Abstract P257: High Fat Diet Induces Metabolic Syndrome-Like Phenotype Associated with Adverse Micro- and Macro-Vascular Remodeling

Abstract

Metabolic diseases such as type 2 diabetes (T2DM), hypertension, and metabolic syndrome (MetS) have been associated with vascular disease, and we have previously demonstrated vascular-bed-specific remodeling in both mouse and porcine models of T2DM and MetS. The aim of this study was to determine whether high-fat diet would induce MetS-associated adverse micro- and macro-vascular remodeling and mechanics in mice. Three week old male C57BL/6J mouse siblings were randomized to receive either a normal low-fat (LFD: 10% fat) or high-fat (HFD: 60% fat) diet for 20 weeks (n=7-10 per group). HFD induced a MetS-like phenotype characterized by increased body weight (LFD: 28.6±0.7 vs. HFD: 43.4±0.8 g, p <0.0001), increased mean arterial pressure (LFD: 65±3 vs. HFD: 91±2 mmHg, p <0.0001), increased plasma insulin (LFD: 106±39 vs. HFD: 368±54 pg/mL, p <0.001), and transient increases in fasting blood glucose. Passive pressure myography of septal coronary resistance microvessels (CRMs) revealed reduced internal (LFD: 151±11 vs. HFD: 113±7 μm at 125 mmHg, p <0.05) and external diameters, increased wall/lumen ratio (LFD: 5.5±0.6 vs. HFD: 7.8±0.5 at 125 mmHg, p <0.01) and reduced incremental modulus of elasticity (LFD: 7.9x10 6 ±1.7x10 6 vs. HFD: 4.5x10 6 ±0.6x10 6 dynes/cm 2 at 125 mmHg, p <0.01) in mice fed HFD. Adverse CRM remodeling was associated with reduced coronary flow at baseline and under hyperemic conditions, which reduced coronary flow reserve (LFD: 7.3±0.5 vs. HFD: 5.5±0.5, p <0.05). Aortic pulse wave velocity was increased (LFD: 0.31±0.02 vs. HFD: 0.36±0.01 cm/ms, p <0.05) and significantly correlated with the increased blood pressure (r=0.67, p<0.01). These data demonstrate that 20 weeks of a high-fat diet induces an early MetS-like pathophysiological state that is associated with vascular-bed-specific remodeling and alterations in vascular biomechanics. Furthermore, the presence of adverse vascular remodeling in the presence of an early MetS-like phenotype, but not overt MetS (i.e. in the presence of sustained elevation in fasting blood glucose), may suggest the presence of underlying sub-clinical disease during the early progression of metabolic syndrome.