Ossabaw miniswine have been naturally selected to efficiently store large amounts of
lipids offering them a survival advantage. Our goal was to evaluate the myocardial response to chronic
ischemia of the Ossabaw consuming a hypercaloric, high-fat/
cholesterol diet with and without
metformin supplementation. At 6 weeks of age animals were fed either a regular diet (OC, n = 9), a hypercaloric high-fat/
cholesterol diet (OHC, n = 9), or a hypercaloric high-fat/
cholesterol diet supplemented with
metformin (OHCM, n = 8). At 9 weeks, all animals underwent
ameroid constrictor placement to the left circumflex coronary artery to simulate chronic
ischemia. Seven weeks after
ameroid placement, all animals underwent hemodynamic and functional measurements followed by cardiac harvest. Both OHC and OHCM animals developed significantly greater
weight gain, total
cholesterol, and
LDL:HDL ratio compared to OC controls.
Metformin administration reversed diet-induced
hypertension and
glucose intolerance. There were no differences in global and regional contractility, myocardial perfusion, capillary and arteriolar density, or total
protein oxidation between groups. Myocardial
protein expression of
VEGF,
PPAR-α, γ, and δ was significantly increased in the OHC and OHCM groups. Microvessel reactivity was improved in the OHC and OHCM groups compared to controls, and correlated with increased p-eNOS expression. Overfed Ossabaw miniswine develop several components of
metabolic syndrome. However, impairments of myocardial function, neovascularization and perfusion were not present, and microvessel reactivity was paradoxically improved in hypercholesterolemic animals. The observed cardioprotection despite metabolic derangements may be due to
lipid-dependant upregulation of the
PPAR pathway which is anti-inflammatory and governs myocardial
fatty acid metabolism.