Improved arterial compliance by a novel advanced glycation end-product crosslink breaker.
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.


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.
Kass
D A
DA
Division of Cardiology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA. dkass@bme.jhu.edu
Shapiro
E P
EP
Kawaguchi
M
M
Capriotti
A R
AR
Scuteri
A
A
deGroof
R C
RC
Lakatta
E G
EG
D000368:Aged; D001158:Arteries / Q000187:drug effects* / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D003187:Compliance; D004311:Double-Blind Method; D004361:Drug Tolerance; D004548:Elasticity / Q000187:drug effects; D005260:Female; D005544:Forecasting; D017127:Glycation End Products, Advanced / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013844:Thiazoles / Q000009:adverse effects / Q000494:pharmacology*
D017127:Glycation End Products, Advanced; D013844:Thiazoles; C406794:alagebrium