Cardiovascular Effects of 1 Year of Alagebrium and Endurance Exercise Training in Healthy Older Individuals

Abstract

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...

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“…Our observations of MICT are consistent with previous studies, where moderate-intensity aerobic exercise appears not to affect systolic function in healthy older adults (Fujimoto et al 2013; Spina et al 1993). Further, a recent study has reported an 8% increase in ejection fraction in older adults following 12 weeks of HIIT on the treadmill, but this finding remains to be confirmed in a randomized controlled trial (Molmen et al 2012).…”

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“…Fujimoto et al (2013) found that a year of exercise training started later in life failed to reverse LV stiffening, possibly because of accumulation of irreversible advanced glycation end products in older humans. But, other two studies reported that a 3-month physical activity intervention induced a significant reduction of AGEs in blood middle-age humans (Goon et al, 2009;Yoshikawa et al, 2009).…”

Future Treatment of Hypertension: Shifting the Focus from Blood Pressure Lowering to Arterial Stiffness Modulation?

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