Diabetes Exacerbates Coronary Atherosclerosis in Ossabaw Miniature Swine with Metabolic Syndrome

Abstract

Over 35% of all US adults are estimated to have metabolic syndrome (MetS), which is defined as the presence of three or more of the following risk factors: obesity, hypertension, glucose intolerance, insulin resistance, and dyslipidemia. Furthermore, the incidence of type 2 diabetes is rapidly growing, often in an overlapping population. MetS and diabetes both substantially increase the risk of coronary artery disease (CAD), which continues to be the leading cause of death in the US. We investigated the extent to which diabetic hyperglycemia superimposed on MetS exacerbates CAD. We performed this study in the well‐characterized Ossabaw miniature swine model of MetS and CAD. The beta‐cell toxin alloxan was administered to swine by intravenous injection, then swine were placed in two groups: pigs that responded only transiently to alloxan thereafter having fasting normoglycemia (MetS, n=8) and those that responded to alloxan becoming permanently diabetic (MetS/D, n=8). After alloxan administration, swine were fed an atherogenic diet for six months to induce the MetS phenotype. At sacrifice, we used intravascular ultrasound (IVUS) imaging to quantify the extent of CAD by assessment of percent plaque burden and spotty calcification in the left anterior descending artery. Percent plaque burden quantifies the percentage of the area within the external elastic membrane (EEM) that is occupied by atherosclerotic plaque, using the formula (EEM area – lumen area)/EEM area*100%. The percent plaque burden was significantly greater in left anterior descending artery of the MetS/D swine compared to MetS swine (12.9% vs. 3.7%; p<0.05). Furthermore, this difference was more prominent in the proximal 15 mm of the artery (17.1% vs. 3.9%; p<0.05). We assessed coronary artery calcification by identifying echogenic signal stronger than adventitia and with acoustic shadowing peripheral to the calcium deposit. We calculated a calcium index for each artery using the formula (Frames with calcification/Total frames analyzed)*(Maximal arc angle of calcium/360°). The calcium index was significantly greater in the proximal 15 mm of the left anterior descending artery of MetS/D swine compared to MetS swine (0.0204 vs. 0.00003; p<0.05). These results show significant positive correlation with Von Kossa stained sections from the proximal 15 mm of each vessel and analyzed for calcified area (r=0.84). Thus, we conclude that CAD, as measured by plaque burden and presence of calcification by IVUS, is exacerbated when diabetes is superimposed on MetS.Support or Funding InformationThis work was supported by NIH T35 HL110854, P30 DK097512, the Fortune‐Fry Ultrasound Research Fund, and Eli Lilly & Co.