Abstract 15827: Impaired Intrinsic Exercise Capacity Predisposes to Progressive Left Ventricular Remodeling: Role of Microvascular Endothelial Dysfunction and Impaired Glucose Utilization
Cardiovascular risk factors are increased with low intrinsic aerobic capacity, but the concomitant impact on the progression of left lentricular (LV) morphology and microvascular function remains unresolved. We tested the hypothesis that low intrinsic running capacity (LCR) induces progressive age-dependent LV remodeling compared to high-intrinsic running capacity (HCR), accompanied by impairments in microvascular function, glucose utilization and β-adrenergic responsiveness. Hearts and vessels isolated from female rats selectively bred for either LCR or HCR were studied at 12 and 35wks of age. Control (founder) rats were studied for comparison. Compared to HCR, LCR rats exhibited characteristics of metabolic syndrome, including impaired glucose tolerance (by 14.7±4.3%, P<0.01), elevated plasma insulin (by 61±18%, P<0.05) and bodymass at 12wks; blood glucose was not elevated until 35wks (by 25.8±4.7%, P<0.005). At 12wks of age, LCR rats exhibited LV remodeling (increased cardiomyocyte width and LV collagen deposition); by 35wks, LV collagen deposition had progressed, and expression of LV β-myosin heavy chain and the insulin-sensitive glucose transporter GLUT4 were impaired, in LCR compared to HCR rats. No differences in LV β-adrenoceptor expression or cAMP content between phenotypes were observed. Macrovascular endothelial function (sensitivity to acetylcholine ACh, regulated largely via nitric oxide, NO) was intact in LCR aorta at 12 and 35 weeks of age. In contrast, microvascular endothelial function (regulated in part via endothelium-derived hyperpolarizing factor, EDHF) was impaired in LCR rat mesentery regardless of age, with reduced β2-adrenoceptor responsiveness. In conclusion, impaired intrinsic exercise capacity impairs systemic glucose utilization, accompanied by progressive development of LV remodeling and GLUT4 downregulation. Impaired microvascular perfusion is a likely contributing factor to the cardiac phenotype.
- Metabolic syndrome
- Ventricular remodeling
- Insulin resistance
- Endothelium-derived relaxing factor
- Beta-adrenergic receptor agonists
- © 2012 by American Heart Association, Inc.