This is a revised competing renewal application to conduct a study entitled Modifiers of Myocardial Infarction Onset (Modifiers Study) to elucidate the pathophysiology of acute myocardial infarction (Ml) onset. We will utilize the methodologic techniques, 50-hospital national study group, and findings of the completed NHLBl-funded Determinants of Myocardial Infarction Onset Study (Determinants Study). The Modifiers Study will identify factors that increase or decrease the susceptibility of patients to the triggers of acute Ml we have previously identified. The Determinants Study began in 1989, shortly after widespread acceptance of the circadian variation in Ml occurrence. The study was initiated to utilize state-of-the art epidemiologic techniques to determine the role of daily activities in the triggering of Ml. The investigators created a new epidemiologic technique (the case-crossover method), developed and tested a 24-page interview form established a large study group of hospitals with trained interviewers, instituted quality control measures, and enrolled over 2,000 subjects. This extensive activity has made the Determinants Study a centerpiece in the developing field of research into triggering of acute disease onset. The Determinants Study accomplished its four Specific Aims. It demonstrated that awakening/activity, rather than the absolute time of day, is responsible for morning triggering, that heavy exertion, anger, and sexual activity are triggers of Ml with relative risks of 6, 3, and 2 respectively, that beta-blockade prevents triggering by awakening/activity, and that a sedentary lifestyle markedly increases the relative risk of triggering of Ml by heavy exertion. The proposed Modifiers Study will answer the major questions raised by the results of the Determinants Study. It will test hypotheses concerning 5 groups of factors that are potential modifiers of susceptibility to the triggering of acute MI: l) Pharmacologic means of Prevention - that beta blockers, aspirin, angiotensin converting enzyme inhibitors and estrogen use decrease susceptibility to triggers; 2) Timing - that susceptibility does not increase in the morning but does in the winter, and that exogenous rather than endogenous daily rhythms determine onset; 3) Traditional chronic risk factors - that diabetes, hypertension, and smoking increase susceptibility and that regular exercise decreases susceptibility (to triggers other than exertion); 4) Gender - that women are less susceptible to triggering; and 5) Dietary factors - that chronic moderate alcohol use and anti- oxidants decrease susceptibility. To test the above hypotheses, 5,700 interviews are needed. By the completion of the Determinants Study in March 1993, over 2,000 interviews will be complete. Continuation in the Modifiers Study of our current 77 interviews per month will provide the required 3,700 additional interviews by December 1997. To maintain the study organization during the 8 month review of the Modifiers Study, we will support nurse interviewing with limited non-federal funds. The long-term goal of the proposed study is to identify more completely the mechanisms by which triggering occurs, and thereby facilitate identification of new means of prevention. Although most potential triggering activities are unavoidable, triggering of acute Ml could be prevented by using drugs or other interventions to sever the physiologic link between potential triggers and their catastrophic consequences.
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