The overall objective is to localize the gene(s) responsible for susceptibility to myocardial ischemia caused by intermittent hypoxia and characterize the physiology in a novel model system. Patients with obstructive sleep apnea have an increased cardiovascular morbidity and mortality. Diseases such as hypertension, hyperlipidemia and diabetes mellitus have an underlying genetic basis and represent risk factors for ischemic heart disease. However, the genetic components(s) underlying the impact of intermittent hypoxia on susceptibility to myocardial ischemia are unknown. It is hypothesized that genetic factors are responsible for increased susceptibility to myocardial ischemia caused by intermittent hypoxia in Dahl S rats compared with Brown Norway rats. This hypothesis will be tested by crossing the Brown Norway with Dahl S rat. The isolated heart model and coronary vessels will be used to facilitate discrete, well-controlled investigations of susceptibility to ischemia with and without prior intermittent hypoxia. A total genome scan will be performed to map quantitative trait loci (QTLs) involved in adaption to intermittent hypoxia and susceptibility to myocardial ischemia. Phenotypic difference between parents and the congenic derivatives resulting form ischemia and reperfusion will be characterized.
The specific aims are to: 1) Determine the phenotypic differences of isolated hearts and coronary vessels from the parental strains by studying the responses to: ischemia alone and adaptation to intermittent hypoxia prior to ischemia; 2) Map the gene(s) responsible for adaption in intermittent hypoxia and susceptibility to myocardial ischemia using a total genome scan approach; 3) Develop congenic strains in response to: ischemia alone and adaptation to intermittent hypoxia prior to ischemia; and 4) Use microarray technology to study the expression of genes within the heart adapted to intermittent hypoxia. This project may provide detailed information regarding the genetic basis for adaption to intermittent hypoxia and susceptibility to myocardial ischemia in a genetic model system, which may prove useful for detailed physiological, biochemical and pharmacological assessment.
