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 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.

Figures

Figure 1

Enrollment, randomization, and retention of the study participants. Exercise & Alagebrium indicates subjects in this group had exercise training and alagebrium (200 mg/d) during the 1-year intervention. GI indicates gastrointestinal.

Figure 2

Frank Starling relationship. Systolic ventricular performance for controls, alagebrium alone, exercise alone, and exercise and alagebrium before and after the 1-year intervention. Note no differences in stroke volume (SV) index for any given pulmonary capillary wedge pressure (PCWP) in any of the 4 groups before and after intervention.

Figure 3

Preload-recruitable stroke work. Lines represent results of linear regression analyses for controls, alagebrium alone, exercise alone, and exercise and alagebrium before and after the intervention. Stroke work was unaffected across all loading conditions in all 4 groups after intervention (P=0.24). LV indicates left ventricle.

Figure 4

Left ventricular (LV) diastolic pressure–volume relationships. Pressure–volume curves before and after 1 year of intervention. In exercise alone, LV pressure–volume curves were shifted rightwards with no changes in the slope of pressure–volume curves. In exercise and alagebirum, pressure–volume curves were modestly flattened after intervention. PCWP indicates pulmonary capillary wedge pressure.

Figure 5

Left ventricular (LV) diastolic transmural pressure (TMP)–volume relationships. Transmural pressure–volume curves before and after 1 year of intervention. No changes were observed in the slopes of pressure–volume curves in the 4 groups.