Background: Lifelong exercise training maintains a youthful compliance of the left ventricle (LV), whereas a year of exercise training started later in life fails to reverse LV stiffening, possibly because of accumulation of irreversible advanced glycation end products. Alagebrium breaks advanced glycation end product crosslinks and improves LV stiffness in aged animals. However, it is unclear whether a strategy of exercise combined with alagebrium would improve LV stiffness in sedentary older humans.
Methods and results: Sixty-two healthy subjects were randomized into 4 groups: sedentary+placebo; sedentary+alagebrium (200 mg/d); exercise+placebo; and exercise+alagebrium. Subjects underwent right heart catheterization to define LV pressure-volume curves; secondary functional outcomes included cardiopulmonary exercise testing and arterial compliance. A total of 57 of 62 subjects (67 ± 6 years; 37 f/20 m) completed 1 year of intervention followed by repeat measurements. Pulmonary capillary wedge pressure and LV end-diastolic volume were measured at baseline, during decreased and increased cardiac filling. LV stiffness was assessed by the slope of LV pressure-volume curve. After intervention, LV mass and end-diastolic volume increased and exercise capacity improved (by ≈8%) only in the exercise groups. Neither LV mass nor exercise capacity was affected by alagebrium. Exercise training had little impact on LV stiffness (training × time effect, P=0.46), whereas alagebrium showed a modest improvement in LV stiffness compared with placebo (medication × time effect, P=0.04).
Conclusions: Alagebrium had no effect on hemodynamics, LV geometry, or exercise capacity in healthy, previously sedentary seniors. However, it did show a modestly favorable effect on age-associated LV stiffening.
Clinical trial registration- url: http://www.clinicaltrials.gov. Unique identifier: NCT01014572.
Keywords: aging; alagebrium; cardiac function tests; hemodynamics.