A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys

Nonenzymatic glycosylation and cross-linking of proteins by glucose contrib utes to an age-associated increase in vascular and myocardial stiffness. So me recently sythesized thiazolium compounds selectively break these protein cross-links, reducing collagen stiffness. We investigated the effects of 3 -phenacyt-4.5-dimethylthiazolium chloride (ALT-711) on arterial and left ve ntricular (LV) properties and their coupling in old, healthy, nondiabetic M acaca mulatta primates (age 21 +/- 3.6 years). Serial measurements of arter ial stiffness indices [i.e., aortic pulse wave velocity (PWV) and augmentat ion (AGI) of carotid arterial pressure waveform] as well as echocardiograph ic determinations of LV structure and function were made before and for 39 weeks after II intramuscular injections of ALT-711 at 1.0 mg/kg body weight every other day. Heart rate, brachial blood pressure, and body weight were unchanged by the drug. PWV and AGI decreased to a nadir at 6 weeks [PWV to 74.2 +/- 4.4% of baseline (B), P = 0.007; AGI to 41 +/- 7.3% of B, P = 0.0 46], and thereafter gradually returned to baseline. Concomitant increases i n LV end diastolic diameter to 116.7 +/- 2.7% of B, P = 0.02; stroke Volume index (SVindex) to 173.1 +/- 40.1% of B, P = 0.01; and systolic fractional shortening to 180 +/- 29.7% of B, P = 0.01 occurred after drug treatment. The LV end systolic pressure/SVindex, an estimate of total LV vascular load , decreased to 60 +/- 12.1% of B (P = 0.02). The LV end systolic diameter/S Vindex, an estimate of arterio-ventricular coupling, was improved (decrease d to 54.3 +/- 11% of B, P < 0.002). Thus, in healthy older primates without diabetes, ALT-711 improved both arterial and ventricular function and opti mized ventriculo-vascular coupling. This previously unidentified cross-link breaker may be an effective pharmacological therapy to improve impaired ca rdiovascular function that occurs in the context of heart failure associate d with aging, diabetes, or hypertension, conditions in which arterial and v entricular stiffness are increased.