (PVD). It is generally accepted that experiencing a recurrent CVD event while taking prophylactic ASA therapy represents a form of aspirin resistance. Increased platelet aggregability, as a function of a chronic or intensive environmental exposure (cigarette smoking, diet, exercise), biological factors (diabetes, depression, hypertension, obesity) and/or a genetic predisposition, are thought to be the principal mechanisms for a recurrent thrombotic CVD event. The benefit of ASA in populations with CVD has been attributed to inhibition of thromboxane-dependent platelet activation. Aspirin causes acetylation of platelet cyclooxygenase 1, resulting in inhibition of thromboxane release, and a reduction in agonist-inducible platelet activation in vitro. We will examine platelet aggregation, environmental and biological variables that influence platelet aggregation as a first step, and ultimately the gene effects, and gene-environment interactions related to recurrent CVD events in affected siblings from the original cohort of The Johns Hopkins Sibling Study who are currently taking ASA prophylaxis. Initially we will focus on variations in the platelet phenotypes to determine if we can identify a subset of people taking ASA who do not have expected suppression of platelets, and we will determine the extent to which this may be a function of environmental and biological variables. In Year 1, we will also concentrate on identifying candidate genes and single nucleotide polymorphisms that might be related to any aspirin "resistance" observed. The affected siblings include 1) those who were the probands with coronary disease in the original study, 2) other siblings who were affected with CVD at baseline, and 3) siblings who were unaffected at baseline but who have since developed CVD. This is a prospective observational study where we hypothesize that specific platelet phenotypes present in people who are taking ASA , will be associated with a high rate of recurrent CVD events, a larger number of recurrent events, and more affected vascular beds. The ultimate long-term goal is to determine the impact of environmental and biological variables on platelet phenotypes and then to study the effect of related genotypes, and gene-environment interactions, on recurrent event rates over 5 years in this high risk population Understanding putative mechanisms of reversible risk factors, genetic determinants, and/or gene environment interactions on the capacity of ASA to adequately suppress platelet aggregability may be extremely important in learning how to tailor secondary prevention therapy in high risk individuals with a prior CVD event.