Improved Arterial Compliance by a Novel Advanced Glycation End-Product Crosslink Breaker

Abstract

Background Arterial stiffening with increased pulse pressure is a leading risk factor for cardiovascular disease in the elderly. We tested whether ALT-711, a novel nonenzymatic breaker of advanced glycation end-product crosslinks, selectively improves arterial compliance and lowers pulse pressure in older individuals with vascular stiffening. Methods and Results Nine US centers recruited and randomly assigned subjects with resting arterial pulse pressures >60 mm Hg and systolic pressures >140 mm Hg to once-daily ALT-711 (210 mg; n=62) or placebo (n=31) for 56 days. Preexisting antihypertensive treatment (90% of subjects) was continued during the study. Morning upright blood pressure, stroke volume, cardiac output, systemic vascular resistance, total arterial compliance, carotid-femoral pulse wave velocity, and drug tolerability were assessed. ALT-711 netted a greater decline in pulse pressures than placebo (−5.3 versus −0.6 mm Hg at day 56; P =0.034 for treatment effect by repeated-measures ANOVA). Systolic pressure declined in both groups, but diastolic pressure fell less with ALT-711 ( P =0.056). Mean pressure declined similarly in both groups (−4 mm Hg; P <0.01 for each group, P =0.34 for treatment effect). Total arterial compliance rose 15% in ALT-711–treated subjects versus no change with placebo ( P =0.015 versus ALT-711), an effect that did not depend on reduced mean pressure. Pulse wave velocity declined 8% with ALT-711 ( P <0.05 at day 56, P =0.08 for treatment effect). Systemic arterial resistance, cardiac output, and heart rate did not significantly change in either group. Conclusions ALT-711 improves total arterial compliance in aged humans with vascular stiffening, and it may provide a novel therapeutic approach for this abnormality, which occurs with aging, diabetes, and isolated systolic hypertension.