An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness

Abstract

Decreased elasticity of the cardiovascular system is one of the hallmarks of the normal aging process of mammals. A potential explanation for this decreased elasticity is that glucose can react nonenzymatically with long-lived proteins, such as collagen and lens crystallin, and link them together, producing advanced glycation endproducts (AGEs). Previous studies have shown that aminoguanidine, an AGE inhibitor, can prevent glucose cross-linking of proteins and the loss of elasticity associated with aging and diabetes. Recently, an AGE cross-link breaker (ALT-711) has been described, which we have evaluated in aged dogs. After 1 month of administration of ALT-711, a significant reduction ( approximately 40%) in age-related left ventricular stiffness was observed [(57.1 +/- 6.8 mmHg x m(2)/ml pretreatment and 33.1 +/- 4.6 mmHg x m(2)/ml posttreatment (1 mmHg = 133 Pa)]. This decrease was accompanied by improvement in cardiac function.

Figures

Figure 1

(A) Under basal conditions, the ventricular dynamics of older (group 2) and younger (group 1) dogs differed in that group 2 exhibited significantly increased EDP and reduced EDV, consistent with increased stiffness. The expansion of intravascular volume by dextran accentuated this difference such that EDV increased in young dogs (group 1) while maintaining EDP below that of older dogs (group 2), which exhibited a smaller increase in volume but a larger increase in EDP. After 4 weeks of treatment with 1 mg/kg ALT-711 orally (group 2*), the EDV–EDP relationship in both basal and volume-expanded states moved toward that of the young animals, consistent with an increase in distensibility. (§ indicates a significant difference when compared with the older animals, whereas † indicates a significant difference between the pre- and posttreatment periods.) (B) Ventricular dynamics at baseline (group 3) and after 4 weeks of sham treatment (group 3‡) of a group of older dogs with identical characteristics to the treated group (group 2). The EDP–EDV relationship remained unchanged at baseline and after volume expansion.

Figure 2

Stroke volume index at baseline (group 2) significantly improves after treatment with ALT-711 (group 2*). §, P < 0.05 versus pretreatment basal value.