Abstract 18213: Advanced Glycation End-Product Inhibition With Alagebrium Slows Age-Related Large Vessel Arterial Stiffening in Healthy Elderly Humans

Abstract

Background: Lifelong exercise training maintains youthful compliance of the central arteries, while even prolonged (1 yr) and intense training started later in life failed to reverse age-related central arterial stiffening, possibly because of accumulation of irreversible advanced glycation end-products (AGE). Alagebrium breaks AGE crosslinks and improves central arterial compliance in animals. However, little is known how Alagebrium would affect central arterial compliance in previously sedentary elderly humans. Moreover, it is unclear whether a strategy of exercise training combined with Alagebrium would improve central arterial compliance. Methods: Sixty two healthy elderly subjects were randomized into 4 groups: a) Sedentary+placebo; b) Sedentary+Alagebrium (200mg/day); c) Exercise+placebo; and d) Exercise+Alagebrium. Fifty seven/62 subjects (67±6 yrs; 37f/20m) completed 1 yr of intervention followed by repeat measurements. Arterial compliance were evaluated with Modelflow generated aortic age (A-age), central and peripheral pulse wave velocity (PWVs), carotid artery, and ascending and descending aorta beta stiffness indices (Beta indices), and augmentation index (AI). A-age was calculated from the finger blood pressure waveform (BMEYE) and stroke volume (Thermodilution) ( Shibata 2010 ). Central blood pressure, PWVs and AI were measured with applantation of tonometry (SphygmoCor). Aortic and carotid arterial geometries were assessed with MRI and ultrasound, respectively. Results: A-age increased less over the 1 yr intervention in the Alagebrium groups (Medication х Time effect p=0.066). Also, AI increased significantly less in the Alagebrium groups (Medication х Time effect p=0.034). However, exercise training did not impact on any of these indices. There were no significant differences in either Beta indices or PWVs. No subject developed aortic dilatation or had any CV complications (safety endpoint). Conclusion: Breaking of AGE cross links with Alagebrium was safe, and slowed but did not reverse age related large vessel arterial stiffening in elderly humans without an additive effect of exercise training. The absence of concordant changes in all indices suggests that these effects were modest.