Rats selectively bred for low (LCR) or high (HCR) intrinsic running capacity simultaneously present with increased risk factors for cardiovascular and metabolic disease states. However, the impact of these phenotypes on left ventricular (LV) morphology and microvascular function, and their progression with ageing, have not been investigated. We tested the hypothesis that low intrinsic running capacity induces progressive age-dependent LV remodelling and impairments in microvascular function, glucose utilization and β-adrenergic responsiveness compared to HCR. Hearts and vessels isolated from female LCR (n=22) or HCR rats (n=26) were studied at 12 and 35 weeks of age. Founder rats (11 weeks of age) were also investigated (n=12). Compared to HCR rats, LCR had impaired glucose tolerance, with elevations in resting plasma insulin concentration and body-mass at 12 weeks of age, although blood glucose levels were not elevated above HCR until 35 weeks of age. At 12 weeks of age, LCR rats exhibited early LV remodelling and by 35 weeks of age, upregulated LV hypertrophic gene expression (β-myosin heavy chain) and down-regulated GLUT4 expression weer evident in the myocardium. No differences in LV β-adrenoceptor expression or cAMP content between phenotypes were observed. Macrovascular endothelial function was predominantly NO•-mediated in both phenotypes and remained intact in all rats for both age-groups. In contrast, LCR (but not HCR) rat mesenteric arteries revealed significant contributions of both NO• and endothelial-derived hyperpolarizing factor (EDHF) to microvascular endothelial function. This was impaired in LCR rats regardless of age, with reduced β2-adrenoceptor responsiveness. In conclusion, an inherited impairment in intrinsic exercise capacity per se is associated with progressive development of LV remodelling and GLUT4 down-regulation in rats, in parallel with early microvascular dysfunction and impaired systemic glucose utilization. Impaired microvascular perfusion is a likely contributing factor to these cardiovascular abnormalities, which are evident even in young adult animals. The potential for exercise training and/or pharmacological insulin-sensitizing approaches to ameliorate these cardiovascular abnormalities over the longer-term, alone or in combination with standard care, is now warranted.