Advanced glycation end-products (AGEs) are believed to increase ventricular (LV) and vascular stiffness, in part via cross-linking proteins. We determined if and where AGEs were increased in elderly hypertensive non-diabetic dogs and whether an AGE cross-link breaker (ALT-711) improved vascular or ventricular function.
Methods and Results
Elderly dogs with experimental hypertension were randomized to receive ALT-711 (OH+ALT, n=11; 1 mg/kg PO) or not (OH, n=11) for 8 weeks. Conscious blood pressure (BP) measurements (weekly), echo (week 8) and anesthetized study (week 8) with LV pressure-volume analysis and aortic pressure-dimension and pressure-flow assessment over a range of preloads and afterloads was performed. In LV and aorta from OH, OH+ALT and young normal (YN) dogs, AGE content (immunohistochemistry and Western analysis for Nε-(carboxymethyl)lysine (CML)) was assessed. Aortic CML content was markedly increased in OH and OH+ALT dogs as compared to YN dogs. CML was localized to aortic and aortic vaso vasorum smooth muscle but not to collagen or elastin. CML was essentially undetectable in YN, OH, or OH+ALT myocardium but was visible in large vessels in the LV. ALT-711 therapy was associated with lower BP and pulse pressure, decreased systemic vascular resistance, increased aortic distensibility and arterial compliance and notably, significant aortic dilatation. Neither LV systolic nor diastolic function was different in OH+ALT vs OH dogs.
In elderly hypertensive canines, AGE accumulation and AGE cross-link breaker effects were confined to the vasculature without evidence of myocardial accumulation or effects. The lack of AGE accumulation in collagen rich areas suggests that the striking vascular effects may be mediated by mechanisms other than collagen cross-linking.
Keywords: Hypertension, Heart Failure, Aorta, Diastole, Aging