CVT-4325 inhibits myocardial fatty acid uptake and improves left ventricular systolic function without increasing myocardial oxygen consumption in dogs with chronic heart failure.

Abstract

BACKGROUND: Inhibition of myocardial fatty acid oxidation has been suggested as a therapeutic approach for improving cardiac function in chronic heart failure (HF). The novel piperazine derivative CVT-4325 was shown to inhibit fatty acid oxidation in cardiac mitochondria and in isolated perfused rat hearts. In the present study, we tested the hemodynamic and metabolic effects of acute intravenous CVT-4325 in dogs with HF. METHODS AND RESULTS: HF (LV ejection fraction <or=35%) was created in eight dogs by multiple sequential intracoronary microembolizations. Treatment with CVT-4325 administered intravenously as 0.5 mg/kg bolus followed by a continuous infusion of 0.8 mg/kg/h for 40 min reduced free fatty acid (FFA) uptake (4.51+/-0.96 to 1.65+/-0.32 micromols/min, p<0.04), coronary blood flow (56+/-3 to 46+/-4 ml/min, p<0.01), and myocardial oxygen consumption (MVO2) (240+/-23 to 172+/-7 micromols/min, p<0.03), and increased LV ejection fraction (30+/-2 to 37+/-1%, p<0.0001). In the same study, but on a different day, the same dogs were treated with an inactive analogue of CVT-4325 (CVT-2540), and no hemodynamic or metabolic effects were observed. CONCLUSIONS: In dogs with HF, acute intravenous infusion of CVT-4325 reduces FFA uptake and improves LV systolic function without increasing MVO2. The improvement in LV systolic function in the absence of an increase in MVO2 and a lower FFA uptake is consistent with the concept that inhibition of myocardial fatty acid oxidation may be an effective treatment for HF.