Abstract
Nonenzymatic glycosylation and cross-linking of proteins by glucose contributes to an age-associated increase in vascular and myocardial stiffness. Some recently sythesized thiazolium compounds selectively break these protein cross-links, reducing collagen stiffness. We investigated the effects of 3-phenacyl-4,5-dimethylthiazolium chloride (ALT-711) on arterial and left ventricular (LV) properties and their coupling in old, healthy, nondiabetic Macaca mulatta primates (age 21 +/- 3.6 years). Serial measurements of arterial stiffness indices [i.e., aortic pulse wave velocity (PWV) and augmentation (AGI) of carotid arterial pressure waveform] as well as echocardiographic determinations of LV structure and function were made before and for 39 weeks after 11 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 = 0.046], and thereafter gradually returned to baseline. Concomitant increases in LV end diastolic diameter to 116.7 +/- 2.7% of B, P = 0.02; stroke volume index (SV(index)) 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/SV(index), an estimate of total LV vascular load, decreased to 60 +/- 12.1% of B (P = 0.02). The LV end systolic diameter/SV(index), an estimate of arterio-ventricular coupling, was improved (decreased 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 optimized ventriculo-vascular coupling. This previously unidentified cross-link breaker may be an effective pharmacological therapy to improve impaired cardiovascular function that occurs in the context of heart failure associated with aging, diabetes, or hypertension, conditions in which arterial and ventricular stiffness are increased.