Abstract 411: Arterial Stiffening Precedes Systolic Hypertension in Diet-induced Obese Mice and Is Reversed by Weight Loss

Abstract

BACKGROUND. Aortic stiffness (AS) is an independent predictor of cardiovascular events and is associated with hypertension (HTN) in aging and obesity however it is unclear whether HTN causes AS or AS could develop in advance of HTN. C57Bl/6J mice fed a diet rich in fat and sucrose (HFHS) develop obesity mimicking the metabolic syndrome. AIMS. We sought to determine: 1) whether AS occurs in HFHS-fed mice; 2) the relation between AS and HTN in such a model and 2) whether weight loss could improve AS and HTN in obese mice. METHODS. Pulse wave velocity (PWV) was measured by ultrasound as an in vivo index of arterial stiffness and confirmed invasively with high-fidelity pressure catheters. Blood pressure was measured by radiotelemetry in conscious mice. Weight loss was achieved by reversing mice to ND after 5 months of HFHS with bi-weekly assessments of metabolic and cardiovascular parameters. RESULTS. AS developed in HFHS-fed mice within 2 months (PWV from 2.3 ± 0.2 to 4.1 ± 0.5 m/s, n=6, mean ± SEM, p<0.05) and remained elevated up to 8 months (5.1 ± 0.5 m/s, n=10). Systolic and mean arterial pressures were significantly elevated after 6 months of HFHS (SBP: from 119.2 ± 1.8 to 140.4 ± 2.5 mmHg and MAP: from 106.9 ± 1.9 to 123 ± 1.6 mmHg; n=6). Within two months, when AS was fully developed, aortas from HFHS-fed mice had impaired endothelium-dependent relaxation and increased transglutaminase-2 activity, both in vitro indices of reduced NO bioactivity and ∼3-fold upregulation of pro-inflammatory cytokines TNFα, MCP-1 and MIP1α. Diet reversal induced a return to normal weight within 8 weeks accompanied by a 2-fold reduction in fat mass and hyperinsulinemia. PWV was significantly reduced from 5.3 ± 0.7 to 3.4 ± 0.4 m/s after reversal to ND and SBP and MAP were decreased to normal values (from 138.1 ± 3.7 to 124.2 ± 2.7 mmHg and from 121.2 ± 3.9 to 109.5 ± 3.4 mmHg, respectively). Atomic force measurements on aortic rings, an in vitro indicator of structural stiffness of the intima, was increased after HFHS (52 ± 4.8, n=7 vs 24 ± 2.8 kPa in ND, n=10) and significantly decreased after reversal to ND (30 ± 3.7 kPa, n=8). CONCLUSIONS. In a model of dietary obesity, arterial stiffness precedes the onset of hypertension and is reversed by normalization of the metabolic state achieved by weight loss.