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

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.

Figures

Figure 1

ALT-711 significantly decreased the AGI of the carotid artery and PWV. Baseline measures before drug are indicated as B1, B2, and B3. Values postdrug are depicted as percent of average baseline value ± SE. The overall drug effect assessed by one-way ANOVA for repeated measures was P = 0.007 for the changes from the average baseline value in PWV and P = 0.046 for AGI. *, significant difference from control by Bonferroni/Dunn post hoc analysis.

Figure 2

Change from baseline in LV ESD and EDD. Measurements before drug (B) were made on two separate occasions in four monkeys; the remaining two had only one single baseline measure. Baseline echocardiographic data did not differ statistically in the four animals with two predrug assessments (Bland–Altman Test). Values postdrug are depicted as percent of average baseline value ± SE. ALT-711 significantly increased EDD (P = 0.02). The effect on ESD was not significant (P < 0.22).

Figure 3

Change from baseline in SVindex and LVFS. Baseline echocardiographic data did not differ statistically in the four animals with two predrug assessments (Bland–Altman Test). Values postdrug are depicted as percent of average baseline value ± SE. ALT-711 significantly changed SVindex (P = 0.01) and FS (P = 0.01). *, differs from baseline by Bonferroni/Dunn test.

Figure 4

Change from baseline in the effective arterial elastance (ESP/SVindex) and ventriculo-vascular coupling (ESD/SVindex). Baseline derived echocardiographic data did not differ statistically in the four animals with two predrug assessments (Bland–Altman Test). Values are depicted as percent control value ± SE. Exposure to ALT-711 was associated with a significant reduction in ESP/SVindex (P = 0.02) and ESD/SVindex (P = 0.002). *, significantly differs from baseline by Bonferroni/Dunn test.