Abstract 15375: Time Course of Coronary Microvascular Dysfunction During Long Term Metabolic Derangement in Swine
Coronary microvascular dysfunction (CMVD) has been proposed as an important component of diabetes mellitus (DM) associated coronary artery disease (CAD). How different aspects of such CMVD manifest during disease progression remains incompletely understood. Hence, we studied the time course of CMVD in a large animal model of metabolic derangement. Swine with streptozotocin-induced DM type II were fed a high fat diet for up to 15 mo. Coronary small arteries (300 μm) were studied in vitro at 2mo (n=6), 6mo (n=7) and 15mo (n=5) follow up and compared to healthy controls (n=12, Control). All DM groups showed marked hyperglycemia (16±3, 18±4 and 18±1 mmol/l at 2mo, 6mo and 15mo resp.) and hypercholesterolemia (14±2, 17±2 and 18±3 mmol/l) as compared to Control (glucose: 5±1 and cholesterol: 2.0±0.3 mmol/l; all P<0.05). Microvessels showed small plaques only in the 15mo DM group, but all DM groups showed increased microvascular stiffness.The 2mo and 6mo, but not the 15mo, DM groups showed impaired endothelium-dependent vasodilation to bradykinin (BK; Fig. left panel, *P<0.05 2mo, 6mo DM vs others), which appeared to result from reduced NO, resp. EDHF bioavailability. Interestingly, the vasoconstriction to endothelin-1 (ET-1) was significantly impaired in the 2mo group (impaired ETA constriction), maintained in the 6mo group, but significantly increased in the 15mo group (reversal ETB dilation to constriction) as compared to Control, (Fig. right panel; *P<0.05). The 15mo group also showed increased ETA and ETB expression. Vasodilation to the exogenous NO-donor (SNAP) was similar between groups. In conclusion, specific aspects of CMVD in DM with regard to NO and ET-1 systems are time-dependent. While impaired endothelium-dependent vasodilation due to altered NO/EDHF bioavailability dominates early on, prolonged exposure to high glucose and cholesterol shifts the balance towards increased ET-1 induced vasoconstriction at later stages during CAD development in DM.
- © 2013 by American Heart Association, Inc.