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 Ͼ60 mm Hg and systolic pressures Ͼ140 mm Hg to once-daily ALT-711 (210 mg; nϭ62) or placebo (nϭ31) 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 (Ϫ5.3 versus Ϫ0.6 mm Hg at day 56; Pϭ0.034 for treatment effect by repeated-measures ANOVA). Systolic pressure declined in both groups, but diastolic pressure fell less with ALT-711 (Pϭ0.056). Mean pressure declined similarly in both groups (Ϫ4 mm Hg; PϽ0.01 for each group, Pϭ0.34 for treatment effect). Total arterial compliance rose 15% in ALT-711-treated subjects versus no change with placebo (Pϭ0.015 versus ALT-711), an effect that did not depend on reduced mean pressure. Pulse wave velocity declined 8% with ALT-711 (PϽ0.05 at day 56, Pϭ0.08 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.

Interaction between pulse wave velocity, augmentation index, pulse pressure and left ventricular function in chronic heart failure

“…Interestingly, in elderly subjects and in animal models of ageing and diabetes, collagen cross-linking breakers have been shown to reduce stiffness of the heart, the large arteries and the kidneys. [39][40][41] This study has certain limitations. In particular, treatments were not standardized, and the differences and relationships found here may be due either to the effect of treatment or to its underlying indications.…”

Advanced glycation end-products induce basement membrane hypertrophy in endoneurial microvessels and disrupt the blood–nerve barrier by stimulating the release of TGF-β and vascular endothelial growth factor (VEGF) by pericytes

“…The prevention or decrease of glycation and glycation-induced tissue damage could be possible therapeutic strategies for the treatment of diabetic neuropathy [39,40]. Recent clinical studies have shown that AGE breakers, including ALT-711 and alagebrium, may be able to decrease the adverse vascular effects of glycation with few side effects [41][42][43], although no benefits have been demonstrated in the area of neuropathy. The inhibition of pathological responses mediated by AGEs may have therapeutic potential for diabetic neuropathy, although the RAGE-mediated molecular mechanisms need to be explored in further studies.…”

The metabolic syndrome in elderly individuals is associated with greater muscular, but not elastic arterial stiffness, independent of low-grade inflammation, endothelial dysfunction or insulin resistance—The Hoorn Study

“…Advanced glycation end products can form crosslinks in and between the arterial pressure load-bearing elements of the arterial wall, thereby increasing arterial stiffness, and accordingly, the glycation crosslink breaker Alagebrium (formerly known as ALT-711) reduces arterial stiffness. 48 No earlier studies have examined whether the relationship between the MetS and arterial stiffness was mediated by ED, as estimated by brachial flow-mediated dilation. In our study, brachial flowmediated vasodilatation did not mediate the association between the MetS and femoral arterial stiffness, whereas it did in the brachial artery.…”