The unique organization of collagen and elastin fibers in extracellular matrix of cardiovascular tissue provides the basis for its structural integrity and optimal function. Physiologically, collagen and elastin fibers are enzymatically cross-linked to form matrix. In addition, collagen fibers may be linked non-enzymatically, most notably by formation of advanced glycation end-products (AGEs). AGEs are formed by a reaction between reducing sugars and body proteins; they slowly accumulate during the lifespan, and their formation is accelerated in diabetes mellitus and hypertension. Importantly, AGEs adversely affect cardiovascular structure and function. Increased collagen cross-linking increases vascular and myocardial stiffness; this leads to elevated systolic and pulse pressures, impaired ventricular relaxation, and diastolic dysfunction. Furthermore, AGEs interact with receptors on endothelial and smooth muscle cells with consequent inflammatory reactions, release of growth factors and cytokines, and increased oxidative stress. Recently, breakers of AGEs related cross-links have been discovered and the cardiovascular effects of one of them, Alagebrium (ALT-711) have been studied. In aged dogs, ALT-711 enhanced diastolic compliance, which was associated with improved diastolic filling and cardiac output (1). Studies in older monkeys demonstrated that ALT-711 improved both arterial and ventricular function, as evidenced by decreased pulse wave velocity and improved stroke volume index and fractional shortening (2). In another study, diabetes was induced with aloxan in 9-12 year old mongrel dogs and five months later one-half of the diabetic dogs received ALT-711, the other half received placebo (3). The results showed that induction of diabetes in aging dogs increased heart mass by 14%, decreased ejection fraction, increased myocardial collagen content, and increased aortic stiffness. Treatment with ALT-711 prevented the increase in heart mass, restored ejection fraction, and reduced aortic stiffness. Furthermore, the treatment also increased left ventricular collagen solubility and reduced collagen content. These results demonstrated that AGEs-related collagen cross-linking have a causative role in the development of cardiovascular complications of diabetes and aging. Two studies in diabetic rats also demonstrated that, in addition to reducing cardiovascular stiffness, beneficial effects of ALT-711 may be mediated by reduction of profibrotic growth factors and cytokines, as well as by diminishing oxidative stress. The beneficial effects of ALT-711 have also been shown clinically (4). In older human subjects with elevation of arterial pulse pressure and reduced arterial compliance at the initiation of the study, the 8-week treatment with ALT-711 lowered pulse pressure and improved arterial compliance. We examined (5, unpublished results) the cardiovascular and renal effects of prolonged treatment (over 6 months) with ALT-711 in 40 weeks old spontaneously hypertensive rats. They were divided into two groups (60 rats in each) that were closely matched as to baseline urinary protein excretion and arterial pressure. One group received ALT-711 (1 mg/kg/day) whereas the other received vehicle by gastric gavage. When the SHR rats were 70 weeks old, 15 rats from each group were randomly selected for hemodynamic study. The remaining rats continued to receive their respective treatment until death. Urinary protein excretion increased with time (34.8±1.7; 58.5±2.3; and 95.5±2.6 mg/24h, at baseline and 3 and 6 months later, respectively) and this increase was attenuated (<0.05) in ALT-treated rats (36.1±1.6; 48.6±2.0; 68.2±2.4 mg/24h). Hemodynamic studies revealed no difference in arterial pressure, cardiac index, total peripheral resistance, and heart rate between the groups. Aortic distensibility was greater in ALT treated rats than in controls (1.12±0.08 microm/mmHg vs. 0.73±0.07, p<0.05) whereas pulse wave velocity was reduced in treated rats (435±13 cm/sec vs. 499±12, p<0.05); both findings suggesting reduced aortic stiffness with ALT-711. No differences in the left ventricular end-diastolic pressure and maximal rate of pressure rise (+dP/dT) between the groups was found. Two indices of left ventricular diastolic function, maximal rate of pressure fall (-dP/dT) (-7435±205 mmHg/sec in ALT-treated vs. -6254±254 in control, p<0.05) and diastolic time constant (15.5±0.4 msec in ALT-treated vs 17.5±0.4, p<0.05), improved in treated rats. Life-span was also extended in ALT-treated rats: control rats lived 84±2 weeks, treated 92±2 (p<0.05). In conclusion, numerous experimental and few clinical studies demonstrate that agents that break AGEs-related collagen cross-links may be useful in the treatment of disorders associated with aging, diabetes and hypertension.