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 pressurevolume 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.(Circ Heart Fail. 2013;6:1155-1164.)Key Words: aging ◼ alagebrium ◼ cardiac function tests ◼ hemodynamics Received April 25, 2013; accepted October 8, 2013. no study that invasively evaluated the effect of alagebrium on LV stiffness in healthy aged individuals. Moreover, it is unclear whether a concurrent pharmacological therapy is required to observe an exercise effect in LV stiffness when significant AGE accumulation and AGE crosslinks are likely to have occurred. Thus, we hypothesized that a combination of alagebrium and exercise training for 1 year would be the optimal strategy to reverse age-associated LV stiffening and atrophy compared with alagebrium or exercise alone in healthy older individuals. To investigate this hypothesis, we performed comprehensive and detailed measurements of hemodynamics and LV structure and function in healthy older individuals before and after 1 year of alagebrium combined with exercise training. Methods Subject Population and Study DesignThis study was a prospective, controlled, randomized (for all subjects), double-blind placebo (alagebrium only) study for 1 year evaluating the efficacy of the combination of alagebrium o...

Background Recent reports have suggested that long term intensive physical training may be associated with adverse cardiovascular effects, including the development of myocardial fibrosis. However, the dose-response association of different levels of lifelong physical activity on myocardial fibrosis has not been evaluated. Methods and Results Seniors free of major chronic illnesses were recruited from predefined populations based on the consistent documentation of stable physical activity over >25 years and were classified into 4 groups by the number of sessions/week of aerobic activities ≥ 30 minutes: Sedentary (Group 1) , < 2 sessions; Casual (Group 2), 2-3 sessions; Committed (Group 3), 4-5 sessions; and Masters athletes (Group 4), 6-7 sessions plus regular competitions. All subjects underwent cardiopulmonary exercise testing and cardiac magnetic resonance imaging (cMRI), including late gadolinium enhancement (LGE) assessment of fibrosis. Ninety-two subjects (mean age 69 years, 27% women) were enrolled. No significant differences in age or sex were seen between groups. Median peak oxygen uptake was 25 ml/kg/min, 26 ml/kg/min, 32 ml/kg/min, and 40 ml/kg/min for Groups 1, 2, 3, and 4, respectively. Cardiac MRI demonstrated increasing left ventricular end diastolic volumes, end systolic volumes, stroke volumes, and masses with increasing doses of lifelong physical activity. One subject in Group 2 had LGE, in a non-coronary distribution, and no subjects in groups 3 and 4 had evidence of LGE. Conclusions A lifelong history of consistent physical activity, regardless of “dose” ranging from sedentary to competitive marathon running, was not associated with the development of focal myocardial fibrosis.