Aerobic capacity is a strong predictor of cardiovascular mortality. To determine the relationship between inborn aerobic capacity and cardiac gene expression we examined genome-wide gene expression in hearts of rats artificially selected for high and low running capacity (HCR and LCR, respectively) over 16 generations. The artificial selection of LCR caused accumulation of risk factors of cardiovascular disease similar to the metabolic syndrome seen in human, whereas HCR had markedly better cardiac function. We also studied alterations in gene expression in response to exercise training in these animals. Left ventricle gene expression of both sedentary and exercise-trained HCR and LCR was characterized by microarray and gene ontology analysis. Out of 28,000 screened genes, 1,540 were differentially expressed between sedentary HCR and LCR. Only one gene was found differentially expressed by exercise training, but this gene had unknown name and function. Sedentary HCR expressed higher amounts of genes involved in lipid metabolism, whereas sedentary LCR expressed higher amounts of the genes involved in glucose metabolism. This suggests a switch in cardiac energy substrate utilization from normal mitochondrial fatty acid -oxidation in HCR to carbohydrate metabolism in LCR, an event that often occurs in diseased hearts. LCR were also associated with pathological growth signaling and cellular stress. Hypoxic conditions seemed to be a common source for several of these observations, triggering hypoxia-induced alterations of transcription. In conclusion, inborn high vs. low aerobic capacity was associated with differences in cardiac energy substrate, growth signaling, and cellular stress. metabolic syndrome; metabolism; hypoxia; V O2max; hypertrophy ALTHOUGH MAXIMAL OXYGEN UPTAKE (V O 2max ) is statistically linked with cardiovascular mortality (23, 36), the mechanistic nature of this association is unknown and difficult to explore in humans. Specifically, it is well defined that the continuum of heart function is linearly related with the level of V O 2max (39). Within the gene-environment interactions, inheritance may account for as much as 70% of the variation in aerobic capacity in human (7). Hence, genetic predisposition and inborn aerobic capacity are likely to contribute toward cardiovascular disease and mortality.Rats with different inborn running capacities have been artificially selected over generations to generate strains with genetically determined high or low intrinsic capacity (25). The evolved strains of high capacity runners (HCR) and low capacity runners (LCR) have a 30% difference in V O 2max (17). Selecting for low running capacity also resulted in accumulation of risk factors that predispose to cardiovascular disease. That is, LCR have features of the metabolic syndrome, whereas HCR show an athletic phenotype with markedly better cardiac and vascular function relative to LCR (17, 52). These models were generated expressly for efficient and invasive evaluation of cardiometabolic disease that can lea...